Chapter 15 | Microbial Mechanisms of Pathogenicity 661

Chapter 15

Microbial Mechanisms of
Pathogenicity

Figure 15.1 Although medical professionals rely heavily on signs and symptoms to diagnose disease and prescribe
treatment, many diseases can produce similar signs and symptoms. (credit left: modification of work by U.S. Navy)

Chapter Outline
15.1 Characteristics of Infectious Disease
15.2 How Pathogens Cause Disease
15.3 Virulence Factors of Bacterial and Viral Pathogens
15.4 Virulence Factors of Eukaryotic Pathogens

Introduction
Jane woke up one spring morning feeling not quite herself. Her throat felt a bit dry and she was sniffling. She
wondered why she felt so lousy. Was it because of a change in the weather? The pollen count? Was she coming down
with something? Did she catch a bug from her coworker who sneezed on her in the elevator yesterday?
The signs and symptoms we associate with illness can have many different causes. Sometimes they are the direct
result of a pathogenic infection, but in other cases they result from a response by our immune system to a pathogen
or another perceived threat. For example, in response to certain pathogens, the immune system may release pyrogens,
chemicals that cause the body temperature to rise, resulting in a fever. This response creates a less-than-favorable
environment for the pathogen, but it also makes us feel sick.
Medical professionals rely heavily on analysis of signs and symptoms to determine the cause of an ailment and
prescribe treatment. In some cases, signs and symptoms alone are enough to correctly identify the causative agent of
a disease, but since few diseases produce truly unique symptoms, it is often necessary to confirm the identity of the
infectious agent by other direct and indirect diagnostic methods.
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15.1 Characteristics of Infectious Disease

Learning Objectives
• Distinguish between signs and symptoms of disease
• Explain the difference between a communicable disease and a noncommunicable disease
• Compare different types of infectious diseases, including iatrogenic, nosocomial, and zoonotic diseases
• Identify and describe the stages of an acute infectious disease in terms of number of pathogens present and
severity of signs and symptoms
A disease is any condition in which the normal structure or functions of the body are damaged or impaired. Physical
injuries or disabilities are not classified as disease, but there can be several causes for disease, including infection by a
pathogen, genetics (as in many cancers or deficiencies), noninfectious environmental causes, or inappropriate immune
responses. Our focus in this chapter will be on infectious diseases, although when diagnosing infectious diseases, it is
always important to consider possible noninfectious causes.

Signs and Symptoms of Disease

An infection is the successful colonization of a host by a microorganism. Infections can lead to disease, which causes
signs and symptoms resulting in a deviation from the normal structure or functioning of the host. Microorganisms that
can cause disease are known as pathogens.
The signs of disease are objective and measurable, and can be directly observed by a clinician. Vital signs, which are
used to measure the body’s basic functions, include body temperature (normally 37 °C [98.6 °F]), heart rate (normally
60–100 beats per minute), breathing rate (normally 12–18 breaths per minute), and blood pressure (normally between
90/60 and 120/80 mm Hg). Changes in any of the body’s vital signs may be indicative of disease. For example, having
a fever (a body temperature significantly higher than 37 °C or 98.6 °F) is a sign of disease because it can be measured.
In addition to changes in vital signs, other observable conditions may be considered signs of disease. For example,
the presence of antibodies in a patient’s serum (the liquid portion of blood that lacks clotting factors) can be observed
and measured through blood tests and, therefore, can be considered a sign. However, it is important to note that the
presence of antibodies is not always a sign of an active disease. Antibodies can remain in the body long after an
infection has resolved; also, they may develop in response to a pathogen that is in the body but not currently causing
disease.

Clinical Focus

Part 1
Michael, a 10-year-old boy in generally good health, went to a birthday party on Sunday with his family. He ate
many different foods but was the only one in the family to eat the undercooked hot dogs served by the hosts.
Monday morning, he woke up feeling achy and nauseous, and he was running a fever of 38 °C (100.4 °F). His
parents, assuming Michael had caught the flu, made him stay home from school and limited his activities. But
after 4 days, Michael began to experience severe headaches, and his fever spiked to 40 °C (104 °F). Growing
worried, his parents finally decide to take Michael to a nearby clinic.
• What signs and symptoms is Michael experiencing?
• What do these signs and symptoms tell us about the stage of Michael’s disease?
Jump to the next Clinical Focus box.

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Chapter 15 | Microbial Mechanisms of Pathogenicity 663

Unlike signs, symptoms of disease are subjective. Symptoms are felt or experienced by the patient, but they cannot be
clinically confirmed or objectively measured. Examples of symptoms include nausea, loss of appetite, and pain. Such
symptoms are important to consider when diagnosing disease, but they are subject to memory bias and are difficult
to measure precisely. Some clinicians attempt to quantify symptoms by asking patients to assign a numerical value
to their symptoms. For example, the Wong-Baker Faces pain-rating scale asks patients to rate their pain on a scale
of 0–10. An alternative method of quantifying pain is measuring skin conductance fluctuations. These fluctuations
reflect sweating due to skin sympathetic nerve activity resulting from the stressor of pain. [1]
A specific group of signs and symptoms characteristic of a particular disease is called a syndrome. Many syndromes
are named using a nomenclature based on signs and symptoms or the location of the disease. Table 15.1 lists some
of the prefixes and suffixes commonly used in naming syndromes.

Nomenclature of Symptoms
Affix Meaning Example

cyto- cell cytopenia: reduction in the number of blood cells

hepat- of the liver hepatitis: inflammation of the liver

-pathy disease neuropathy: a disease affecting nerves

-emia of the blood bacteremia: presence of bacteria in blood

-itis inflammation colitis: inflammation of the colon

-lysis destruction hemolysis: destruction of red blood cells

-oma tumor lymphoma: cancer of the lymphatic system

-osis diseased or abnormal condition leukocytosis: abnormally high number of white blood cells

-derma of the skin keratoderma: a thickening of the skin

Table 15.1

Clinicians must rely on signs and on asking questions about symptoms, medical history, and the patient’s recent
activities to identify a particular disease and the potential causative agent. Diagnosis is complicated by the fact that
different microorganisms can cause similar signs and symptoms in a patient. For example, an individual presenting
with symptoms of diarrhea may have been infected by one of a wide variety of pathogenic microorganisms. Bacterial
pathogens associated with diarrheal disease include Vibrio cholerae, Listeria monocytogenes, Campylobacter jejuni,
and enteropathogenic Escherichia coli (EPEC). Viral pathogens associated with diarrheal disease include norovirus
and rotavirus. Parasitic pathogens associated with diarrhea include Giardia lamblia and Cryptosporidium parvum.
Likewise, fever is indicative of many types of infection, from the common cold to the deadly Ebola hemorrhagic
fever.
Finally, some diseases may be asymptomatic or subclinical, meaning they do not present any noticeable signs or
symptoms. For example, most individual infected with herpes simplex virus remain asymptomatic and are unaware
that they have been infected.

• Explain the difference between signs and symptoms.

1. F. Savino et al. “Pain Assessment in Children Undergoing Venipuncture: The Wong–Baker Faces Scale Versus Skin Conductance
Fluctuations.” PeerJ 1 (2013):e37; https://peerj.com/articles/37/
664 Chapter 15 | Microbial Mechanisms of Pathogenicity

Classifications of Disease
The World Health Organization’s (WHO) International Classification of Diseases (ICD) is used in clinical fields to
classify diseases and monitor morbidity (the number of cases of a disease) and mortality (the number of deaths due to
a disease). In this section, we will introduce terminology used by the ICD (and in health-care professions in general)
to describe and categorize various types of disease.
An infectious disease is any disease caused by the direct effect of a pathogen. A pathogen may be cellular (bacteria,
parasites, and fungi) or acellular (viruses, viroids, and prions). Some infectious diseases are also communicable,
meaning they are capable of being spread from person to person through either direct or indirect mechanisms. Some
infectious communicable diseases are also considered contagious diseases, meaning they are easily spread from
person to person. Not all contagious diseases are equally so; the degree to which a disease is contagious usually
depends on how the pathogen is transmitted. For example, measles is a highly contagious viral disease that can be
transmitted when an infected person coughs or sneezes and an uninfected person breathes in droplets containing
the virus. Gonorrhea is not as contagious as measles because transmission of the pathogen (Neisseria gonorrhoeae)
requires close intimate contact (usually sexual) between an infected person and an uninfected person.
Diseases that are contracted as the result of a medical procedure are known as iatrogenic diseases. Iatrogenic diseases
can occur after procedures involving wound treatments, catheterization, or surgery if the wound or surgical site
becomes contaminated. For example, an individual treated for a skin wound might acquire necrotizing fasciitis (an
aggressive, “flesh-eating” disease) if bandages or other dressings became contaminated by Clostridium perfringens
or one of several other bacteria that can cause this condition.
Diseases acquired in hospital settings are known as nosocomial diseases. Several factors contribute to the prevalence
and severity of nosocomial diseases. First, sick patients bring numerous pathogens into hospitals, and some of these
pathogens can be transmitted easily via improperly sterilized medical equipment, bed sheets, call buttons, door
handles, or by clinicians, nurses, or therapists who do not wash their hands before touching a patient. Second, many
hospital patients have weakened immune systems, making them more susceptible to infections. Compounding this,
the prevalence of antibiotics in hospital settings can select for drug-resistant bacteria that can cause very serious
infections that are difficult to treat.
Certain infectious diseases are not transmitted between humans directly but can be transmitted from animals to
humans. Such a disease is called zoonotic disease (or zoonosis). According to WHO, a zoonosis is a disease that
occurs when a pathogen is transferred from a vertebrate animal to a human; however, sometimes the term is defined
more broadly to include diseases transmitted by all animals (including invertebrates). For example, rabies is a viral
zoonotic disease spread from animals to humans through bites and contact with infected saliva. Many other zoonotic
diseases rely on insects or other arthropods for transmission. Examples include yellow fever (transmitted through the
bite of mosquitoes infected with yellow fever virus) and Rocky Mountain spotted fever (transmitted through the bite
of ticks infected with Rickettsia rickettsii).
In contrast to communicable infectious diseases, a noncommunicable infectious disease is not spread from one
person to another. One example is tetanus, caused by Clostridium tetani, a bacterium that produces endospores that
can survive in the soil for many years. This disease is typically only transmitted through contact with a skin wound; it
cannot be passed from an infected person to another person. Similarly, Legionnaires disease is caused by Legionella
pneumophila, a bacterium that lives within amoebae in moist locations like water-cooling towers. An individual may
contract Legionnaires disease via contact with the contaminated water, but once infected, the individual cannot pass
the pathogen to other individuals.
In addition to the wide variety of noncommunicable infectious diseases, noninfectious diseases (those not caused
by pathogens) are an important cause of morbidity and mortality worldwide. Noninfectious diseases can be caused
by a wide variety factors, including genetics, the environment, or immune system dysfunction, to name a few. For
example, sickle cell anemia is an inherited disease caused by a genetic mutation that can be passed from parent to
offspring (Figure 15.2). Other types of noninfectious diseases are listed in Table 15.2.

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Chapter 15 | Microbial Mechanisms of Pathogenicity 665

Types of Noninfectious Diseases

Type Definition Example

Inherited A genetic disease Sickle cell anemia

Congenital Disease that is present at or before birth Down syndrome

Degenerative Progressive, irreversible loss of function Parkinson disease (affecting central nervous
system)

Nutritional Impaired body function due to lack of Scurvy (vitamin C deficiency)

deficiency nutrients

Endocrine Disease involving malfunction of glands Hypothyroidism – thyroid does not produce
that release hormones to regulate body enough thyroid hormone, which is important for
functions metabolism

Neoplastic Abnormal growth (benign or malignant) Some forms of cancer

Idiopathic Disease for which the cause is unknown Idiopathic juxtafoveal retinal telangiectasia
(dilated, twisted blood vessels in the retina of the
eye)

Table 15.2

Figure 15.2 Blood smears showing two diseases of the blood. (a) Malaria is an infectious, zoonotic disease caused
by the protozoan pathogen Plasmodium falciparum (shown here) and several other species of the genus
Plasmodium. It is transmitted by mosquitoes to humans. (b) Sickle cell disease is a noninfectious genetic disorder
that results in abnormally shaped red blood cells, which can stick together and obstruct the flow of blood through the
circulatory system. It is not caused by a pathogen, but rather a genetic mutation. (credit a: modification of work by
Centers for Disease Control and Prevention; credit b: modification of work by Ed Uthman)
666 Chapter 15 | Microbial Mechanisms of Pathogenicity

Link to Learning

Lists of common infectious diseases can be found at the following Centers for
Disease Control and Prevention (https://openstax.org/l/22CDCdis) (CDC),
World Health Organization (https://openstax.org/l/22WHOdis) (WHO), and
International Classification of Diseases (https://openstax.org/l/
22WHOclass) websites.

• Describe how a disease can be infectious but not contagious.

• Explain the difference between iatrogenic disease and nosocomial disease.

Periods of Disease
The five periods of disease (sometimes referred to as stages or phases) include the incubation, prodromal, illness,
decline, and convalescence periods (Figure 15.3). The incubation period occurs in an acute disease after the initial
entry of the pathogen into the host (patient). It is during this time the pathogen begins multiplying in the host.
However, there are insufficient numbers of pathogen particles (cells or viruses) present to cause signs and symptoms
of disease. Incubation periods can vary from a day or two in acute disease to months or years in chronic disease,
depending upon the pathogen. Factors involved in determining the length of the incubation period are diverse, and
can include strength of the pathogen, strength of the host immune defenses, site of infection, type of infection, and
the size infectious dose received. During this incubation period, the patient is unaware that a disease is beginning to
develop.

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Chapter 15 | Microbial Mechanisms of Pathogenicity 667

Figure 15.3 The progression of an infectious disease can be divided into five periods, which are related to the
number of pathogen particles (red) and the severity of signs and symptoms (blue).

The prodromal period occurs after the incubation period. During this phase, the pathogen continues to multiply and
the host begins to experience general signs and symptoms of illness, which typically result from activation of the
immune system, such as fever, pain, soreness, swelling, or inflammation. Usually, such signs and symptoms are too
general to indicate a particular disease. Following the prodromal period is the period of illness, during which the
signs and symptoms of disease are most obvious and severe.
The period of illness is followed by the period of decline, during which the number of pathogen particles begins to
decrease, and the signs and symptoms of illness begin to decline. However, during the decline period, patients may
become susceptible to developing secondary infections because their immune systems have been weakened by the
primary infection. The final period is known as the period of convalescence. During this stage, the patient generally
returns to normal functions, although some diseases may inflict permanent damage that the body cannot fully repair.
Infectious diseases can be contagious during all five of the periods of disease. Which periods of disease are more
likely to associated with transmissibility of an infection depends upon the disease, the pathogen, and the mechanisms
by which the disease develops and progresses. For example, with meningitis (infection of the lining of brain), the
periods of infectivity depend on the type of pathogen causing the infection. Patients with bacterial meningitis are
contagious during the incubation period for up to a week before the onset of the prodromal period, whereas patients
with viral meningitis become contagious when the first signs and symptoms of the prodromal period appear. With
many viral diseases associated with rashes (e.g., chickenpox, measles, rubella, roseola), patients are contagious during
the incubation period up to a week before the rash develops. In contrast, with many respiratory infections (e.g., colds,
influenza, diphtheria, strep throat, and pertussis) the patient becomes contagious with the onset of the prodromal
period. Depending upon the pathogen, the disease, and the individual infected, transmission can still occur during the
periods of decline, convalescence, and even long after signs and symptoms of the disease disappear. For example, an
individual recovering from a diarrheal disease may continue to carry and shed the pathogen in feces for some time,
posing a risk of transmission to others through direct contact or indirect contact (e.g., through contaminated objects
or food).
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• Name some of the factors that can affect the length of the incubation period of a particular disease.

Acute and Chronic Diseases

The duration of the period of illness can vary greatly, depending on the pathogen, effectiveness of the immune
response in the host, and any medical treatment received. For an acute disease, pathologic changes occur over a
relatively short time (e.g., hours, days, or a few weeks) and involve a rapid onset of disease conditions. For example,
influenza (caused by Influenzavirus) is considered an acute disease because the incubation period is approximately
1–2 days. Infected individuals can spread influenza to others for approximately 5 days after becoming ill. After
approximately 1 week, individuals enter the period of decline.
For a chronic disease, pathologic changes can occur over longer time spans (e.g., months, years, or a lifetime). For
example, chronic gastritis (inflammation of the lining of the stomach) is caused by the gram-negative bacterium
Helicobacter pylori. H. pylori is able to colonize the stomach and persist in its highly acidic environment by
producing the enzyme urease, which modifies the local acidity, allowing the bacteria to survive indefinitely.[2]
Consequently, H. pylori infections can recur indefinitely unless the infection is cleared using antibiotics.[3] Hepatitis
B virus can cause a chronic infection in some patients who do not eliminate the virus after the acute illness. A chronic
infection with hepatitis B virus is characterized by the continued production of infectious virus for 6 months or longer
after the acute infection, as measured by the presence of viral antigen in blood samples.
In latent diseases, as opposed to chronic infections, the causal pathogen goes dormant for extended periods of
time with no active replication. Examples of diseases that go into a latent state after the acute infection include
herpes (herpes simplex viruses [HSV-1 and HSV-2]), chickenpox (varicella-zoster virus [VZV]), and mononucleosis
(Epstein-Barr virus [EBV]). HSV-1, HSV-2, and VZV evade the host immune system by residing in a latent form
within cells of the nervous system for long periods of time, but they can reactivate to become active infections during
times of stress and immunosuppression. For example, an initial infection by VZV may result in a case of childhood
chickenpox, followed by a long period of latency. The virus may reactivate decades later, causing episodes of shingles
in adulthood. EBV goes into latency in B cells of the immune system and possibly epithelial cells; it can reactivate
years later to produce B-cell lymphoma.

• Explain the difference between latent disease and chronic disease.

2. J.G. Kusters et al. Pathogenesis of Helicobacter pylori Infection. Clinical Microbiology Reviews 19 no. 3 (2006):449–490.
3. N.R. Salama et al. “Life in the Human Stomach: Persistence Strategies of the Bacterial Pathogen Helicobacter pylori.” Nature Reviews
Microbiology 11 (2013):385–399.

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Chapter 15 | Microbial Mechanisms of Pathogenicity 669

15.2 How Pathogens Cause Disease

Learning Objectives
• Summarize Koch’s postulates and molecular Koch’s postulates, respectively, and explain their significance and
limitations
• Explain the concept of pathogenicity (virulence) in terms of infectious and lethal dose
• Distinguish between primary and opportunistic pathogens and identify specific examples of each
• Summarize the stages of pathogenesis
• Explain the roles of portals of entry and exit in the transmission of disease and identify specific examples of
these portals
For most infectious diseases, the ability to accurately identify the causative pathogen is a critical step in finding or
prescribing effective treatments. Today’s physicians, patients, and researchers owe a sizable debt to the physician
Robert Koch (1843–1910), who devised a systematic approach for confirming causative relationships between
diseases and specific pathogens.

Koch’s Postulates
In 1884, Koch published four postulates (Table 15.3) that summarized his method for determining whether a
particular microorganism was the cause of a particular disease. Each of Koch’s postulates represents a criterion that
must be met before a disease can be positively linked with a pathogen. In order to determine whether the criteria are
met, tests are performed on laboratory animals and cultures from healthy and diseased animals are compared (Figure
15.4).

Koch’s Postulates
(1) The suspected pathogen must be found in every case of disease and not be found in healthy individuals.

(2) The suspected pathogen can be isolated and grown in pure culture.

(3) A healthy test subject infected with the suspected pathogen must develop the same signs and symptoms of
disease as seen in postulate 1.

(4) The pathogen must be re-isolated from the new host and must be identical to the pathogen from postulate 2.

Table 15.3
670 Chapter 15 | Microbial Mechanisms of Pathogenicity

Figure 15.4 The steps for confirming that a pathogen is the cause of a particular disease using Koch’s postulates.

In many ways, Koch’s postulates are still central to our current understanding of the causes of disease. However,
advances in microbiology have revealed some important limitations in Koch’s criteria. Koch made several
assumptions that we now know are untrue in many cases. The first relates to postulate 1, which assumes that
pathogens are only found in diseased, not healthy, individuals. This is not true for many pathogens. For example, H.
pylori, described earlier in this chapter as a pathogen causing chronic gastritis, is also part of the normal microbiota of
the stomach in many healthy humans who never develop gastritis. It is estimated that upwards of 50% of the human
population acquires H. pylori early in life, with most maintaining it as part of the normal microbiota for the rest of
their life without ever developing disease.
Koch’s second faulty assumption was that all healthy test subjects are equally susceptible to disease. We now know
that individuals are not equally susceptible to disease. Individuals are unique in terms of their microbiota and the
state of their immune system at any given time. The makeup of the resident microbiota can influence an individual’s
susceptibility to an infection. Members of the normal microbiota play an important role in immunity by inhibiting the
growth of transient pathogens. In some cases, the microbiota may prevent a pathogen from establishing an infection;
in others, it may not prevent an infection altogether but may influence the severity or type of signs and symptoms.
As a result, two individuals with the same disease may not always present with the same signs and symptoms. In
addition, some individuals have stronger immune systems than others. Individuals with immune systems weakened
by age or an unrelated illness are much more susceptible to certain infections than individuals with strong immune
systems.
Koch also assumed that all pathogens are microorganisms that can be grown in pure culture (postulate 2) and that
animals could serve as reliable models for human disease. However, we now know that not all pathogens can be
grown in pure culture, and many human diseases cannot be reliably replicated in animal hosts. Viruses and certain

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Chapter 15 | Microbial Mechanisms of Pathogenicity 671

bacteria, including Rickettsia and Chlamydia, are obligate intracellular pathogens that can grow only when inside a
host cell. If a microbe cannot be cultured, a researcher cannot move past postulate 2. Likewise, without a suitable
nonhuman host, a researcher cannot evaluate postulate 2 without deliberately infecting humans, which presents
obvious ethical concerns. AIDS is an example of such a disease because the human immunodeficiency virus (HIV)
only causes disease in humans.

• Briefly summarize the limitations of Koch’s postulates.

Molecular Koch’s Postulates

In 1988, Stanley Falkow (1934–) proposed a revised form of Koch’s postulates known as molecular Koch’s
postulates. These are listed in the left column of Table 15.4. The premise for molecular Koch’s postulates is not in
the ability to isolate a particular pathogen but rather to identify a gene that may cause the organism to be pathogenic.
Falkow’s modifications to Koch’s original postulates explain not only infections caused by intracellular pathogens but
also the existence of pathogenic strains of organisms that are usually nonpathogenic. For example, the predominant
form of the bacterium Escherichia coli is a member of the normal microbiota of the human intestine and is generally
considered harmless. However, there are pathogenic strains of E. coli such as enterotoxigenic E. coli (ETEC) and
enterohemorrhagic E. coli (O157:H7) (EHEC). We now know ETEC and EHEC exist because of the acquisition of
new genes by the once-harmless E. coli, which, in the form of these pathogenic strains, is now capable of producing
toxins and causing illness. The pathogenic forms resulted from minor genetic changes. The right-side column of
Table 15.4 illustrates how molecular Koch’s postulates can be applied to identify EHEC as a pathogenic bacterium.

Molecular Koch’s Postulates Applied to EHEC

Molecular Koch’s Postulates Application to EHEC

(1) The phenotype (sign or symptom of EHEC causes intestinal inflammation and diarrhea, whereas
disease) should be associated only with nonpathogenic strains of E. coli do not.
pathogenic strains of a species.

(2) Inactivation of the suspected gene(s) One of the genes in EHEC encodes for Shiga toxin, a bacterial
associated with pathogenicity should result toxin (poison) that inhibits protein synthesis. Inactivating this
in a measurable loss of pathogenicity. gene reduces the bacteria’s ability to cause disease.

(3) Reversion of the inactive gene should By adding the gene that encodes the toxin back into the genome
restore the disease phenotype. (e.g., with a phage or plasmid), EHEC’s ability to cause disease
is restored.

Table 15.4

As with Koch’s original postulates, the molecular Koch’s postulates have limitations. For example, genetic
manipulation of some pathogens is not possible using current methods of molecular genetics. In a similar vein, some
diseases do not have suitable animal models, which limits the utility of both the original and molecular postulates.

• Explain the differences between Koch’s original postulates and the molecular Koch’s postulates.
672 Chapter 15 | Microbial Mechanisms of Pathogenicity

Pathogenicity and Virulence

The ability of a microbial agent to cause disease is called pathogenicity, and the degree to which an organism is
pathogenic is called virulence. Virulence is a continuum. On one end of the spectrum are organisms that are avirulent
(not harmful) and on the other are organisms that are highly virulent. Highly virulent pathogens will almost always
lead to a disease state when introduced to the body, and some may even cause multi-organ and body system failure in
healthy individuals. Less virulent pathogens may cause an initial infection, but may not always cause severe illness.
Pathogens with low virulence would more likely result in mild signs and symptoms of disease, such as low-grade
fever, headache, or muscle aches. Some individuals might even be asymptomatic.
An example of a highly virulent microorganism is Bacillus anthracis, the pathogen responsible for anthrax. B.
anthracis can produce different forms of disease, depending on the route of transmission (e.g., cutaneous injection,
inhalation, ingestion). The most serious form of anthrax is inhalation anthrax. After B. anthracis spores are inhaled,
they germinate. An active infection develops and the bacteria release potent toxins that cause edema (fluid buildup in
tissues), hypoxia (a condition preventing oxygen from reaching tissues), and necrosis (cell death and inflammation).
Signs and symptoms of inhalation anthrax include high fever, difficulty breathing, vomiting and coughing up
blood, and severe chest pains suggestive of a heart attack. With inhalation anthrax, the toxins and bacteria enter
the bloodstream, which can lead to multi-organ failure and death of the patient. If a gene (or genes) involved in
pathogenesis is inactivated, the bacteria become less virulent or nonpathogenic.
Virulence of a pathogen can be quantified using controlled experiments with laboratory animals. Two important
indicators of virulence are the median infectious dose (ID50) and the median lethal dose (LD50), both of which
are typically determined experimentally using animal models. The ID50 is the number of pathogen cells or virions
required to cause active infection in 50% of inoculated animals. The LD50 is the number of pathogenic cells, virions,
or amount of toxin required to kill 50% of infected animals. To calculate these values, each group of animals is
inoculated with one of a range of known numbers of pathogen cells or virions. In graphs like the one shown in
Figure 15.5, the percentage of animals that have been infected (for ID50) or killed (for LD50) is plotted against
the concentration of pathogen inoculated. Figure 15.5 represents data graphed from a hypothetical experiment
measuring the LD50 of a pathogen. Interpretation of the data from this graph indicates that the LD50 of the pathogen
for the test animals is 104 pathogen cells or virions (depending upon the pathogen studied).

Figure 15.5 A graph like this is used to determine LD50 by plotting pathogen concentration against the percent of
infected test animals that have died. In this example, the LD50 = 104 pathogenic particles.

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Chapter 15 | Microbial Mechanisms of Pathogenicity 673

Table 15.5 lists selected foodborne pathogens and their ID50 values in humans (as determined from epidemiologic
data and studies on human volunteers). Keep in mind that these are median values. The actual infective dose for an
individual can vary widely, depending on factors such as route of entry; the age, health, and immune status of the
host; and environmental and pathogen-specific factors such as susceptibility to the acidic pH of the stomach. It is also
important to note that a pathogen’s infective dose does not necessarily correlate with disease severity. For example,
just a single cell of Salmonella enterica serotype Typhimurium can result in an active infection. The resultant disease,
Salmonella gastroenteritis or salmonellosis, can cause nausea, vomiting, and diarrhea, but has a mortality rate of less
than 1% in healthy adults. In contrast, S. enterica serotype Typhi has a much higher ID50, typically requiring as many
as 1,000 cells to produce infection. However, this serotype causes typhoid fever, a much more systemic and severe
disease that has a mortality rate as high as 10% in untreated individuals.

ID50 for Selected Foodborne Diseases[4]

Pathogen ID50

Viruses

Hepatitis A virus 10–100

Norovirus 1–10

Rotavirus 10–100

Bacteria

Escherichia coli, enterohemorrhagic (EHEC, serotype O157) 10–100

E. coli, enteroinvasive (EIEC) 200–5,000

E. coli, enteropathogenic (EPEC) 10,000,000–10,000,000,000

E. coli, enterotoxigenic (ETEC) 10,000,000–10,000,000,000

Salmonella enterica serovar Typhi <1,000

S. enterica serovar Typhimurium ≥1

Shigella dysenteriae 10–200

Vibrio cholerae (serotypes O139, O1) 1,000,000

V. parahemolyticus 100,000,000

Protozoa

Giardia lamblia 1

Cryptosporidium parvum 10–100

Table 15.5

• What is the difference between a pathogen’s infective dose and lethal dose?
• Which is more closely related to the severity of a disease?

4. Food and Drug Administration. “Bad Bug Book, Foodborne Pathogenic Microorganisms and Natural Toxins.” 2nd ed. Silver Spring,
MD: US Food and Drug Administration; 2012.
674 Chapter 15 | Microbial Mechanisms of Pathogenicity

Primary Pathogens versus Opportunistic Pathogens

Pathogens can be classified as either primary pathogens or opportunistic pathogens. A primary pathogen can cause
disease in a host regardless of the host’s resident microbiota or immune system. An opportunistic pathogen, by
contrast, can only cause disease in situations that compromise the host’s defenses, such as the body’s protective
barriers, immune system, or normal microbiota. Individuals susceptible to opportunistic infections include the very
young, the elderly, women who are pregnant, patients undergoing chemotherapy, people with immunodeficiencies
(such as acquired immunodeficiency syndrome [AIDS]), patients who are recovering from surgery, and those who
have had a breach of protective barriers (such as a severe wound or burn).
An example of a primary pathogen is enterohemorrhagic E. coli (EHEC), which produces a virulence factor known
as Shiga toxin. This toxin inhibits protein synthesis, leading to severe and bloody diarrhea, inflammation, and
renal failure, even in patients with healthy immune systems. Staphylococcus epidermidis, on the other hand, is an
opportunistic pathogen that is among the most frequent causes of nosocomial disease.[5] S. epidermidis is a member of
the normal microbiota of the skin, where it is generally avirulent. However, in hospitals, it can also grow in biofilms
that form on catheters, implants, or other devices that are inserted into the body during surgical procedures. Once
inside the body, S. epidermidis can cause serious infections such as endocarditis, and it produces virulence factors that
promote the persistence of such infections.
Other members of the normal microbiota can also cause opportunistic infections under certain conditions. This often
occurs when microbes that reside harmlessly in one body location end up in a different body system, where they cause
disease. For example, E. coli normally found in the large intestine can cause a urinary tract infection if it enters the
bladder. This is the leading cause of urinary tract infections among women.
Members of the normal microbiota may also cause disease when a shift in the environment of the body leads to
overgrowth of a particular microorganism. For example, the yeast Candida is part of the normal microbiota of the
skin, mouth, intestine, and vagina, but its population is kept in check by other organisms of the microbiota. If an
individual is taking antibacterial medications, however, bacteria that would normally inhibit the growth of Candida
can be killed off, leading to a sudden growth in the population of Candida, which is not affected by antibacterial
medications because it is a fungus. An overgrowth of Candida can manifest as oral thrush (growth on mouth, throat,
and tongue), a vaginal yeast infection, or cutaneous candidiasis. Other scenarios can also provide opportunities for
Candida infections. Untreated diabetes can result in a high concentration of glucose in the saliva, which provides
an optimal environment for the growth of Candida, resulting in thrush. Immunodeficiencies such as those seen in
patients with HIV, AIDS, and cancer also lead to higher incidence of thrush. Vaginal yeast infections can result from
decreases in estrogen levels during the menstruation or menopause. The amount of glycogen available to lactobacilli
in the vagina is controlled by levels of estrogen; when estrogen levels are low, lactobacilli produce less lactic acid.
The resultant increase in vaginal pH allows overgrowth of Candida in the vagina.

• Explain the difference between a primary pathogen and an opportunistic pathogen.

• Describe some conditions under which an opportunistic infection can occur.

Stages of Pathogenesis
To cause disease, a pathogen must successfully achieve four steps or stages of pathogenesis: exposure (contact),
adhesion (colonization), invasion, and infection. The pathogen must be able to gain entry to the host, travel to the
location where it can establish an infection, evade or overcome the host’s immune response, and cause damage (i.e.,
disease) to the host. In many cases, the cycle is completed when the pathogen exits the host and is transmitted to a
new host.

5. M. Otto. “Staphylococcus epidermidis--The ‘Accidental’ Pathogen.” Nature Reviews Microbiology 7 no. 8 (2009):555–567.

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Chapter 15 | Microbial Mechanisms of Pathogenicity 675

Exposure
An encounter with a potential pathogen is known as exposure or contact. The food we eat and the objects we handle
are all ways that we can come into contact with potential pathogens. Yet, not all contacts result in infection and
disease. For a pathogen to cause disease, it needs to be able to gain access into host tissue. An anatomic site through
which pathogens can pass into host tissue is called a portal of entry. These are locations where the host cells are in
direct contact with the external environment. Major portals of entry are identified in Figure 15.6 and include the
skin, mucous membranes, and parenteral routes.

Figure 15.6 Shown are different portals of entry where pathogens can gain access into the body. With the exception
of the placenta, many of these locations are directly exposed to the external environment.

Mucosal surfaces are the most important portals of entry for microbes; these include the mucous membranes of the
respiratory tract, the gastrointestinal tract, and the genitourinary tract. Although most mucosal surfaces are in the
interior of the body, some are contiguous with the external skin at various body openings, including the eyes, nose,
mouth, urethra, and anus.
Most pathogens are suited to a particular portal of entry. A pathogen’s portal specificity is determined by the
organism’s environmental adaptions and by the enzymes and toxins they secrete. The respiratory and gastrointestinal
tracts are particularly vulnerable portals of entry because particles that include microorganisms are constantly inhaled
or ingested, respectively.
Pathogens can also enter through a breach in the protective barriers of the skin and mucous membranes. Pathogens
that enter the body in this way are said to enter by the parenteral route. For example, the skin is a good natural barrier
676 Chapter 15 | Microbial Mechanisms of Pathogenicity

to pathogens, but breaks in the skin (e.g., wounds, insect bites, animal bites, needle pricks) can provide a parenteral
portal of entry for microorganisms.
In pregnant women, the placenta normally prevents microorganisms from passing from the mother to the fetus.
However, a few pathogens are capable of crossing the blood-placental barrier. The gram-positive bacterium Listeria
monocytogenes, which causes the foodborne disease listeriosis, is one example that poses a serious risk to the fetus
and can sometimes lead to spontaneous abortion. Other pathogens that can pass the placental barrier to infect the fetus
are known collectively by the acronym TORCH (Table 15.6).
Transmission of infectious diseases from mother to baby is also a concern at the time of birth when the baby passes
through the birth canal. Babies whose mothers have active chlamydia or gonorrhea infections may be exposed to
the causative pathogens in the vagina, which can result in eye infections that lead to blindness. To prevent this, it is
standard practice to administer antibiotic drops to infants’ eyes shortly after birth.

Pathogens Capable of Crossing the Placental Barrier (TORCH Infections)

Disease Pathogen

T Toxoplasmosis Toxoplasma gondii (protozoan)

Syphilis Treponema pallidum (bacterium)

Chickenpox Varicella-zoster virus (human herpesvirus 3)
O[6] Hepatitis B Hepatitis B virus (hepadnavirus)
HIV Retrovirus
Fifth disease (erythema infectiosum) Parvovirus B19

R Rubella (German measles) Togavirus

C Cytomegalovirus Human herpesvirus 5

H Herpes Herpes simplex viruses (HSV) 1 and 2

Table 15.6

Clinical Focus

Part 2
At the clinic, a physician takes down Michael’s medical history and asks about his activities and diet over the
past week. Upon learning that Michael became sick the day after the party, the physician orders a blood test to
check for pathogens associated with foodborne diseases. After tests confirm that presence of a gram-positive
rod in Michael’s blood, he is given an injection of a broad-spectrum antibiotic and sent to a nearby hospital,
where he is admitted as a patient. There he is to receive additional intravenous antibiotic therapy and fluids.
• Is this bacterium in Michael’s blood part of normal microbiota?
• What portal of entry did the bacteria use to cause this infection?
Jump to the next Clinical Focus box. Go back to the previous Clinical Focus box.

Adhesion
Following the initial exposure, the pathogen adheres at the portal of entry. The term adhesion refers to the capability
of pathogenic microbes to attach to the cells of the body using adhesion factors, and different pathogens use various
mechanisms to adhere to the cells of host tissues.
Molecules (either proteins or carbohydrates) called adhesins are found on the surface of certain pathogens and bind to

6. The O in TORCH stands for “other.”

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Chapter 15 | Microbial Mechanisms of Pathogenicity 677

specific receptors (glycoproteins) on host cells. Adhesins are present on the fimbriae and flagella of bacteria, the cilia
of protozoa, and the capsids or membranes of viruses. Protozoans can also use hooks and barbs for adhesion; spike
proteins on viruses also enhance viral adhesion. The production of glycocalyces (slime layers and capsules) (Figure
15.7), with their high sugar and protein content, can also allow certain bacterial pathogens to attach to cells.
Biofilm growth can also act as an adhesion factor. A biofilm is a community of bacteria that produce a glycocalyx,
known as extrapolymeric substance (EPS), that allows the biofilm to attach to a surface. Persistent Pseudomonas
aeruginosa infections are common in patients suffering from cystic fibrosis, burn wounds, and middle-ear infections
(otitis media) because P. aeruginosa produces a biofilm. The EPS allows the bacteria to adhere to the host cells and
makes it harder for the host to physically remove the pathogen. The EPS not only allows for attachment but provides
protection against the immune system and antibiotic treatments, preventing antibiotics from reaching the bacterial
cells within the biofilm. In addition, not all bacteria in a biofilm are rapidly growing; some are in stationary phase.
Since antibiotics are most effective against rapidly growing bacteria, portions of bacteria in a biofilm are protected
against antibiotics.[7]

Figure 15.7 Glycocalyx produced by bacteria in a biofilm allows the cells to adhere to host tissues and to medical
devices such as the catheter surface shown here. (credit: modification of work by Centers for Disease Control and
Prevention)

Invasion
Once adhesion is successful, invasion can proceed. Invasion involves the dissemination of a pathogen throughout
local tissues or the body. Pathogens may produce exoenzymes or toxins, which serve as virulence factors that allow
them to colonize and damage host tissues as they spread deeper into the body. Pathogens may also produce virulence
factors that protect them against immune system defenses. A pathogen’s specific virulence factors determine the
degree of tissue damage that occurs. Figure 15.8 shows the invasion of H. pylori into the tissues of the stomach,
causing damage as it progresses.

7. D. Davies. “Understanding Biofilm Resistance to Antibacterial Agents.” Nature Reviews Drug Discovery 2 (2003):114–122.
678 Chapter 15 | Microbial Mechanisms of Pathogenicity

Figure 15.8 H. pylori is able to invade the lining of the stomach by producing virulence factors that enable it pass
through the mucin layer covering epithelial cells. (credit: modification of work by Zina Deretsky, National Science
Foundation)

Intracellular pathogens achieve invasion by entering the host’s cells and reproducing. Some are obligate intracellular
pathogens (meaning they can only reproduce inside of host cells) and others are facultative intracellular pathogens
(meaning they can reproduce either inside or outside of host cells). By entering the host cells, intracellular pathogens
are able to evade some mechanisms of the immune system while also exploiting the nutrients in the host cell.
Entry to a cell can occur by endocytosis. For most kinds of host cells, pathogens use one of two different mechanisms
for endocytosis and entry. One mechanism relies on effector proteins secreted by the pathogen; these effector proteins
trigger entry into the host cell. This is the method that Salmonella and Shigella use when invading intestinal epithelial
cells. When these pathogens come in contact with epithelial cells in the intestine, they secrete effector molecules
that cause protrusions of membrane ruffles that bring the bacterial cell in. This process is called membrane ruffling.
The second mechanism relies on surface proteins expressed on the pathogen that bind to receptors on the host cell,
resulting in entry. For example, Yersinia pseudotuberculosis produces a surface protein known as invasin that binds
to beta-1 integrins expressed on the surface of host cells.
Some host cells, such as white blood cells and other phagocytes of the immune system, actively endocytose pathogens
in a process called phagocytosis. Although phagocytosis allows the pathogen to gain entry to the host cell, in
most cases, the host cell kills and degrades the pathogen by using digestive enzymes. Normally, when a pathogen
is ingested by a phagocyte, it is enclosed within a phagosome in the cytoplasm; the phagosome fuses with a
lysosome to form a phagolysosome, where digestive enzymes kill the pathogen (see Pathogen Recognition and
Phagocytosis). However, some intracellular pathogens have the ability to survive and multiply within phagocytes.
Examples include Listeria monocytogenes and Shigella; these bacteria produce proteins that lyse the phagosome
before it fuses with the lysosome, allowing the bacteria to escape into the phagocyte’s cytoplasm where they can
multiply. Bacteria such as Mycobacterium tuberculosis, Legionella pneumophila, and Salmonella species use a
slightly different mechanism to evade being digested by the phagocyte. These bacteria prevent the fusion of the
phagosome with the lysosome, thus remaining alive and dividing within the phagosome.

Infection
Following invasion, successful multiplication of the pathogen leads to infection. Infections can be described as local,
focal, or systemic, depending on the extent of the infection. A local infection is confined to a small area of the body,
typically near the portal of entry. For example, a hair follicle infected by Staphylococcus aureus infection may result
in a boil around the site of infection, but the bacterium is largely contained to this small location. Other examples of
local infections that involve more extensive tissue involvement include urinary tract infections confined to the bladder

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Chapter 15 | Microbial Mechanisms of Pathogenicity 679

or pneumonia confined to the lungs.

In a focal infection, a localized pathogen, or the toxins it produces, can spread to a secondary location. For example,
a dental hygienist nicking the gum with a sharp tool can lead to a local infection in the gum by Streptococcus bacteria
of the normal oral microbiota. These Streptococcus spp. may then gain access to the bloodstream and make their way
to other locations in the body, resulting in a secondary infection.
When an infection becomes disseminated throughout the body, we call it a systemic infection. For example, infection
by the varicella-zoster virus typically gains entry through a mucous membrane of the upper respiratory system. It then
spreads throughout the body, resulting in the classic red skin lesions associated with chickenpox. Since these lesions
are not sites of initial infection, they are signs of a systemic infection.
Sometimes a primary infection, the initial infection caused by one pathogen, can lead to a secondary infection
by another pathogen. For example, the immune system of a patient with a primary infection by HIV becomes
compromised, making the patient more susceptible to secondary diseases like oral thrush and others caused by
opportunistic pathogens. Similarly, a primary infection by Influenzavirus damages and decreases the defense
mechanisms of the lungs, making patients more susceptible to a secondary pneumonia by a bacterial pathogen like
Haemophilus influenzae or Streptococcus pneumoniae. Some secondary infections can even develop as a result of
treatment for a primary infection. Antibiotic therapy targeting the primary pathogen can cause collateral damage to
the normal microbiota, creating an opening for opportunistic pathogens (see Case in Point: A Secondary Yeast
Infection).

Case in Point

A Secondary Yeast Infection

Anita, a 36-year-old mother of three, goes to an urgent care center complaining of pelvic pressure, frequent
and painful urination, abdominal cramps, and occasional blood-tinged urine. Suspecting a urinary tract
infection (UTI), the physician requests a urine sample and sends it to the lab for a urinalysis. Since it will
take approximately 24 hours to get the results of the culturing, the physician immediately starts Anita on the
antibiotic ciprofloxacin. The next day, the microbiology lab confirms the presence of E. coli in Anita’s urine,
which is consistent with the presumptive diagnosis. However, the antimicrobial susceptibility test indicates that
ciprofloxacin would not effectively treat Anita’s UTI, so the physician prescribes a different antibiotic.
After taking her antibiotics for 1 week, Anita returns to the clinic complaining that the prescription is not working.
Although the painful urination has subsided, she is now experiencing vaginal itching, burning, and discharge.
After a brief examination, the physician explains to Anita that the antibiotics were likely successful in killing the
E. coli responsible for her UTI; however, in the process, they also wiped out many of the “good” bacteria in
Anita’s normal microbiota. The new symptoms that Anita has reported are consistent with a secondary yeast
infection by Candida albicans, an opportunistic fungus that normally resides in the vagina but is inhibited by
the bacteria that normally reside in the same environment.
To confirm this diagnosis, a microscope slide of a direct vaginal smear is prepared from the discharge to
check for the presence of yeast. A sample of the discharge accompanies this slide to the microbiology lab to
determine if there has been an increase in the population of yeast causing vaginitis. After the microbiology lab
confirms the diagnosis, the physician prescribes an antifungal drug for Anita to use to eliminate her secondary
yeast infection.
• Why was Candida not killed by the antibiotics prescribed for the UTI?

• List three conditions that could lead to a secondary infection.

680 Chapter 15 | Microbial Mechanisms of Pathogenicity

Transmission of Disease
For a pathogen to persist, it must put itself in a position to be transmitted to a new host, leaving the infected host
through a portal of exit (Figure 15.9). As with portals of entry, many pathogens are adapted to use a particular portal
of exit. Similar to portals of entry, the most common portals of exit include the skin and the respiratory, urogenital,
and gastrointestinal tracts. Coughing and sneezing can expel pathogens from the respiratory tract. A single sneeze can
send thousands of virus particles into the air. Secretions and excretions can transport pathogens out of other portals of
exit. Feces, urine, semen, vaginal secretions, tears, sweat, and shed skin cells can all serve as vehicles for a pathogen
to leave the body. Pathogens that rely on insect vectors for transmission exit the body in the blood extracted by a
biting insect. Similarly, some pathogens exit the body in blood extracted by needles.

Figure 15.9 Pathogens leave the body of an infected host through various portals of exit to infect new hosts.

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Chapter 15 | Microbial Mechanisms of Pathogenicity 681

15.3 Virulence Factors of Bacterial and Viral Pathogens

Learning Objectives
• Explain how virulence factors contribute to signs and symptoms of infectious disease
• Differentiate between endotoxins and exotoxins
• Describe and differentiate between various types of exotoxins
• Describe the mechanisms viruses use for adhesion and antigenic variation
In the previous section, we explained that some pathogens are more virulent than others. This is due to the unique
virulence factors produced by individual pathogens, which determine the extent and severity of disease they may
cause. A pathogen’s virulence factors are encoded by genes that can be identified using molecular Koch’s postulates.
When genes encoding virulence factors are inactivated, virulence in the pathogen is diminished. In this section,
we examine various types and specific examples of virulence factors and how they contribute to each step of
pathogenesis.

Virulence Factors for Adhesion

As discussed in the previous section, the first two steps in pathogenesis are exposure and adhesion. Recall that an
adhesin is a protein or glycoprotein found on the surface of a pathogen that attaches to receptors on the host cell.
Adhesins are found on bacterial, viral, fungal, and protozoan pathogens. One example of a bacterial adhesin is type
1 fimbrial adhesin, a molecule found on the tips of fimbriae of enterotoxigenic E. coli (ETEC). Recall that fimbriae
are hairlike protein bristles on the cell surface. Type 1 fimbrial adhesin allows the fimbriae of ETEC cells to attach to
the mannose glycans expressed on intestinal epithelial cells. Table 15.7 lists common adhesins found in some of the
pathogens we have discussed or will be seeing later in this chapter.

Some Bacterial Adhesins and Their Host Attachment Sites

Pathogen Disease Adhesin Attachment Site

Respiratory epithelial
Streptococcus pyogenes Strep throat Protein F
cells

Streptococcus mutans Dental caries Adhesin P1 Teeth

Neisseria gonorrhoeae Gonorrhea Type IV pili Urethral epithelial cells

Enterotoxigenic E. coli Traveler’s

Type 1 fimbriae Intestinal epithelial cells
(ETEC) diarrhea

N-methylphenylalanine
Vibrio cholerae Cholera Intestinal epithelial cells
pili

Table 15.7

Clinical Focus

Part 3
The presence of bacteria in Michael’s blood is a sign of infection, since blood is normally sterile. There is no
indication that the bacteria entered the blood through an injury. Instead, it appears the portal of entry was the
gastrointestinal route. Based on Michael’s symptoms, the results of his blood test, and the fact that Michael
was the only one in the family to partake of the hot dogs, the physician suspects that Michael is suffering from
682 Chapter 15 | Microbial Mechanisms of Pathogenicity

a case of listeriosis.
Listeria monocytogenes, the facultative intracellular pathogen that causes listeriosis, is a common contaminant
in ready-to-eat foods such as lunch meats and dairy products. Once ingested, these bacteria invade intestinal
epithelial cells and translocate to the liver, where they grow inside hepatic cells. Listeriosis is fatal in about one
in five normal healthy people, and mortality rates are slightly higher in patients with pre-existing conditions that
weaken the immune response. A cluster of virulence genes encoded on a pathogenicity island is responsible
for the pathogenicity of L. monocytogenes. These genes are regulated by a transcriptional factor known as
peptide chain release factor 1 (PrfA). One of the genes regulated by PrfA is hyl, which encodes a toxin known
as listeriolysin O (LLO), which allows the bacterium to escape vacuoles upon entry into a host cell. A second
gene regulated by PrfA is actA, which encodes for a surface protein known as actin assembly-inducing protein
(ActA). ActA is expressed on the surface of Listeria and polymerizes host actin. This enables the bacterium
to produce actin tails, move around the cell’s cytoplasm, and spread from cell to cell without exiting into the
extracellular compartment.
Michael’s condition has begun to worsen. He is now experiencing a stiff neck and hemiparesis (weakness of
one side of the body). Concerned that the infection is spreading, the physician decides to conduct additional
tests to determine what is causing these new symptoms.
• What kind of pathogen causes listeriosis, and what virulence factors contribute to the signs and
symptoms Michael is experiencing?
• Is it likely that the infection will spread from Michael’s blood? If so, how might this explain his new
symptoms?
Jump to the next Clinical Focus box. Go back to the previous Clinical Focus box.

Bacterial Exoenzymes and Toxins as Virulence Factors

After exposure and adhesion, the next step in pathogenesis is invasion, which can involve enzymes and toxins. Many
pathogens achieve invasion by entering the bloodstream, an effective means of dissemination because blood vessels
pass close to every cell in the body. The downside of this mechanism of dispersal is that the blood also includes
numerous elements of the immune system. Various terms ending in –emia are used to describe the presence of
pathogens in the bloodstream. The presence of bacteria in blood is called bacteremia. Bacteremia involving pyogens
(pus-forming bacteria) is called pyemia. When viruses are found in the blood, it is called viremia. The term toxemia
describes the condition when toxins are found in the blood. If bacteria are both present and multiplying in the blood,
this condition is called septicemia.
Patients with septicemia are described as septic, which can lead to shock, a life-threatening decrease in blood pressure
(systolic pressure <90 mm Hg) that prevents cells and organs from receiving enough oxygen and nutrients. Some
bacteria can cause shock through the release of toxins (virulence factors that can cause tissue damage) and lead to
low blood pressure. Gram-negative bacteria are engulfed by immune system phagocytes, which then release tumor
necrosis factor, a molecule involved in inflammation and fever. Tumor necrosis factor binds to blood capillaries to
increase their permeability, allowing fluids to pass out of blood vessels and into tissues, causing swelling, or edema
(Figure 15.10). With high concentrations of tumor necrosis factor, the inflammatory reaction is severe and enough
fluid is lost from the circulatory system that blood pressure decreases to dangerously low levels. This can have dire
consequences because the heart, lungs, and kidneys rely on normal blood pressure for proper function; thus, multi-
organ failure, shock, and death can occur.

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Chapter 15 | Microbial Mechanisms of Pathogenicity 683

Figure 15.10 This patient has edema in the tissue of the right hand. Such swelling can occur when bacteria cause
the release of pro-inflammatory molecules from immune cells and these molecules cause an increased permeability
of blood vessels, allowing fluid to escape the bloodstream and enter tissue.

Exoenzymes
Some pathogens produce extracellular enzymes, or exoenzymes, that enable them to invade host cells and deeper
tissues. Exoenzymes have a wide variety of targets. Some general classes of exoenzymes and associated pathogens
are listed in Table 15.8. Each of these exoenzymes functions in the context of a particular tissue structure to facilitate
invasion or support its own growth and defend against the immune system. For example, hyaluronidase S, an
enzyme produced by pathogens like Staphylococcus aureus, Streptococcus pyogenes, and Clostridium perfringens,
degrades the glycoside hyaluronan (hyaluronic acid), which acts as an intercellular cement between adjacent cells in
connective tissue (Figure 15.11). This allows the pathogen to pass through the tissue layers at the portal of entry
and disseminate elsewhere in the body (Figure 15.11).

Some Classes of Exoenzymes and Their Targets

Class Example Function

Glycohydrolases Hyaluronidase S in Degrades hyaluronic acid that cements cells together to promote
Staphylococcus spreading through tissues
aureus

Nucleases DNAse produced Degrades DNA released by dying cells (bacteria and host cells) that
by S. aureus can trap the bacteria, thus promoting spread

Phospholipases Phospholipase C Degrades phospholipid bilayer of host cells, causing cellular lysis,
of Bacillus and degrade membrane of phagosomes to enable escape into the
anthracis cytoplasm

Proteases Collagenase in Degrades collagen in connective tissue to promote spread

Clostridium
perfringens

Table 15.8
684 Chapter 15 | Microbial Mechanisms of Pathogenicity

Figure 15.11 (a) Hyaluronan is a polymer found in the layers of epidermis that connect adjacent cells. (b)
Hyaluronidase produced by bacteria degrades this adhesive polymer in the extracellular matrix, allowing passage
between cells that would otherwise be blocked.

Pathogen-produced nucleases, such as DNAse produced by S. aureus, degrade extracellular DNA as a means of
escape and spreading through tissue. As bacterial and host cells die at the site of infection, they lyse and release their
intracellular contents. The DNA chromosome is the largest of the intracellular molecules, and masses of extracellular
DNA can trap bacteria and prevent their spread. S. aureus produces a DNAse to degrade the mesh of extracellular
DNA so it can escape and spread to adjacent tissues. This strategy is also used by S. aureus and other pathogens to
degrade and escape webs of extracellular DNA produced by immune system phagocytes to trap the bacteria.
Enzymes that degrade the phospholipids of cell membranes are called phospholipases. Their actions are specific in
regard to the type of phospholipids they act upon and where they enzymatically cleave the molecules. The pathogen
responsible for anthrax, B. anthracis, produces phospholipase C. When B. anthracis is ingested by phagocytic cells of
the immune system, phospholipase C degrades the membrane of the phagosome before it can fuse with the lysosome,
allowing the pathogen to escape into the cytoplasm and multiply. Phospholipases can also target the membrane that
encloses the phagosome within phagocytic cells. As described earlier in this chapter, this is the mechanism used
by intracellular pathogens such as L. monocytogenes and Rickettsia to escape the phagosome and multiply within
the cytoplasm of phagocytic cells. The role of phospholipases in bacterial virulence is not restricted to phagosomal
escape. Many pathogens produce phospholipases that act to degrade cell membranes and cause lysis of target cells.
These phospholipases are involved in lysis of red blood cells, white blood cells, and tissue cells.
Bacterial pathogens also produce various protein-digesting enzymes, or proteases. Proteases can be classified
according to their substrate target (e.g., serine proteases target proteins with the amino acid serine) or if they contain
metals in their active site (e.g., zinc metalloproteases contain a zinc ion, which is necessary for enzymatic activity).
One example of a protease that contains a metal ion is the exoenzyme collagenase. Collagenase digests collagen,
the dominant protein in connective tissue. Collagen can be found in the extracellular matrix, especially near mucosal
membranes, blood vessels, nerves, and in the layers of the skin. Similar to hyaluronidase, collagenase allows the
pathogen to penetrate and spread through the host tissue by digesting this connective tissue protein. The collagenase
produced by the gram-positive bacterium Clostridium perfringens, for example, allows the bacterium to make its
way through the tissue layers and subsequently enter and multiply in the blood (septicemia). C. perfringens then
uses toxins and a phospholipase to cause cellular lysis and necrosis. Once the host cells have died, the bacterium
produces gas by fermenting the muscle carbohydrates. The widespread necrosis of tissue and accompanying gas are
characteristic of the condition known as gas gangrene (Figure 15.12).

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Chapter 15 | Microbial Mechanisms of Pathogenicity 685

Figure 15.12 The illustration depicts a blood vessel with a single layer of endothelial cells surrounding the lumen
and dense connective tissue (shown in red) surrounding the endothelial cell layer. Collagenase produced by C.
perfringens degrades the collagen between the endothelial cells, allowing the bacteria to enter the bloodstream.
(credit illustration: modification of work by Bruce Blaus; credit micrograph: Micrograph provided by the Regents of
University of Michigan Medical School © 2012)

Link to Learning

Two types of cell death are apoptosis and necrosis. Visit this website
(https://openstax.org/l/22CellDeath) to learn more about the differences
between these mechanisms of cell death and their causes.

Toxins
In addition to exoenzymes, certain pathogens are able to produce toxins, biological poisons that assist in their ability
to invade and cause damage to tissues. The ability of a pathogen to produce toxins to cause damage to host cells is
called toxigenicity.
Toxins can be categorized as endotoxins or exotoxins. The lipopolysaccharide (LPS) found on the outer membrane
of gram-negative bacteria is called endotoxin (Figure 15.13). During infection and disease, gram-negative bacterial
pathogens release endotoxin either when the cell dies, resulting in the disintegration of the membrane, or when the
bacterium undergoes binary fission. The lipid component of endotoxin, lipid A, is responsible for the toxic properties
of the LPS molecule. Lipid A is relatively conserved across different genera of gram-negative bacteria; therefore,
the toxic properties of lipid A are similar regardless of the gram-negative pathogen. In a manner similar to that of
tumor necrosis factor, lipid A triggers the immune system’s inflammatory response (see Inflammation and Fever).
If the concentration of endotoxin in the body is low, the inflammatory response may provide the host an effective
defense against infection; on the other hand, high concentrations of endotoxin in the blood can cause an excessive
inflammatory response, leading to a severe drop in blood pressure, multi-organ failure, and death.
686 Chapter 15 | Microbial Mechanisms of Pathogenicity

Figure 15.13 Lipopolysaccharide is composed of lipid A, a core glycolipid, and an O-specific polysaccharide side
chain. Lipid A is the toxic component that promotes inflammation and fever.

A classic method of detecting endotoxin is by using the Limulus amebocyte lysate (LAL) test. In this procedure,
the blood cells (amebocytes) of the horseshoe crab (Limulus polyphemus) is mixed with a patient’s serum. The
amebocytes will react to the presence of any endotoxin. This reaction can be observed either chromogenically (color)
or by looking for coagulation (clotting reaction) to occur within the serum. An alternative method that has been used
is an enzyme-linked immunosorbent assay (ELISA) that uses antibodies to detect the presence of endotoxin.
Unlike the toxic lipid A of endotoxin, exotoxins are protein molecules that are produced by a wide variety of living
pathogenic bacteria. Although some gram-negative pathogens produce exotoxins, the majority are produced by gram-
positive pathogens. Exotoxins differ from endotoxin in several other key characteristics, summarized in Table 15.9.
In contrast to endotoxin, which stimulates a general systemic inflammatory response when released, exotoxins are
much more specific in their action and the cells they interact with. Each exotoxin targets specific receptors on specific
cells and damages those cells through unique molecular mechanisms. Endotoxin remains stable at high temperatures,
and requires heating at 121 °C (250 °F) for 45 minutes to inactivate. By contrast, most exotoxins are heat labile
because of their protein structure, and many are denatured (inactivated) at temperatures above 41 °C (106 °F).
As discussed earlier, endotoxin can stimulate a lethal inflammatory response at very high concentrations and has
a measured LD50 of 0.24 mg/kg. By contrast, very small concentrations of exotoxins can be lethal. For example,
botulinum toxin, which causes botulism, has an LD50 of 0.000001 mg/kg (240,000 times more lethal than endotoxin).

Comparison of Endotoxin and Exotoxins Produced by Bacteria

Characteristic Endotoxin Exotoxin

Source Gram-negative bacteria Gram-positive (primarily) and gram-negative bacteria

Composition Lipid A component of Protein

lipopolysaccharide

Effect on host General systemic symptoms Specific damage to cells dependent upon receptor-mediated
of inflammation and fever targeting of cells and specific mechanisms of action

Heat stability Heat stable Most are heat labile, but some are heat stable

LD50 High Low

Table 15.9

The exotoxins can be grouped into three categories based on their target: intracellular targeting, membrane disrupting,
and superantigens. Table 15.10 provides examples of well-characterized toxins within each of these three categories.

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Chapter 15 | Microbial Mechanisms of Pathogenicity 687

Some Common Exotoxins and Associated Bacterial Pathogens

Category Example Pathogen Mechanism and Disease

Intracellular- Cholera toxin Vibrio cholerae Activation of adenylate cyclase in intestinal cells,
targeting causing increased levels of cyclic adenosine
toxins monophosphate (cAMP) and secretion of fluids and
electrolytes out of cell, causing diarrhea

Tetanus toxin Clostridium Inhibits the release of inhibitory neurotransmitters in

tetani the central nervous system, causing spastic paralysis

Botulinum Clostridium Inhibits release of the neurotransmitter acetylcholine

toxin botulinum from neurons, resulting in flaccid paralysis

Diphtheria Corynebacterium Inhibition of protein synthesis, causing cellular death

toxin diphtheriae

Membrane- Streptolysin Streptococcus Proteins that assemble into pores in cell membranes,
disrupting pyogenes disrupting their function and killing the cell
toxins
Pneumolysin Streptococcus
pneumoniae

Alpha-toxin Staphylococcus
aureus

Alpha-toxin Clostridium Phospholipases that degrade cell membrane

perfringens phospholipids, disrupting membrane function and
killing the cell
Phospholipase Pseudomonas
C aeruginosa

Beta-toxin Staphylococcus
aureus

Superantigens Toxic shock Staphylococcus Stimulates excessive activation of immune system

syndrome aureus cells and release of cytokines (chemical mediators)
toxin from immune system cells. Life-threatening fever,
inflammation, and shock are the result.
Streptococcal Streptococcus
mitogenic pyogenes
exotoxin

Streptococcal Streptococcus
pyrogenic pyogenes
toxins

Table 15.10

The intracellular targeting toxins comprise two components: A for activity and B for binding. Thus, these types of
toxins are known as A-B exotoxins (Figure 15.14). The B component is responsible for the cellular specificity of
the toxin and mediates the initial attachment of the toxin to specific cell surface receptors. Once the A-B toxin binds
to the host cell, it is brought into the cell by endocytosis and entrapped in a vacuole. The A and B subunits separate
as the vacuole acidifies. The A subunit then enters the cell cytoplasm and interferes with the specific internal cellular
function that it targets.
688 Chapter 15 | Microbial Mechanisms of Pathogenicity

Figure 15.14 (a) In A-B toxins, the B component binds to the host cell through its interaction with specific cell
surface receptors. (b) The toxin is brought in through endocytosis. (c) Once inside the vacuole, the A component
(active component) separates from the B component and the A component gains access to the cytoplasm. (credit:
modification of work by “Biology Discussion Forum”/YouTube)

Four unique examples of A-B toxins are the diphtheria, cholera, botulinum, and tetanus toxins. The diphtheria toxin
is produced by the gram-positive bacterium Corynebacterium diphtheriae, the causative agent of nasopharyngeal
and cutaneous diphtheria. After the A subunit of the diphtheria toxin separates and gains access to the cytoplasm, it
facilitates the transfer of adenosine diphosphate (ADP)-ribose onto an elongation-factor protein (EF-2) that is needed
for protein synthesis. Hence, diphtheria toxin inhibits protein synthesis in the host cell, ultimately killing the cell
(Figure 15.15).

Figure 15.15 The mechanism of the diphtheria toxin inhibiting protein synthesis. The A subunit inactivates
elongation factor 2 by transferring an ADP-ribose. This stops protein elongation, inhibiting protein synthesis and
killing the cell.

Cholera toxin is an enterotoxin produced by the gram-negative bacterium Vibrio cholerae and is composed of one
A subunit and five B subunits. The mechanism of action of the cholera toxin is complex. The B subunits bind to
receptors on the intestinal epithelial cell of the small intestine. After gaining entry into the cytoplasm of the epithelial
cell, the A subunit activates an intracellular G protein. The activated G protein, in turn, leads to the activation of
the enzyme adenyl cyclase, which begins to produce an increase in the concentration of cyclic AMP (a secondary
messenger molecule). The increased cAMP disrupts the normal physiology of the intestinal epithelial cells and causes

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Chapter 15 | Microbial Mechanisms of Pathogenicity 689

them to secrete excessive amounts of fluid and electrolytes into the lumen of the intestinal tract, resulting in severe
“rice-water stool” diarrhea characteristic of cholera.
Botulinum toxin (also known as botox) is a neurotoxin produced by the gram-positive bacterium Clostridium
botulinum. It is the most acutely toxic substance known to date. The toxin is composed of a light A subunit and
heavy protein chain B subunit. The B subunit binds to neurons to allow botulinum toxin to enter the neurons at
the neuromuscular junction. The A subunit acts as a protease, cleaving proteins involved in the neuron’s release
of acetylcholine, a neurotransmitter molecule. Normally, neurons release acetylcholine to induce muscle fiber
contractions. The toxin’s ability to block acetylcholine release results in the inhibition of muscle contractions,
leading to muscle relaxation. This has the potential to stop breathing and cause death. Because of its action, low
concentrations of botox are used for cosmetic and medical procedures, including the removal of wrinkles and
treatment of overactive bladder.

Link to Learning

Click this link (https://openstax.org/l/22pathochol) to see an animation of how

the cholera toxin functions.
Click this link (https://openstax.org/l/22Botulin) to see an animation of how
the botulinum toxin functions.

Another neurotoxin is tetanus toxin, which is produced by the gram-positive bacterium Clostridium tetani. This toxin
also has a light A subunit and heavy protein chain B subunit. Unlike botulinum toxin, tetanus toxin binds to inhibitory
interneurons, which are responsible for release of the inhibitory neurotransmitters glycine and gamma-aminobutyric
acid (GABA). Normally, these neurotransmitters bind to neurons at the neuromuscular junction, resulting in the
inhibition of acetylcholine release. Tetanus toxin inhibits the release of glycine and GABA from the interneuron,
resulting in permanent muscle contraction. The first symptom is typically stiffness of the jaw (lockjaw). Violent
muscle spasms in other parts of the body follow, typically culminating with respiratory failure and death. Figure
15.16 shows the actions of both botulinum and tetanus toxins.
690 Chapter 15 | Microbial Mechanisms of Pathogenicity

Figure 15.16 Mechanisms of botulinum and tetanus toxins. (credit micrographs: modification of work by Centers for
Disease Control and Prevention)

Membrane-disrupting toxins affect cell membrane function either by forming pores or by disrupting the phospholipid
bilayer in host cell membranes. Two types of membrane-disrupting exotoxins are hemolysins and leukocidins, which
form pores in cell membranes, causing leakage of the cytoplasmic contents and cell lysis. These toxins were originally
thought to target red blood cells (erythrocytes) and white blood cells (leukocytes), respectively, but we now know they
can affect other cells as well. The gram-positive bacterium Streptococcus pyogenes produces streptolysins, water-
soluble hemolysins that bind to the cholesterol moieties in the host cell membrane to form a pore. The two types of
streptolysins, O and S, are categorized by their ability to cause hemolysis in erythrocytes in the absence or presence
of oxygen. Streptolysin O is not active in the presence of oxygen, whereas streptolysin S is active in the presence of
oxygen. Other important pore-forming membrane-disrupting toxins include alpha toxin of Staphylococcus aureus and
pneumolysin of Streptococcus pneumoniae.
Bacterial phospholipases are membrane-disrupting toxins that degrade the phospholipid bilayer of cell membranes
rather than forming pores. We have already discussed the phospholipases associated with B. anthracis, L.
pneumophila, and Rickettsia species that enable these bacteria to effect the lysis of phagosomes. These same
phospholipases are also hemolysins. Other phospholipases that function as hemolysins include the alpha toxin of
Clostridium perfringens, phospholipase C of P. aeruginosa, and beta toxin of Staphylococcus aureus.
Some strains of S. aureus also produce a leukocidin called Panton-Valentine leukocidin (PVL). PVL consists of two
subunits, S and F. The S component acts like the B subunit of an A-B exotoxin in that it binds to glycolipids on the
outer plasma membrane of animal cells. The F-component acts like the A subunit of an A-B exotoxin and carries the
enzymatic activity. The toxin inserts and assembles into a pore in the membrane. Genes that encode PVL are more
frequently present in S. aureus strains that cause skin infections and pneumonia.[8] PVL promotes skin infections by

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Chapter 15 | Microbial Mechanisms of Pathogenicity 691

causing edema, erythema (reddening of the skin due to blood vessel dilation), and skin necrosis. PVL has also been
shown to cause necrotizing pneumonia. PVL promotes pro-inflammatory and cytotoxic effects on alveolar leukocytes.
This results in the release of enzymes from the leukocytes, which, in turn, cause damage to lung tissue.
The third class of exotoxins is the superantigens. These are exotoxins that trigger an excessive, nonspecific
stimulation of immune cells to secrete cytokines (chemical messengers). The excessive production of cytokines,
often called a cytokine storm, elicits a strong immune and inflammatory response that can cause life-threatening
high fevers, low blood pressure, multi-organ failure, shock, and death. The prototype superantigen is the toxic shock
syndrome toxin of S. aureus. Most toxic shock syndrome cases are associated with vaginal colonization by toxin-
producing S. aureus in menstruating women; however, colonization of other body sites can also occur. Some strains
of Streptococcus pyogenes also produce superantigens; they are referred to as the streptococcal mitogenic exotoxins
and the streptococcal pyrogenic toxins.

• Describe how exoenzymes contribute to bacterial invasion.

• Explain the difference between exotoxins and endotoxin.
• Name the three classes of exotoxins.

Virulence Factors for Survival in the Host and Immune Evasion

Evading the immune system is also important to invasiveness. Bacteria use a variety of virulence factors to evade
phagocytosis by cells of the immune system. For example, many bacteria produce capsules, which are used in
adhesion but also aid in immune evasion by preventing ingestion by phagocytes. The composition of the capsule
prevents immune cells from being able to adhere and then phagocytose the cell. In addition, the capsule makes the
bacterial cell much larger, making it harder for immune cells to engulf the pathogen (Figure 15.17). A notable
capsule-producing bacterium is the gram-positive pathogen Streptococcus pneumoniae, which causes pneumococcal
pneumonia, meningitis, septicemia, and other respiratory tract infections. Encapsulated strains of S. pneumoniae are
more virulent than nonencapsulated strains and are more likely to invade the bloodstream and cause septicemia and
meningitis.
Some pathogens can also produce proteases to protect themselves against phagocytosis. As described in Adaptive
Specific Host Defenses, the human immune system produces antibodies that bind to surface molecules found on
specific bacteria (e.g., capsules, fimbriae, flagella, LPS). This binding initiates phagocytosis and other mechanisms
of antibacterial killing and clearance. Proteases combat antibody-mediated killing and clearance by attacking and
digesting the antibody molecules (Figure 15.17).
In addition to capsules and proteases, some bacterial pathogens produce other virulence factors that allow them to
evade the immune system. The fimbriae of certain species of Streptococcus contain M protein, which alters the
surface of Streptococcus and inhibits phagocytosis by blocking the binding of the complement molecules that assist
phagocytes in ingesting bacterial pathogens. The acid-fast bacterium Mycobacterium tuberculosis (the causative
agent of tuberculosis) produces a waxy substance known as mycolic acid in its cell envelope. When it is engulfed
by phagocytes in the lung, the protective mycolic acid coat enables the bacterium to resist some of the killing
mechanisms within the phagolysosome.

8. V. Meka. “Panton-Valentine Leukocidin.” http://www.antimicrobe.org/h04c.files/history/PVL-S-aureus.asp

692 Chapter 15 | Microbial Mechanisms of Pathogenicity

Figure 15.17 (a) A micrograph of capsules around bacterial cells. (b) Antibodies normally function by binding to
antigens, molecules on the surface of pathogenic bacteria. Phagocytes then bind to the antibody, initiating
phagocytosis. (c) Some bacteria also produce proteases, virulence factors that break down host antibodies to evade
phagocytosis. (credit a: modification of work by Centers for Disease Control and Prevention)

Some bacteria produce virulence factors that promote infection by exploiting molecules naturally produced by the
host. For example, most strains of Staphylococcus aureus produce the exoenzyme coagulase, which exploits the
natural mechanism of blood clotting to evade the immune system. Normally, blood clotting is triggered in response to
blood vessel damage; platelets begin to plug the clot, and a cascade of reactions occurs in which fibrinogen, a soluble
protein made by the liver, is cleaved into fibrin. Fibrin is an insoluble, thread-like protein that binds to blood platelets,
cross-links, and contracts to form a mesh of clumped platelets and red blood cells. The resulting clot prevents further
loss of blood from the damaged blood vessels. However, if bacteria release coagulase into the bloodstream, the
fibrinogen-to-fibrin cascade is triggered in the absence of blood vessel damage. The resulting clot coats the bacteria
in fibrin, protecting the bacteria from exposure to phagocytic immune cells circulating in the bloodstream.
Whereas coagulase causes blood to clot, kinases have the opposite effect by triggering the conversion of plasminogen
to plasmin, which is involved in the digestion of fibrin clots. By digesting a clot, kinases allow pathogens trapped in
the clot to escape and spread, similar to the way that collagenase, hyaluronidase, and DNAse facilitate the spread of
infection. Examples of kinases include staphylokinases and streptokinases, produced by Staphylococcus aureus and
Streptococcus pyogenes, respectively. It is intriguing that S. aureus can produce both coagulase to promote clotting
and staphylokinase to stimulate the digestion of clots. The action of the coagulase provides an important protective
barrier from the immune system, but when nutrient supplies are diminished or other conditions signal a need for the
pathogen to escape and spread, the production of staphylokinase can initiate this process.
A final mechanism that pathogens can use to protect themselves against the immune system is called antigenic
variation, which is the alteration of surface proteins so that a pathogen is no longer recognized by the host’s immune
system. For example, the bacterium Borrelia burgdorferi, the causative agent of Lyme disease, contains a surface
lipoprotein known as VlsE. Because of genetic recombination during DNA replication and repair, this bacterial
protein undergoes antigenic variation. Each time fever occurs, the VlsE protein in B. burgdorferi can differ so
much that antibodies against previous VlsE sequences are not effective. It is believed that this variation in the VlsE
contributes to the ability B. burgdorferi to cause chronic disease. Another important human bacterial pathogen that
uses antigenic variation to avoid the immune system is Neisseria gonorrhoeae, which causes the sexually transmitted
disease gonorrhea. This bacterium is well known for its ability to undergo antigenic variation of its type IV pili to
avoid immune defenses.

• Name at least two ways that a capsule provides protection from the immune system.
• Besides capsules, name two other virulence factors used by bacteria to evade the immune system.

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Chapter 15 | Microbial Mechanisms of Pathogenicity 693

Clinical Focus

Resolution
Based on Michael’s reported symptoms of stiff neck and hemiparesis, the physician suspects that the infection
may have spread to his nervous system. The physician decides to order a spinal tap to look for any bacteria
that may have invaded the meninges and cerebrospinal fluid (CSF), which would normally be sterile. To
perform the spinal tap, Michael’s lower back is swabbed with an iodine antiseptic and then covered with a
sterile sheet. The needle is aseptically removed from the manufacturer’s sealed plastic packaging by the
clinician’s gloved hands. The needle is inserted and a small volume of fluid is drawn into an attached sample
tube. The tube is removed, capped and a prepared label with Michael’s data is affixed to it. This STAT (urgent
or immediate analysis required) specimen is divided into three separate sterile tubes, each with 1 mL of CSF.
These tubes are immediately taken to the hospital’s lab, where they are analyzed in the clinical chemistry,
hematology, and microbiology departments. The preliminary results from all three departments indicate there is
a cerebrospinal infection occurring, with the microbiology department reporting the presence of a gram-positive
rod in Michael’s CSF.
These results confirm what his physician had suspected: Michael’s new symptoms are the result of meningitis,
acute inflammation of the membranes that protect the brain and spinal cord. Because meningitis can be life
threatening and because the first antibiotic therapy was not effective in preventing the spread of infection,
Michael is prescribed an aggressive course of two antibiotics, ampicillin and gentamicin, to be delivered
intravenously. Michael remains in the hospital for several days for supportive care and for observation. After a
week, he is allowed to return home for bed rest and oral antibiotics. After 3 weeks of this treatment, he makes
a full recovery.
Go back to the previous Clinical Focus box.

Viral Virulence
Although viral pathogens are not similar to bacterial pathogens in terms of structure, some of the properties that
contribute to their virulence are similar. Viruses use adhesins to facilitate adhesion to host cells, and certain enveloped
viruses rely on antigenic variation to avoid the host immune defenses. These virulence factors are discussed in more
detail in the following sections.

Viral Adhesins
One of the first steps in any viral infection is adhesion of the virus to specific receptors on the surface of cells.
This process is mediated by adhesins that are part of the viral capsid or membrane envelope. The interaction of viral
adhesins with specific cell receptors defines the tropism (preferential targeting) of viruses for specific cells, tissues,
and organs in the body. The spike protein hemagglutinin found on Influenzavirus is an example of a viral adhesin;
it allows the virus to bind to the sialic acid on the membrane of host respiratory and intestinal cells. Another viral
adhesin is the glycoprotein gp20, found on HIV. For HIV to infect cells of the immune system, it must interact with
two receptors on the surface of cells. The first interaction involves binding between gp120 and the CD4 cellular
marker that is found on some essential immune system cells. However, before viral entry into the cell can occur,
a second interaction between gp120 and one of two chemokine receptors (CCR5 and CXCR4) must occur. Table
15.11 lists the adhesins for some common viral pathogens and the specific sites to which these adhesins allow viruses
to attach.
694 Chapter 15 | Microbial Mechanisms of Pathogenicity

Some Viral Adhesins and Their Host Attachment Sites

Pathogen Disease Adhesin Attachment Site

Influenzavirus Influenza Hemagglutinin Sialic acid of respiratory and intestinal cells

Herpes simplex virus Oral herpes, Glycoproteins Heparan sulfate on mucosal surfaces of the
I or II genital herpes gB, gC, gD mouth and genitals

Human
Glycoprotein CD4 and CCR5 or CXCR4 of immune
immunodeficiency HIV/AIDS
gp120 system cells
virus

Table 15.11

Antigenic Variation in Viruses

Antigenic variation also occurs in certain types of enveloped viruses, including influenza viruses, which exhibit two
forms of antigenic variation: antigenic drift and antigenic shift (Figure 15.18). Antigenic drift is the result of point
mutations causing slight changes in the spike proteins hemagglutinin (H) and neuraminidase (N). On the other hand,
antigenic shift is a major change in spike proteins due to gene reassortment. This reassortment for antigenic shift
occurs typically when two different influenza viruses infect the same host.
The rate of antigenic variation in influenza viruses is very high, making it difficult for the immune system to recognize
the many different strains of Influenzavirus. Although the body may develop immunity to one strain through natural
exposure or vaccination, antigenic variation results in the continual emergence of new strains that the immune system
will not recognize. This is the main reason that vaccines against Influenzavirus must be given annually. Each year’s
influenza vaccine provides protection against the most prevalent strains for that year, but new or different strains may
be more prevalent the following year.

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Chapter 15 | Microbial Mechanisms of Pathogenicity 695

Figure 15.18 Antigenic drift and antigenic shift in influenza viruses. (a) In antigenic drift, mutations in the genes for
the surface proteins neuraminidase and/or hemagglutinin result in small antigenic changes over time. (b) In antigenic
shift, simultaneous infection of a cell with two different influenza viruses results in mixing of the genes. The resultant
virus possesses a mixture of the proteins of the original viruses. Influenza pandemics can often be traced to antigenic
shifts.

Link to Learning

For another explanation of how antigenic shift and drift (https://openstax.org/

l/22Antigenic) occur, watch this video.

• Describe the role of adhesins in viral tropism.

• Explain the difference between antigenic drift and antigenic shift.
696 Chapter 15 | Microbial Mechanisms of Pathogenicity

15.4 Virulence Factors of Eukaryotic Pathogens

Learning Objectives
• Describe virulence factors unique to fungi and parasites
• Compare virulence factors of fungi and bacteria
• Explain the difference between protozoan parasites and helminths
• Describe how helminths evade the host immune system
Although fungi and parasites are important pathogens causing infectious diseases, their pathogenic mechanisms and
virulence factors are not as well characterized as those of bacteria. Despite the relative lack of detailed mechanisms,
the stages of pathogenesis and general mechanisms of virulence involved in disease production by these pathogens
are similar to those of bacteria.

Fungal Virulence
Pathogenic fungi can produce virulence factors that are similar to the bacterial virulence factors that have been
discussed earlier in this chapter. In this section, we will look at the virulence factors associated with species of
Candida, Cryptococcus, Claviceps, and Aspergillus.
Candida albicans is an opportunistic fungal pathogen and causative agent of oral thrush, vaginal yeast infections, and
cutaneous candidiasis. Candida produces adhesins (surface glycoproteins) that bind to the phospholipids of epithelial
and endothelial cells. To assist in spread and tissue invasion, Candida produces proteases and phospholipases (i.e.,
exoenzymes). One of these proteases degrades keratin, a structural protein found on epithelial cells, enhancing the
ability of the fungus to invade host tissue. In animal studies, it has been shown that the addition of a protease inhibitor
led to attenuation of Candida infection.[9] Similarly, the phospholipases can affect the integrity of host cell membranes
to facilitate invasion.
The main virulence factor for Cryptococcus, a fungus that causes pneumonia and meningitis, is capsule production.
The polysaccharide glucuronoxylomannan is the principal constituent of the Cryptococcus capsule. Similar to
encapsulated bacterial cells, encapsulated Cryptococcus cells are more resistant to phagocytosis than nonencapsulated
Cryptococcus, which are effectively phagocytosed and, therefore, less virulent.
Like some bacteria, many fungi produce exotoxins. Fungal toxins are called mycotoxins. Claviceps purpurea, a
fungus that grows on rye and related grains, produces a mycotoxin called ergot toxin, an alkaloid responsible for the
disease known as ergotism. There are two forms of ergotism: gangrenous and convulsive. In gangrenous ergotism,
the ergot toxin causes vasoconstriction, resulting in improper blood flow to the extremities, eventually leading to
gangrene. A famous outbreak of gangrenous ergotism occurred in Eastern Europe during the 5th century AD due to
the consumption of rye contaminated with C. purpurea. In convulsive ergotism, the toxin targets the central nervous
system, causing mania and hallucinations.
The mycotoxin aflatoxin is a virulence factor produced by the fungus Aspergillus, an opportunistic pathogen that can
enter the body via contaminated food or by inhalation. Inhalation of the fungus can lead to the chronic pulmonary
disease aspergillosis, characterized by fever, bloody sputum, and/or asthma. Aflatoxin acts in the host as both a
mutagen (a substance that causes mutations in DNA) and a carcinogen (a substance involved in causing cancer), and
has been associated with the development of liver cancer. Aflatoxin has also been shown to cross the blood-placental
barrier.[10] A second mycotoxin produced by Aspergillus is gliotoxin. This toxin promotes virulence by inducing host
cells to self-destruct and by evading the host’s immune response by inhibiting the function of phagocytic cells as well
as the pro-inflammatory response. Like Candida, Aspergillus also produces several proteases. One is elastase, which
breaks down the protein elastin found in the connective tissue of the lung, leading to the development of lung disease.

9. K. Fallon et al. “Role of Aspartic Proteases in Disseminated Candida albicans Infection in Mice.” Infection and Immunity 65 no. 2
(1997):551–556.
10. C.P. Wild et al. “In-utero exposure to aflatoxin in west Africa.” Lancet 337 no. 8757 (1991):1602.

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Chapter 15 | Microbial Mechanisms of Pathogenicity 697

Another is catalase, an enzyme that protects the fungus from hydrogen peroxide produced by the immune system to
destroy pathogens.

• List virulence factors common to bacteria and fungi.

• What functions do mycotoxins perform to help fungi survive in the host?

Protozoan Virulence
Protozoan pathogens are unicellular eukaryotic parasites that have virulence factors and pathogenic mechanisms
analogous to prokaryotic and viral pathogens, including adhesins, toxins, antigenic variation, and the ability to survive
inside phagocytic vesicles.
Protozoans often have unique features for attaching to host cells. The protozoan Giardia lamblia, which causes the
intestinal disease giardiasis, uses a large adhesive disc composed of microtubules to attach to the intestinal mucosa.
During adhesion, the flagella of G. lamblia move in a manner that draws fluid out from under the disc, resulting in
an area of lower pressure that facilitates adhesion to epithelial cells. Giardia does not invade the intestinal cells but
rather causes inflammation (possibly through the release of cytopathic substances that cause damage to the cells) and
shortens the intestinal villi, inhibiting absorption of nutrients.
Some protozoans are capable of antigenic variation. The obligate intracellular pathogen Plasmodium falciparum (one
of the causative agents of malaria) resides inside red blood cells, where it produces an adhesin membrane protein
known as PfEMP1. This protein is expressed on the surface of the infected erythrocytes, causing blood cells to stick
to each other and to the walls of blood vessels. This process impedes blood flow, sometimes leading to organ failure,
anemia, jaundice (yellowing of skin and sclera of the eyes due to buildup of bilirubin from lysed red blood cells),
and, subsequently, death. Although PfEMP1 can be recognized by the host’s immune system, antigenic variations in
the structure of the protein over time prevent it from being easily recognized and eliminated. This allows malaria to
persist as a chronic infection in many individuals.
The virulence factors of Trypanosoma brucei, the causative agent of African sleeping sickness, include the abilities
to form capsules and undergo antigenic variation. T. brucei evades phagocytosis by producing a dense glycoprotein
coat that resembles a bacterial capsule. Over time, host antibodies are produced that recognize this coat, but T. brucei
is able to alter the structure of the glycoprotein to evade recognition.

• Explain how antigenic variation by protozoan pathogens helps them survive in the host.

Helminth Virulence
Helminths, or parasitic worms, are multicellular eukaryotic parasites that depend heavily on virulence factors that
allow them to gain entry to host tissues. For example, the aquatic larval form of Schistosoma mansoni, which causes
schistosomiasis, penetrates intact skin with the aid of proteases that degrade skin proteins, including elastin.
To survive within the host long enough to perpetuate their often-complex life cycles, helminths need to evade the
immune system. Some helminths are so large that the immune system is ineffective against them. Others, such as
adult roundworms (which cause trichinosis, ascariasis, and other diseases), are protected by a tough outer cuticle.
Over the course of their life cycles, the surface characteristics of the parasites vary, which may help prevent an
effective immune response. Some helminths express polysaccharides called glycans on their external surface; because
698 Chapter 15 | Microbial Mechanisms of Pathogenicity

these glycans resemble molecules produced by host cells, the immune system fails to recognize and attack the
helminth as a foreign body. This “glycan gimmickry,” as it has been called, serves as a protective cloak that allows
the helminth to escape detection by the immune system.[11]
In addition to evading host defenses, helminths can actively suppress the immune system. S. mansoni, for example,
degrades host antibodies with proteases. Helminths produce many other substances that suppress elements of both
innate nonspecific and adaptive specific host defenses. They also release large amounts of material into the host that
may locally overwhelm the immune system or cause it to respond inappropriately.

• Describe how helminths avoid being destroyed by the host immune system.

Summary
15.1 Characteristics of Infectious Disease
• In an infection, a microorganism enters a host and begins to multiply. Some infections cause disease, which
is any deviation from the normal function or structure of the host.
• Signs of a disease are objective and are measured. Symptoms of a disease are subjective and are reported by
the patient.
• Diseases can either be noninfectious (due to genetics and environment) or infectious (due to pathogens).
Some infectious diseases are communicable (transmissible between individuals) or contagious (easily
transmissible between individuals); others are noncommunicable, but may be contracted via contact with
environmental reservoirs or animals (zoonoses)
• Nosocomial diseases are contracted in hospital settings, whereas iatrogenic disease are the direct result of a
medical procedure
• An acute disease is short in duration, whereas a chronic disease lasts for months or years. Latent diseases
last for years, but are distinguished from chronic diseases by the lack of active replication during extended
dormant periods.
• The periods of disease include the incubation period, the prodromal period, the period of illness, the
period of decline, and the period of convalescence. These periods are marked by changes in the number of
infectious agents and the severity of signs and symptoms.
15.2 How Pathogens Cause Disease
• Koch’s postulates are used to determine whether a particular microorganism is a pathogen. Molecular
Koch’s postulates are used to determine what genes contribute to a pathogen’s ability to cause disease.
• Virulence, the degree to which a pathogen can cause disease, can be quantified by calculating either the ID50
or LD50 of a pathogen on a given population.
• Primary pathogens are capable of causing pathological changes associated with disease in a healthy
individual, whereas opportunistic pathogens can only cause disease when the individual is compromised by
a break in protective barriers or immunosuppression.
• Infections and disease can be caused by pathogens in the environment or microbes in an individual’s resident
microbiota.
• Infections can be classified as local, focal, or systemic depending on the extent to which the pathogen spreads
in the body.
• A secondary infection can sometimes occur after the host’s defenses or normal microbiota are compromised

11. I. van Die, R.D. Cummings. “Glycan Gimmickry by Parasitic Helminths: A Strategy for Modulating the Host Immune Response?”
Glycobiology 20 no. 1 (2010):2–12.

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Chapter 15 | Microbial Mechanisms of Pathogenicity 699

by a primary infection or antibiotic treatment.

• Pathogens enter the body through portals of entry and leave through portals of exit. The stages of
pathogenesis include exposure, adhesion, invasion, infection, and transmission.
15.3 Virulence Factors of Bacterial and Viral Pathogens
• Virulence factors contribute to a pathogen’s ability to cause disease.
• Exoenzymes and toxins allow pathogens to invade host tissue and cause tissue damage. Exoenzymes are
classified according to the macromolecule they target and exotoxins are classified based on their mechanism
of action.
• Bacterial toxins include endotoxin and exotoxins. Endotoxin is the lipid A component of the LPS of the gram-
negative cell envelope. Exotoxins are proteins secreted mainly by gram-positive bacteria, but also are secreted
by gram-negative bacteria.
• Bacterial pathogens may evade the host immune response by producing capsules to avoid phagocytosis,
surviving the intracellular environment of phagocytes, degrading antibodies, or through antigenic variation.
• Viral pathogens use adhesins for initiating infections and antigenic variation to avoid immune defenses.
• Influenza viruses use both antigenic drift and antigenic shift to avoid being recognized by the immune
system.
15.4 Virulence Factors of Eukaryotic Pathogens
• Fungal and parasitic pathogens use pathogenic mechanisms and virulence factors that are similar to those of
bacterial pathogens
• Fungi initiate infections through the interaction of adhesins with receptors on host cells. Some fungi produce
toxins and exoenzymes involved in disease production and capsules that provide protection of phagocytosis.
• Protozoa adhere to target cells through complex mechanisms and can cause cellular damage through release
of cytopathic substances. Some protozoa avoid the immune system through antigenic variation and production
of capsules.
• Helminthic worms are able to avoid the immune system by coating their exteriors with glycan molecules that
make them look like host cells or by suppressing the immune system.

Review Questions
Multiple Choice 3. During an oral surgery, the surgeon nicked the
1. Which of the following would be a sign of an patient’s gum with a sharp instrument. This allowed
infection? Streptococcus, a bacterium normally present in the
a. muscle aches mouth, to gain access to the blood. As a result, the
b. headache patient developed bacterial endocarditis (an infection of
c. fever the heart). Which type of disease is this?
d. nausea a. iatrogenic
b. nosocomial
2. Which of the following is an example of a c. vectors
noncommunicable infectious disease? d. zoonotic
a. infection with a respiratory virus
b. food poisoning due to a preformed bacterial 4. Which period is the stage of disease during which the
toxin in food patient begins to present general signs and symptoms?
c. skin infection acquired from a dog bite a. convalescence
d. infection acquired from the stick of a b. incubation
contaminated needle c. illness
d. prodromal
700 Chapter 15 | Microbial Mechanisms of Pathogenicity

5. A communicable disease that can be easily 11. Which of the following applies to hyaluronidase?
transmitted from person to person is which type of a. It acts as a spreading factor.
disease? b. It promotes blood clotting.
a. contagious c. It is an example of an adhesin.
b. iatrogenic d. It is produced by immune cells to target
c. acute pathogens.
d. nosocomial
12. Phospholipases are enzymes that do which of the
6. Which of the following is a pathogen that could not following?
be identified by the original Koch’s postulates? a. degrade antibodies
a. Staphylococcus aureus b. promote pathogen spread through connective
b. Pseudomonas aeruginosa tissue.
c. Human immunodeficiency virus c. degrade nucleic acid to promote spread of
d. Salmonella enterica serovar Typhimurium pathogen
d. degrade cell membranes to allow pathogens to
7. Pathogen A has an ID50 of 50 particles, pathogen
escape phagosomes
B has an ID50 of 1,000 particles, and pathogen C has
an ID50 of 1 × 106 particles. Which pathogen is most 13. Which of the following is a major virulence factor
virulent? for the fungal pathogen Cryptococcus?
a. pathogen A a. hemolysin
b. pathogen B b. capsule
c. pathogen C c. collagenase
d. fimbriae
8. Which of the following choices lists the steps of
pathogenesis in the correct order? 14. Which of the following pathogens undergoes
a. invasion, infection, adhesion, exposure antigenic variation to avoid immune defenses?
b. adhesion, exposure, infection, invasion a. Candida
c. exposure, adhesion, invasion, infection b. Cryptococcus
d. disease, infection, exposure, invasion c. Plasmodium
d. Giardia
9. Which of the following would be a virulence factor
of a pathogen?
a. a surface protein allowing the pathogen to bind
to host cells
b. a secondary host the pathogen can infect
c. a surface protein the host immune system
recognizes
d. the ability to form a provirus

10. You have recently identified a new toxin. It is

produced by a gram-negative bacterium. It is composed
mostly of protein, has high toxicity, and is not heat
stable. You also discover that it targets liver cells. Based
on these characteristics, how would you classify this
toxin?
a. superantigen
b. endotoxin
c. exotoxin
d. leukocidin

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Chapter 15 | Microbial Mechanisms of Pathogenicity 701

Fill in the Blank

15. A difference between an acute disease and chronic disease is that chronic diseases have an extended period of
__________.

16. A person steps on a rusty nail and develops tetanus. In this case, the person has acquired a(n) __________
disease.

17. A(n) __________ pathogen causes disease only when conditions are favorable for the microorganism because of
transfer to an inappropriate body site or weakened immunity in an individual.

18. The concentration of pathogen needed to kill 50% of an infected group of test animals is the __________.

19. A(n) __________ infection is a small region of infection from which a pathogen may move to another part of
the body to establish a second infection.

20. Cilia, fimbriae, and pili are all examples of structures used by microbes for __________.

21. The glycoprotein adhesion gp120 on HIV must interact with __________ on some immune cells as the first step
in the process of infecting the cell.

22. Adhesins are usually located on __________ of the pathogen and are composed mainly of __________ and
__________.

23. The Shiga and diphtheria toxins target __________ in host cells.

24. Antigenic __________ is the result of reassortment of genes responsible for the production of influenza virus
spike proteins between different virus particles while in the same host, whereas antigenic __________ is the result of
point mutations in the spike proteins.

25. Candida can invade tissue by producing the exoenzymes __________ and __________.

26. The larval form of Schistosoma mansoni uses a __________ to help it gain entry through intact skin.

Short Answer
27. Brian goes to the hospital after not feeling well for a week. He has a fever of 38 °C (100.4 °F) and complains of
nausea and a constant migraine. Distinguish between the signs and symptoms of disease in Brian’s case.

28. Describe the virulence factors associated with the fungal pathogen Aspergillus.

29. Explain how helminths evade the immune system.

Critical Thinking
30. Two periods of acute disease are the periods of illness and period of decline. (a) In what way are both of these
periods similar? (b) In terms of quantity of pathogen, in what way are these periods different? (c) What initiates the
period of decline?

31. In July 2015, a report[12] was released indicating the gram-negative bacterium Pseudomonas aeruginosa was
found on hospital sinks 10 years after the initial outbreak in a neonatal intensive care unit. P. aeruginosa usually
causes localized ear and eye infections but can cause pneumonia or septicemia in vulnerable individuals like newborn
babies. Explain how the current discovery of the presence of this reported P. aeruginosa could lead to a recurrence of
nosocomial disease.

12. C. Owens. “P. aeruginosa survives in sinks 10 years after hospital outbreak.” 2015. http://www.healio.com/infectious-disease/
nosocomial-infections/news/online/%7B5afba909-56d9-48cc-a9b0-ffe4568161e8%7D/p-aeruginosa-survives-in-sinks-10-years-after-
hospital-outbreak
702 Chapter 15 | Microbial Mechanisms of Pathogenicity

32. Diseases that involve biofilm-producing bacteria are of serious concern. They are not as easily treated compared
with those involving free-floating (or planktonic) bacteria. Explain three reasons why biofilm formers are more
pathogenic.

33. A microbiologist has identified a new gram-negative pathogen that causes liver disease in rats. She suspects that
the bacterium’s fimbriae are a virulence factor. Describe how molecular Koch’s postulates could be used to test this
hypothesis.

34. Acupuncture is a form of alternative medicine that is used for pain relief. Explain how acupuncture could
facilitate exposure to pathogens.

35. Two types of toxins are hemolysins and leukocidins. (a) How are these toxins similar? (b) How do they differ?

36. Imagine that a mutation in the gene encoding the cholera toxin was made. This mutation affects the A-subunit,
preventing it from interacting with any host protein. (a) Would the toxin be able to enter into the intestinal epithelial
cell? (b) Would the toxin be able to cause diarrhea?

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Chapter 16 | Disease and Epidemiology 703

Chapter 16

Disease and Epidemiology

Figure 16.1 Signs like this may seem self-explanatory today, but a few short centuries ago, people lacked a basic
understanding of how diseases spread. Microbiology has greatly contributed to the field of epidemiology, which
focuses on containing the spread of disease. (credit: modification of work by Tony Webster)

Chapter Outline
16.1 The Language of Epidemiologists
16.2 Tracking Infectious Diseases
16.3 Modes of Disease Transmission
16.4 Global Public Health

Introduction
In the United States and other developed nations, public health is a key function of government. A healthy citizenry
is more productive, content, and prosperous; high rates of death and disease, on the other hand, can severely hamper
economic productivity and foster social and political instability. The burden of disease makes it difficult for citizens to
work consistently, maintain employment, and accumulate wealth to better their lives and support a growing economy.
In this chapter, we will explore the intersections between microbiology and epidemiology, the science that underlies
public health. Epidemiology studies how disease originates and spreads throughout a population, with the goal
of preventing outbreaks and containing them when they do occur. Over the past two centuries, discoveries in
epidemiology have led to public health policies that have transformed life in developed nations, leading to the
eradication (or near eradication) of many diseases that were once causes of great human suffering and premature
death. However, the work of epidemiologists is far from finished. Numerous diseases continue to plague humanity,
and new diseases are always emerging. Moreover, in the developing world, lack of infrastructure continues to pose
many challenges to efforts to contain disease.
704 Chapter 16 | Disease and Epidemiology

16.1 The Language of Epidemiologists

Learning Objectives
• Explain the difference between prevalence and incidence of disease
• Distinguish the characteristics of sporadic, endemic, epidemic, and pandemic diseases
• Explain the use of Koch’s postulates and their modifications to determine the etiology of disease
• Explain the relationship between epidemiology and public health
The field of epidemiology concerns the geographical distribution and timing of infectious disease occurrences
and how they are transmitted and maintained in nature, with the goal of recognizing and controlling outbreaks.
The science of epidemiology includes etiology (the study of the causes of disease) and investigation of disease
transmission (mechanisms by which a disease is spread).

Analyzing Disease in a Population

Epidemiological analyses are always carried out with reference to a population, which is the group of individuals that
are at risk for the disease or condition. The population can be defined geographically, but if only a portion of the
individuals in that area are susceptible, additional criteria may be required. Susceptible individuals may be defined by
particular behaviors, such as intravenous drug use, owning particular pets, or membership in an institution, such as a
college. Being able to define the population is important because most measures of interest in epidemiology are made
with reference to the size of the population.
The state of being diseased is called morbidity. Morbidity in a population can be expressed in a few different ways.
Morbidity or total morbidity is expressed in numbers of individuals without reference to the size of the population.
The morbidity rate can be expressed as the number of diseased individuals out of a standard number of individuals
in the population, such as 100,000, or as a percent of the population.
There are two aspects of morbidity that are relevant to an epidemiologist: a disease’s prevalence and its incidence.
Prevalence is the number, or proportion, of individuals with a particular illness in a given population at a point in
time. For example, the Centers for Disease Control and Prevention (CDC) estimated that in 2012, there were about
1.2 million people 13 years and older with an active human immunodeficiency virus (HIV) infection. Expressed as a
proportion, or rate, this is a prevalence of 467 infected persons per 100,000 in the population.[1] On the other hand,

Clinical Focus

Part 1
In late November and early December, a hospital in western Florida started to see a spike in the number
of cases of acute gastroenteritis-like symptoms. Patients began arriving at the emergency department
complaining of excessive bouts of emesis (vomiting) and diarrhea (with no blood in the stool). They also
complained of abdominal pain and cramping, and most were severely dehydrated. Alarmed by the number
of cases, hospital staff made some calls and learned that other regional hospitals were also seeing 10 to 20
similar cases per day.
• What are some possible causes of this outbreak?
• In what ways could these cases be linked, and how could any suspected links be confirmed?
Jump to the next Clinical Focus box.

1. H. Irene Hall, Qian An, Tian Tang, Ruiguang Song, Mi Chen, Timothy Green, and Jian Kang. “Prevalence of Diagnosed and

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Chapter 16 | Disease and Epidemiology 705

incidence is the number or proportion of new cases in a period of time. For the same year and population, the CDC
estimates that there were 43,165 newly diagnosed cases of HIV infection, which is an incidence of 13.7 new cases
per 100,000 in the population.[2] The relationship between incidence and prevalence can be seen in Figure 16.2.
For a chronic disease like HIV infection, prevalence will generally be higher than incidence because it represents the
cumulative number of new cases over many years minus the number of cases that are no longer active (e.g., because
the patient died or was cured).
In addition to morbidity rates, the incidence and prevalence of mortality (death) may also be reported. A mortality
rate can be expressed as the percentage of the population that has died from a disease or as the number of deaths per
100,000 persons (or other suitable standard number).

Figure 16.2 This graph compares the incidence of HIV (the number of new cases reported each year) with the
prevalence (the total number of cases each year). Prevalence and incidence can also be expressed as a rate or
proportion for a given population.

• Explain the difference between incidence and prevalence.

• Describe how morbidity and mortality rates are expressed.

Patterns of Incidence
Diseases that are seen only occasionally, and usually without geographic concentration, are called sporadic diseases.
Examples of sporadic diseases include tetanus, rabies, and plague. In the United States, Clostridium tetani, the
bacterium that causes tetanus, is ubiquitous in the soil environment, but incidences of infection occur only rarely and
in scattered locations because most individuals are vaccinated, clean wounds appropriately, or are only rarely in a
situation that would cause infection.[3] Likewise in the United States there are a few scattered cases of plague each
year, usually contracted from rodents in rural areas in the western states.[4]

Undiagnosed HIV Infection—United States, 2008–2012.” Morbidity and Mortality Weekly Report 64, no. 24 (2015): 657–662.
2. Centers for Disease Control and Prevention. “Diagnoses of HIV Infection in the United States and Dependent Areas, 2014.” HIV
Surveillance Report 26 (2015).
3. Centers for Disease Control and Prevention. “Tetanus Surveillance—United States, 2001–2008.” Morbidity and Mortality Weekly Report
60, no. 12 (2011): 365.
706 Chapter 16 | Disease and Epidemiology

Diseases that are constantly present (often at a low level) in a population within a particular geographic region are
called endemic diseases. For example, malaria is endemic to some regions of Brazil, but is not endemic to the United
States.
Diseases for which a larger than expected number of cases occurs in a short time within a geographic region are called
epidemic diseases. Influenza is a good example of a commonly epidemic disease. Incidence patterns of influenza
tend to rise each winter in the northern hemisphere. These seasonal increases are expected, so it would not be accurate
to say that influenza is epidemic every winter; however, some winters have an usually large number of seasonal
influenza cases in particular regions, and such situations would qualify as epidemics (Figure 16.3 and Figure 16.4).
An epidemic disease signals the breakdown of an equilibrium in disease frequency, often resulting from some change
in environmental conditions or in the population. In the case of influenza, the disruption can be due to antigenic shift
or drift (see Virulence Factors of Bacterial and Viral Pathogens), which allows influenza virus strains to
circumvent the acquired immunity of their human hosts.
An epidemic that occurs on a worldwide scale is called a pandemic disease. For example, HIV/AIDS is a pandemic
disease and novel influenza virus strains often become pandemic.

Figure 16.3 The 2007–2008 influenza season in the United States saw much higher than normal numbers of visits
to emergency departments for influenza-like symptoms as compared to the previous and the following years. (credit:
modification of work by Centers for Disease Control and Prevention)

4. Centers for Disease Control and Prevention. “Plague in the United States.” 2015. http://www.cdc.gov/plague/maps. Accessed June 1,
2016.

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Chapter 16 | Disease and Epidemiology 707

Figure 16.4 The seasonal epidemic threshold (blue curve) is set by the CDC-based data from the previous five
years. When actual mortality rates exceed this threshold, a disease is considered to be epidemic. As this graph
shows, pneumonia- and influenza-related mortality saw pronounced epidemics during the winters of 2003–2004,
2005, and 2008. (credit: modification of work by Centers for Disease Control and Prevention)

• Explain the difference between sporadic and endemic disease.

• Explain the difference between endemic and epidemic disease.

Clinical Focus

Part 2
Hospital physicians suspected that some type of food poisoning was to blame for the sudden post-
Thanksgiving outbreak of gastroenteritis in western Florida. Over a two-week period, 254 cases were
observed, but by the end of the first week of December, the epidemic ceased just as quickly as it had started.
Suspecting a link between the cases based on the localized nature of the outbreak, hospitals handed over their
medical records to the regional public health office for study.
Laboratory testing of stool samples had indicated that the infections were caused by Salmonella bacteria.
Patients ranged from children as young as three to seniors in their late eighties. Cases were nearly evenly
split between males and females. Across the region, there had been three confirmed deaths in the outbreak,
all due to severe dehydration. In each of the fatal cases, the patients had not sought medical care until their
symptoms were severe; also, all of the deceased had preexisting medical conditions such as congestive heart
failure, diabetes, or high blood pressure.
708 Chapter 16 | Disease and Epidemiology

After reviewing the medical records, epidemiologists with the public health office decided to conduct interviews
with a randomly selected sample of patients.
• What conclusions, if any, can be drawn from the medical records?
• What would epidemiologists hope to learn by interviewing patients? What kinds of questions might they
ask?
Jump to the next Clinical Focus box. Go back to the previous Clinical Focus box.

Etiology
When studying an epidemic, an epidemiologist’s first task is to determinate the cause of the disease, called the
etiologic agent or causative agent. Connecting a disease to a specific pathogen can be challenging because of the
extra effort typically required to demonstrate direct causation as opposed to a simple association. It is not enough to
observe an association between a disease and a suspected pathogen; controlled experiments are needed to eliminate
other possible causes. In addition, pathogens are typically difficult to detect when there is no immediate clue as to
what is causing the outbreak. Signs and symptoms of disease are also commonly nonspecific, meaning that many
different agents can give rise to the same set of signs and symptoms. This complicates diagnosis even when a
causative agent is familiar to scientists.
Robert Koch was the first scientist to specifically demonstrate the causative agent of a disease (anthrax) in the late
1800s. Koch developed four criteria, now known as Koch’s postulates, which had to be met in order to positively
link a disease with a pathogenic microbe. Without Koch’s postulates, the Golden Age of Microbiology would not
have occurred. Between 1876 and 1905, many common diseases were linked with their etiologic agents, including
cholera, diphtheria, gonorrhea, meningitis, plague, syphilis, tetanus, and tuberculosis. Today, we use the molecular
Koch’s postulates, a variation of Koch’s original postulates that can be used to establish a link between the disease
state and virulence traits unique to a pathogenic strain of a microbe. Koch’s original postulates and molecular Koch’s
postulates were described in more detail in How Pathogens Cause Disease.

• List some challenges to determining the causative agent of a disease outbreak.

The Role of Public Health Organizations

The main national public health agency in the United States is the Centers for Disease Control and Prevention
(CDC), an agency of the Department of Health and Human Services. The CDC is charged with protecting the public
from disease and injury. One way that the CDC carries out this mission is by overseeing the National Notifiable
Disease Surveillance System (NNDSS) in cooperation with regional, state, and territorial public health departments.
The NNDSS monitors diseases considered to be of public health importance on a national scale. Such diseases are
called notifiable diseases or reportable diseases because all cases must be reported to the CDC. A physician treating
a patient with a notifiable disease is legally required to submit a report on the case. Notifiable diseases include HIV
infection, measles, West Nile virus infections, and many others. Some states have their own lists of notifiable diseases
that include diseases beyond those on the CDC’s list.
Notifiable diseases are tracked by epidemiological studies and the data is used to inform health-care providers and
the public about possible risks. The CDC publishes the Morbidity and Mortality Weekly Report (MMWR), which
provides physicians and health-care workers with updates on public health issues and the latest data pertaining to
notifiable diseases. Table 16.1 is an example of the kind of data contained in the MMWR.

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Chapter 16 | Disease and Epidemiology 709

Incidence of Four Notifiable Diseases in the United States, Week Ending January 2, 2016
Disease Current Week Median of Maximum of Cumulative
(Jan 2, 2016) Previous 52 Previous 52 Weeks Cases 2015
Weeks

Campylobacteriosis 406 869 1,385 46,618

Chlamydia 11,024 28,562 31,089 1,425,303

trachomatis
infection

Giardiasis 115 230 335 11,870

Gonorrhea 3,207 7,155 8,283 369,926

Table 16.1

Link to Learning

The current Morbidity and Mortality Weekly Report (https://openstax.org/l/

22mortweekrep) is available online.

• Describe how health agencies obtain data about the incidence of diseases of public health importance.

16.2 Tracking Infectious Diseases

Learning Objectives
• Explain the research approaches used by the pioneers of epidemiology
• Explain how descriptive, analytical, and experimental epidemiological studies go about determining the cause of
morbidity and mortality
Epidemiology has its roots in the work of physicians who looked for patterns in disease occurrence as a way to
understand how to prevent it. The idea that disease could be transmitted was an important precursor to making sense
of some of the patterns. In 1546, Girolamo Fracastoro first proposed the germ theory of disease in his essay De
Contagione et Contagiosis Morbis, but this theory remained in competition with other theories, such as the miasma
hypothesis, for many years (see What Our Ancestors Knew). Uncertainty about the cause of disease was not
an absolute barrier to obtaining useful knowledge from patterns of disease. Some important researchers, such as
Florence Nightingale, subscribed to the miasma hypothesis. The transition to acceptance of the germ theory during
the 19th century provided a solid mechanistic grounding to the study of disease patterns. The studies of 19th century
physicians and researchers such as John Snow, Florence Nightingale, Ignaz Semmelweis, Joseph Lister, Robert Koch,
Louis Pasteur, and others sowed the seeds of modern epidemiology.
710 Chapter 16 | Disease and Epidemiology

Pioneers of Epidemiology
John Snow (Figure 16.5) was a British physician known as the father of epidemiology for determining the source
of the 1854 Broad Street cholera epidemic in London. Based on observations he had made during an earlier cholera
outbreak (1848–1849), Snow proposed that cholera was spread through a fecal-oral route of transmission and that
a microbe was the infectious agent. He investigated the 1854 cholera epidemic in two ways. First, suspecting that
contaminated water was the source of the epidemic, Snow identified the source of water for those infected. He found
a high frequency of cholera cases among individuals who obtained their water from the River Thames downstream
from London. This water contained the refuse and sewage from London and settlements upstream. He also noted
that brewery workers did not contract cholera and on investigation found the owners provided the workers with beer
to drink and stated that they likely did not drink water.[5] Second, he also painstakingly mapped the incidence of
cholera and found a high frequency among those individuals using a particular water pump located on Broad Street.
In response to Snow’s advice, local officials removed the pump’s handle,[6] resulting in the containment of the Broad
Street cholera epidemic.
Snow’s work represents an early epidemiological study and it resulted in the first known public health response to an
epidemic. Snow’s meticulous case-tracking methods are now common practice in studying disease outbreaks and in
associating new diseases with their causes. His work further shed light on unsanitary sewage practices and the effects
of waste dumping in the Thames. Additionally, his work supported the germ theory of disease, which argued disease
could be transmitted through contaminated items, including water contaminated with fecal matter.
Snow’s work illustrated what is referred to today as a common source spread of infectious disease, in which there is
a single source for all of the individuals infected. In this case, the single source was the contaminated well below the
Broad Street pump. Types of common source spread include point source spread, continuous common source spread,
and intermittent common source spread. In point source spread of infectious disease, the common source operates
for a short time period—less than the incubation period of the pathogen. An example of point source spread is a
single contaminated potato salad at a group picnic. In continuous common source spread, the infection occurs for an
extended period of time, longer than the incubation period. An example of continuous common source spread would
be the source of London water taken downstream of the city, which was continuously contaminated with sewage
from upstream. Finally, with intermittent common source spread, infections occur for a period, stop, and then begin
again. This might be seen in infections from a well that was contaminated only after large rainfalls and that cleared
itself of contamination after a short period.
In contrast to common source spread, propagated spread occurs through direct or indirect person-to-person contact.
With propagated spread, there is no single source for infection; each infected individual becomes a source for one or
more subsequent infections. With propagated spread, unless the spread is stopped immediately, infections occur for
longer than the incubation period. Although point sources often lead to large-scale but localized outbreaks of short
duration, propagated spread typically results in longer duration outbreaks that can vary from small to large, depending
on the population and the disease (Figure 16.6). In addition, because of person-to-person transmission, propagated
spread cannot be easily stopped at a single source like point source spread.

5. John Snow. On the Mode of Communication of Cholera. Second edition, Much Enlarged. John Churchill, 1855.
6. John Snow. “The Cholera near Golden-Wquare, and at Deptford.” Medical Times and Gazette 9 (1854): 321–322.
http://www.ph.ucla.edu/epi/snow/choleragoldensquare.html.

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Chapter 16 | Disease and Epidemiology 711

Figure 16.5 (a) John Snow (1813–1858), British physician and father of epidemiology. (b) Snow’s detailed mapping
of cholera incidence led to the discovery of the contaminated water pump on Broad street (red square) responsible
for the 1854 cholera epidemic. (credit a: modification of work by “Rsabbatini”/Wikimedia Commons)

Figure 16.6 (a) Outbreaks that can be attributed to point source spread often have a short duration. (b) Outbreaks
attributed to propagated spread can have a more extended duration. (credit a, b: modification of work by Centers for
Disease Control and Prevention)

Florence Nightingale’s work is another example of an early epidemiological study. In 1854, Nightingale was part
of a contingent of nurses dispatched by the British military to care for wounded soldiers during the Crimean War.
Nightingale kept meticulous records regarding the causes of illness and death during the war. Her recordkeeping was a
fundamental task of what would later become the science of epidemiology. Her analysis of the data she collected was
published in 1858. In this book, she presented monthly frequency data on causes of death in a wedge chart histogram
(Figure 16.7). This graphical presentation of data, unusual at the time, powerfully illustrated that the vast majority of
712 Chapter 16 | Disease and Epidemiology

casualties during the war occurred not due to wounds sustained in action but to what Nightingale deemed preventable
infectious diseases. Often these diseases occurred because of poor sanitation and lack of access to hospital facilities.
Nightingale’s findings led to many reforms in the British military’s system of medical care.
Joseph Lister provided early epidemiological evidence leading to good public health practices in clinics and hospitals.
These settings were notorious in the mid-1800s for fatal infections of surgical wounds at a time when the germ
theory of disease was not yet widely accepted (see Foundations of Modern Cell Theory). Most physicians did
not wash their hands between patient visits or clean and sterilize their surgical tools. Lister, however, discovered
the disinfecting properties of carbolic acid, also known as phenol (see Using Chemicals to Control
Microorganisms). He introduced several disinfection protocols that dramatically lowered post-surgical infection
rates.[7] He demanded that surgeons who worked for him use a 5% carbolic acid solution to clean their surgical
tools between patients, and even went so far as to spray the solution onto bandages and over the surgical site during
operations (Figure 16.8). He also took precautions not to introduce sources of infection from his skin or clothing by
removing his coat, rolling up his sleeves, and washing his hands in a dilute solution of carbolic acid before and during
the surgery.

Figure 16.7 (a) Florence Nightingale reported on the data she collected as a nurse in the Crimean War. (b)
Nightingale’s diagram shows the number of fatalities in soldiers by month of the conflict from various causes. The
total number dead in a particular month is equal to the area of the wedge for that month. The colored sections of the
wedge represent different causes of death: wounds (pink), preventable infectious diseases (gray), and all other
causes (brown).

7. O.M. Lidwell. “Joseph Lister and Infection from the Air.” Epidemiology and Infection 99 (1987): 569–578. http://www.ncbi.nlm.nih.gov/
pmc/articles/PMC2249236/pdf/epidinfect00006-0004.pdf.

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Chapter 16 | Disease and Epidemiology 713

Figure 16.8 Joseph Lister initiated the use of a carbolic acid (phenol) during surgeries. This illustration of a surgery
shows a pressurized canister of carbolic acid being sprayed over the surgical site.

Link to Learning

Visit the website (https://openstax.org/l/22theghostmap) for The Ghost Map,

a book about Snow’s work related to the Broad Street pump cholera outbreak.
John Snow’s own account of his work (https://openstax.org/l/
22JohnSnowacco) has additional links and information.
This CDC resource (https://openstax.org/l/22CDCpointsourc) further breaks down
the pattern expected from a point-source outbreak.
Learn more about Nightingale’s wedge chart (https://openstax.org/l/
22nightwedgecha) here.

• Explain the difference between common source spread and propagated spread of disease.
• Describe how the observations of John Snow, Florence Nightingale, and Joseph Lister led to improvements
in public health.

Types of Epidemiological Studies

Today, epidemiologists make use of study designs, the manner in which data are gathered to test a hypothesis,
similar to those of researchers studying other phenomena that occur in populations. These approaches can be divided
into observational studies (in which subjects are not manipulated) and experimental studies (in which subjects
are manipulated). Collectively, these studies give modern-day epidemiologists multiple tools for exploring the
connections between infectious diseases and the populations of susceptible individuals they might infect.

Observational Studies
In an observational study, data are gathered from study participants through measurements (such as physiological
variables like white blood cell count), or answers to questions in interviews (such as recent travel or exercise
714 Chapter 16 | Disease and Epidemiology

frequency). The subjects in an observational study are typically chosen at random from a population of affected or
unaffected individuals. However, the subjects in an observational study are in no way manipulated by the researcher.
Observational studies are typically easier to carry out than experimental studies, and in certain situations they may be
the only studies possible for ethical reasons.
Observational studies are only able to measure associations between disease occurrence and possible causative agents;
they do not necessarily prove a causal relationship. For example, suppose a study finds an association between heavy
coffee drinking and lower incidence of skin cancer. This might suggest that coffee prevents skin cancer, but there
may be another unmeasured factor involved, such as the amount of sun exposure the participants receive. If it turns
out that coffee drinkers work more in offices and spend less time outside in the sun than those who drink less coffee,
then it may be possible that the lower rate of skin cancer is due to less sun exposure, not to coffee consumption. The
observational study cannot distinguish between these two potential causes.
There are several useful approaches in observational studies. These include methods classified as descriptive
epidemiology and analytical epidemiology. Descriptive epidemiology gathers information about a disease outbreak,
the affected individuals, and how the disease has spread over time in an exploratory stage of study. This type of study
will involve interviews with patients, their contacts, and their family members; examination of samples and medical
records; and even histories of food and beverages consumed. Such a study might be conducted while the outbreak is
still occurring. Descriptive studies might form the basis for developing a hypothesis of causation that could be tested
by more rigorous observational and experimental studies.
Analytical epidemiology employs carefully selected groups of individuals in an attempt to more convincingly
evaluate hypotheses about potential causes for a disease outbreak. The selection of cases is generally made at random,
so the results are not biased because of some common characteristic of the study participants. Analytical studies
may gather their data by going back in time (retrospective studies), or as events unfold forward in time (prospective
studies).
Retrospective studies gather data from the past on present-day cases. Data can include things like the medical history,
age, gender, or occupational history of the affected individuals. This type of study examines associations between
factors chosen or available to the researcher and disease occurrence.
Prospective studies follow individuals and monitor their disease state during the course of the study. Data on the
characteristics of the study subjects and their environments are gathered at the beginning and during the study so that
subjects who become ill may be compared with those who do not. Again, the researchers can look for associations
between the disease state and variables that were measured during the study to shed light on possible causes.
Analytical studies incorporate groups into their designs to assist in teasing out associations with disease. Approaches
to group-based analytical studies include cohort studies, case-control studies, and cross-sectional studies. The cohort
method examines groups of individuals (called cohorts) who share a particular characteristic. For example, a cohort
might consist of individuals born in the same year and the same place; or it might consist of people who practice or
avoid a particular behavior, e.g., smokers or nonsmokers. In a cohort study, cohorts can be followed prospectively
or studied retrospectively. If only a single cohort is followed, then the affected individuals are compared with the
unaffected individuals in the same group. Disease outcomes are recorded and analyzed to try to identify correlations
between characteristics of individuals in the cohort and disease incidence. Cohort studies are a useful way to
determine the causes of a condition without violating the ethical prohibition of exposing subjects to a risk factor.
Cohorts are typically identified and defined based on suspected risk factors to which individuals have already been
exposed through their own choices or circumstances.
Case-control studies are typically retrospective and compare a group of individuals with a disease to a similar group
of individuals without the disease. Case-control studies are far more efficient than cohort studies because researchers
can deliberately select subjects who are already affected with the disease as opposed to waiting to see which subjects
from a random sample will develop a disease.
A cross-sectional study analyzes randomly selected individuals in a population and compares individuals affected
by a disease or condition to those unaffected at a single point in time. Subjects are compared to look for associations
between certain measurable variables and the disease or condition. Cross-sectional studies are also used to determine

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Chapter 16 | Disease and Epidemiology 715

the prevalence of a condition.

Experimental Studies
Experimental epidemiology uses laboratory or clinical studies in which the investigator manipulates the study
subjects to study the connections between diseases and potential causative agents or to assess treatments. Examples
of treatments might be the administration of a drug, the inclusion or exclusion of different dietary items, physical
exercise, or a particular surgical procedure. Animals or humans are used as test subjects. Because experimental
studies involve manipulation of subjects, they are typically more difficult and sometimes impossible for ethical
reasons.
Koch’s postulates require experimental interventions to determine the causative agent for a disease. Unlike
observational studies, experimental studies can provide strong evidence supporting cause because other factors are
typically held constant when the researcher manipulates the subject. The outcomes for one group receiving the
treatment are compared to outcomes for a group that does not receive the treatment but is treated the same in every
other way. For example, one group might receive a regimen of a drug administered as a pill, while the untreated group
receives a placebo (a pill that looks the same but has no active ingredient). Both groups are treated as similarly as
possible except for the administration of the drug. Because other variables are held constant in both the treated and
the untreated groups, the researcher is more certain that any change in the treated group is a result of the specific
manipulation.
Experimental studies provide the strongest evidence for the etiology of disease, but they must also be designed
carefully to eliminate subtle effects of bias. Typically, experimental studies with humans are conducted as double-
blind studies, meaning neither the subjects nor the researchers know who is a treatment case and who is not. This
design removes a well-known cause of bias in research called the placebo effect, in which knowledge of the treatment
by either the subject or the researcher can influence the outcomes.

• Describe the advantages and disadvantages of observational studies and experimental studies.
• Explain the ways that groups of subjects can be selected for analytical studies.

Clinical Focus

Part 3
Since laboratory tests had confirmed Salmonella, a common foodborne pathogen, as the etiologic agent,
epidemiologists suspected that the outbreak was caused by contamination at a food processing facility
serving the region. Interviews with patients focused on food consumption during and after the Thanksgiving
holiday, corresponding with the timing of the outbreak. During the interviews, patients were asked to list items
consumed at holiday gatherings and describe how widely each item was consumed among family members
and relatives. They were also asked about the sources of food items (e.g., brand, location of purchase, date
of purchase). By asking such questions, health officials hoped to identify patterns that would lead back to the
source of the outbreak.
Analysis of the interview responses eventually linked almost all of the cases to consumption of a holiday dish
known as the turducken—a chicken stuffed inside a duck stuffed inside a turkey. Turducken is a dish not
generally consumed year-round, which would explain the spike in cases just after the Thanksgiving holiday.
Additional analysis revealed that the turduckens consumed by the affected patients were purchased already
stuffed and ready to be cooked. Moreover, the pre-stuffed turduckens were all sold at the same regional
grocery chain under two different brand names. Upon further investigation, officials traced both brands to a
716 Chapter 16 | Disease and Epidemiology

single processing plant that supplied stores throughout the Florida panhandle.
• Is this an example of common source spread or propagated spread?
• What next steps would the public health office likely take after identifying the source of the outbreak?
Jump to the next Clinical Focus box. Go back to the previous Clinical Focus box.

16.3 Modes of Disease Transmission

Learning Objectives
• Describe the different types of disease reservoirs
• Compare contact, vector, and vehicle modes of transmission
• Identify important disease vectors
• Explain the prevalence of nosocomial infections
Understanding how infectious pathogens spread is critical to preventing infectious disease. Many pathogens require
a living host to survive, while others may be able to persist in a dormant state outside of a living host. But having
infected one host, all pathogens must also have a mechanism of transfer from one host to another or they will die
when their host dies. Pathogens often have elaborate adaptations to exploit host biology, behavior, and ecology to live
in and move between hosts. Hosts have evolved defenses against pathogens, but because their rates of evolution are
typically slower than their pathogens (because their generation times are longer), hosts are usually at an evolutionary
disadvantage. This section will explore where pathogens survive—both inside and outside hosts—and some of the
many ways they move from one host to another.

Reservoirs and Carriers

For pathogens to persist over long periods of time they require reservoirs where they normally reside. Reservoirs
can be living organisms or nonliving sites. Nonliving reservoirs can include soil and water in the environment. These
may naturally harbor the organism because it may grow in that environment. These environments may also become
contaminated with pathogens in human feces, pathogens shed by intermediate hosts, or pathogens contained in the
remains of intermediate hosts.
Pathogens may have mechanisms of dormancy or resilience that allow them to survive (but typically not to reproduce)
for varying periods of time in nonliving environments. For example, Clostridium tetani survives in the soil and in
the presence of oxygen as a resistant endospore. Although many viruses are soon destroyed once in contact with air,
water, or other non-physiological conditions, certain types are capable of persisting outside of a living cell for varying
amounts of time. For example, a study that looked at the ability of influenza viruses to infect a cell culture after
varying amounts of time on a banknote showed survival times from 48 hours to 17 days, depending on how they were
deposited on the banknote.[8] On the other hand, cold-causing rhinoviruses are somewhat fragile, typically surviving
less than a day outside of physiological fluids.
A human acting as a reservoir of a pathogen may or may not be capable of transmitting the pathogen, depending
on the stage of infection and the pathogen. To help prevent the spread of disease among school children, the CDC
has developed guidelines based on the risk of transmission during the course of the disease. For example, children
with chickenpox are considered contagious for five days from the start of the rash, whereas children with most
gastrointestinal illnesses should be kept home for 24 hours after the symptoms disappear.

8. Yves Thomas, Guido Vogel, Werner Wunderli, Patricia Suter, Mark Witschi, Daniel Koch, Caroline Tapparel, and Laurent Kaiser.
“Survival of Influenza Virus on Banknotes.” Applied and Environmental Microbiology 74, no. 10 (2008): 3002–3007.

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Chapter 16 | Disease and Epidemiology 717

An individual capable of transmitting a pathogen without displaying symptoms is referred to as a carrier. A passive
carrier is contaminated with the pathogen and can mechanically transmit it to another host; however, a passive carrier
is not infected. For example, a health-care professional who fails to wash his hands after seeing a patient harboring an
infectious agent could become a passive carrier, transmitting the pathogen to another patient who becomes infected.
By contrast, an active carrier is an infected individual who can transmit the disease to others. An active carrier
may or may not exhibit signs or symptoms of infection. For example, active carriers may transmit the disease during
the incubation period (before they show signs and symptoms) or the period of convalescence (after symptoms have
subsided). Active carriers who do not present signs or symptoms of disease despite infection are called asymptomatic
carriers. Pathogens such as hepatitis B virus, herpes simplex virus, and HIV are frequently transmitted by
asymptomatic carriers. Mary Mallon, better known as Typhoid Mary, is a famous historical example of an
asymptomatic carrier. An Irish immigrant, Mallon worked as a cook for households in and around New York City
between 1900 and 1915. In each household, the residents developed typhoid fever (caused by Salmonella typhi) a
few weeks after Mallon started working. Later investigations determined that Mallon was responsible for at least 122
cases of typhoid fever, five of which were fatal.[9] See Eye on Ethics: Typhoid Mary for more about the Mallon
case.
A pathogen may have more than one living reservoir. In zoonotic diseases, animals act as reservoirs of human disease
and transmit the infectious agent to humans through direct or indirect contact. In some cases, the disease also affects
the animal, but in other cases the animal is asymptomatic.
In parasitic infections, the parasite’s preferred host is called the definitive host. In parasites with complex life cycles,
the definitive host is the host in which the parasite reaches sexual maturity. Some parasites may also infect one
or more intermediate hosts in which the parasite goes through several immature life cycle stages or reproduces
asexually.

Link to Learning

George Soper, the sanitary engineer who traced the typhoid outbreak to Mary
Mallon, gives an account (https://openstax.org/l/22geosopcurtyp) of his
investigation, an example of descriptive epidemiology, in “The Curious Career of
Typhoid Mary.”

• List some nonliving reservoirs for pathogens.

• Explain the difference between a passive carrier and an active carrier.

Transmission
Regardless of the reservoir, transmission must occur for an infection to spread. First, transmission from the reservoir
to the individual must occur. Then, the individual must transmit the infectious agent to other susceptible individuals,
either directly or indirectly. Pathogenic microorganisms employ diverse transmission mechanisms.

9. Filio Marineli, Gregory Tsoucalas, Marianna Karamanou, and George Androutsos. “Mary Mallon (1869–1938) and the History of
Typhoid Fever.” Annals of Gastroenterology 26 (2013): 132–134. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3959940/pdf/
AnnGastroenterol-26-132.pdf.
718 Chapter 16 | Disease and Epidemiology

Contact Transmission
Contact transmission includes direct contact or indirect contact. Person-to-person transmission is a form of direct
contact transmission. Here the agent is transmitted by physical contact between two individuals (Figure 16.9)
through actions such as touching, kissing, sexual intercourse, or droplet sprays. Direct contact can be categorized
as vertical, horizontal, or droplet transmission. Vertical direct contact transmission occurs when pathogens are
transmitted from mother to child during pregnancy, birth, or breastfeeding. Other kinds of direct contact transmission
are called horizontal direct contact transmission. Often, contact between mucous membranes is required for entry
of the pathogen into the new host, although skin-to-skin contact can lead to mucous membrane contact if the new
host subsequently touches a mucous membrane. Contact transmission may also be site-specific; for example, some
diseases can be transmitted by sexual contact but not by other forms of contact.
When an individual coughs or sneezes, small droplets of mucus that may contain pathogens are ejected. This leads
to direct droplet transmission, which refers to droplet transmission of a pathogen to a new host over distances of
one meter or less. A wide variety of diseases are transmitted by droplets, including influenza and many forms of
pneumonia. Transmission over distances greater than one meter is called airborne transmission.
Indirect contact transmission involves inanimate objects called fomites that become contaminated by pathogens
from an infected individual or reservoir (Figure 16.10). For example, an individual with the common cold may
sneeze, causing droplets to land on a fomite such as a tablecloth or carpet, or the individual may wipe her nose and
then transfer mucus to a fomite such as a doorknob or towel. Transmission occurs indirectly when a new susceptible
host later touches the fomite and transfers the contaminated material to a susceptible portal of entry. Fomites can
also include objects used in clinical settings that are not properly sterilized, such as syringes, needles, catheters,
and surgical equipment. Pathogens transmitted indirectly via such fomites are a major cause of healthcare-associated
infections (see Controlling Microbial Growth).

Figure 16.9 Direct contact transmission of pathogens can occur through physical contact. Many pathogens require
contact with a mucous membrane to enter the body, but the host may transfer the pathogen from another point of
contact (e.g., hand) to a mucous membrane (e.g., mouth or eye). (credit left: modification of work by Lisa Doehnert)

Figure 16.10 Fomites are nonliving objects that facilitate the indirect transmission of pathogens. Contaminated
doorknobs, towels, and syringes are all common examples of fomites. (credit left: modification of work by Kate Ter
Haar; credit middle: modification of work by Vernon Swanepoel; credit right: modification of work by “Zaldylmg”/Flickr)

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Chapter 16 | Disease and Epidemiology 719

Vehicle Transmission
The term vehicle transmission refers to the transmission of pathogens through vehicles such as water, food, and
air. Water contamination through poor sanitation methods leads to waterborne transmission of disease. Waterborne
disease remains a serious problem in many regions throughout the world. The World Health Organization (WHO)
estimates that contaminated drinking water is responsible for more than 500,000 deaths each year.[10] Similarly, food
contaminated through poor handling or storage can lead to foodborne transmission of disease (Figure 16.11).
Dust and fine particles known as aerosols, which can float in the air, can carry pathogens and facilitate the airborne
transmission of disease. For example, dust particles are the dominant mode of transmission of hantavirus to humans.
Hantavirus is found in mouse feces, urine, and saliva, but when these substances dry, they can disintegrate into fine
particles that can become airborne when disturbed; inhalation of these particles can lead to a serious and sometimes
fatal respiratory infection.
Although droplet transmission over short distances is considered contact transmission as discussed above, longer
distance transmission of droplets through the air is considered vehicle transmission. Unlike larger particles that drop
quickly out of the air column, fine mucus droplets produced by coughs or sneezes can remain suspended for long
periods of time, traveling considerable distances. In certain conditions, droplets desiccate quickly to produce a droplet
nucleus that is capable of transmitting pathogens; air temperature and humidity can have an impact on effectiveness
of airborne transmission.
Tuberculosis is often transmitted via airborne transmission when the causative agent, Mycobacterium tuberculosis,
is released in small particles with coughs. Because tuberculosis requires as few as 10 microbes to initiate a new
infection, patients with tuberculosis must be treated in rooms equipped with special ventilation, and anyone entering
the room should wear a mask.

Figure 16.11 Food is an important vehicle of transmission for pathogens, especially of the gastrointestinal and
upper respiratory systems. Notice the glass shield above the food trays, designed to prevent pathogens ejected in
coughs and sneezes from entering the food. (credit: Fort George G. Meade Public Affairs Office)

Clinical Focus

Resolution
After identifying the source of the contaminated turduckens, the Florida public health office notified the CDC,
which requested an expedited inspection of the facility by state inspectors. Inspectors found that a machine
used to process the chicken was contaminated with Salmonella as a result of substandard cleaning protocols.
Inspectors also found that the process of stuffing and packaging the turduckens prior to refrigeration allowed
the meat to remain at temperatures conducive to bacterial growth for too long. The contamination and the

10. World Health Organization. Fact sheet No. 391—Drinking Water. June 2005. http://www.who.int/mediacentre/factsheets/fs391/en.
720 Chapter 16 | Disease and Epidemiology

delayed refrigeration led to vehicle (food) transmission of the bacteria in turduckens.

Based on these findings, the plant was shut down for a full and thorough decontamination. All turduckens
produced in the plant were recalled and pulled from store shelves ahead of the December holiday season,
preventing further outbreaks.
Go back to the previous Clinical Focus Box.

Vector Transmission
Diseases can also be transmitted by a mechanical or biological vector, an animal (typically an arthropod) that carries
the disease from one host to another. Mechanical transmission is facilitated by a mechanical vector, an animal that
carries a pathogen from one host to another without being infected itself. For example, a fly may land on fecal matter
and later transmit bacteria from the feces to food that it lands on; a human eating the food may then become infected
by the bacteria, resulting in a case of diarrhea or dysentery (Figure 16.12).
Biological transmission occurs when the pathogen reproduces within a biological vector that transmits the pathogen
from one host to another (Figure 16.12). Arthropods are the main vectors responsible for biological transmission
(Figure 16.13). Most arthropod vectors transmit the pathogen by biting the host, creating a wound that serves as
a portal of entry. The pathogen may go through part of its reproductive cycle in the gut or salivary glands of the
arthropod to facilitate its transmission through the bite. For example, hemipterans (called “kissing bugs” or “assassin
bugs”) transmit Chagas disease to humans by defecating when they bite, after which the human scratches or rubs the
infected feces into a mucous membrane or break in the skin.
Biological insect vectors include mosquitoes, which transmit malaria and other diseases, and lice, which transmit
typhus. Other arthropod vectors can include arachnids, primarily ticks, which transmit Lyme disease and other
diseases, and mites, which transmit scrub typhus and rickettsial pox. Biological transmission, because it involves
survival and reproduction within a parasitized vector, complicates the biology of the pathogen and its transmission.
There are also important non-arthropod vectors of disease, including mammals and birds. Various species of mammals
can transmit rabies to humans, usually by means of a bite that transmits the rabies virus. Chickens and other domestic
poultry can transmit avian influenza to humans through direct or indirect contact with avian influenza virus A shed in
the birds’ saliva, mucous, and feces.

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Chapter 16 | Disease and Epidemiology 721

Figure 16.12 (a) A mechanical vector carries a pathogen on its body from one host to another, not as an infection.
(b) A biological vector carries a pathogen from one host to another after becoming infected itself.
722 Chapter 16 | Disease and Epidemiology

Figure 16.13 (credit “Black fly”, “Tick”, “Tsetse fly”: modification of work by USDA; credit: “Flea”: modification of work
by Centers for Disease Control and Prevention; credit: “Louse”, “Mosquito”, “Sand fly”: modification of work by James
Gathany, Centers for Disease Control and Prevention; credit “Kissing bug”: modification of work by Glenn Seplak;
credit “Mite”: modification of work by Michael Wunderli)

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Chapter 16 | Disease and Epidemiology 723

• Describe how diseases can be transmitted through the air.

• Explain the difference between a mechanical vector and a biological vector.

Eye on Ethics

Using GMOs to Stop the Spread of Zika

In 2016, an epidemic of the Zika virus was linked to a high incidence of birth defects in South America and
Central America. As winter turned to spring in the northern hemisphere, health officials correctly predicted the
virus would spread to North America, coinciding with the breeding season of its major vector, the Aedes aegypti
mosquito.
The range of the A. aegypti mosquito extends well into the southern United States (Figure 16.14). Because
these same mosquitoes serve as vectors for other problematic diseases (dengue fever, yellow fever, and
others), various methods of mosquito control have been proposed as solutions. Chemical pesticides have
been used effectively in the past, and are likely to be used again; but because chemical pesticides can have
negative impacts on the environment, some scientists have proposed an alternative that involves genetically
engineering A. aegypti so that it cannot reproduce. This method, however, has been the subject of some
controversy.
One method that has worked in the past to control pests, with little apparent downside, has been sterile male
introductions. This method controlled the screw-worm fly pest in the southwest United States and fruit fly pests
of fruit crops. In this method, males of the target species are reared in the lab, sterilized with radiation, and
released into the environment where they mate with wild females, who subsequently bear no live offspring.
Repeated releases shrink the pest population.
A similar method, taking advantage of recombinant DNA technology,[11] introduces a dominant lethal allele
into male mosquitoes that is suppressed in the presence of tetracycline (an antibiotic) during laboratory
rearing. The males are released into the environment and mate with female mosquitoes. Unlike the sterile
male method, these matings produce offspring, but they die as larvae from the lethal gene in the absence of
tetracycline in the environment. As of 2016, this method has yet to be implemented in the United States, but
a UK company tested the method in Piracicaba, Brazil, and found an 82% reduction in wild A. aegypti larvae
and a 91% reduction in dengue cases in the treated area.[12] In August 2016, amid news of Zika infections
in several Florida communities, the FDA gave the UK company permission to test this same mosquito control
method in Key West, Florida, pending compliance with local and state regulations and a referendum in the
affected communities.
The use of genetically modified organisms (GMOs) to control a disease vector has its advocates as well
as its opponents. In theory, the system could be used to drive the A. aegypti mosquito extinct—a noble
goal according to some, given the damage they do to human populations.[13] But opponents of the idea are
concerned that the gene could escape the species boundary of A. aegypti and cause problems in other
species, leading to unforeseen ecological consequences. Opponents are also wary of the program because it
is being administered by a for-profit corporation, creating the potential for conflicts of interest that would have
to be tightly regulated; and it is not clear how any unintended consequences of the program could be reversed.
There are other epidemiological considerations as well. Aedes aegypti is apparently not the only vector for the
Zika virus. Aedes albopictus, the Asian tiger mosquito, is also a vector for the Zika virus.[14] A. albopictus is
now widespread around the planet including much of the United States (Figure 16.14). Many other mosquitoes
724 Chapter 16 | Disease and Epidemiology

have been found to harbor Zika virus, though their capacity to act as vectors is unknown.[15] Genetically
modified strains of A. aegypti will not control the other species of vectors. Finally, the Zika virus can apparently
be transmitted sexually between human hosts, from mother to child, and possibly through blood transfusion.
All of these factors must be considered in any approach to controlling the spread of the virus.
Clearly there are risks and unknowns involved in conducting an open-environment experiment of an as-yet
poorly understood technology. But allowing the Zika virus to spread unchecked is also risky. Does the threat
of a Zika epidemic justify the ecological risk of genetically engineering mosquitos? Are current methods of
mosquito control sufficiently ineffective or harmful that we need to try untested alternatives? These are the
questions being put to public health officials now.

Figure 16.14 The Zika virus is an enveloped virus transmitted by mosquitoes, especially Aedes aegypti. The
range of this mosquito includes much of the United States, from the Southwest and Southeast to as far north
as the Mid-Atlantic. The range of A. albopictus, another vector, extends even farther north to New England
and parts of the Midwest. (credit micrograph: modification of work by Cynthia Goldsmith, Centers for Disease
Control and Prevention; credit photo: modification of work by James Gathany, Centers for Disease Control
and Prevention; credit map: modification of work by Centers for Disease Control and Prevention)

Quarantining
Individuals suspected or known to have been exposed to certain contagious pathogens may be quarantined, or

11. Blandine Massonnet-Bruneel, Nicole Corre-Catelin, Renaud Lacroix, Rosemary S. Lees, Kim Phuc Hoang, Derric Nimmo, Luke
Alphey, and Paul Reiter. “Fitness of Transgenic Mosquito Aedes aegypti Males Carrying a Dominant Lethal Genetic System.” PLOS ONE 8,
no. 5 (2013): e62711.
12. Richard Levine. “Cases of Dengue Drop 91 Percent Due to Genetically Modified Mosquitoes.” Entomology Today.
https://entomologytoday.org/2016/07/14/cases-of-dengue-drop-91-due-to-genetically-modified-mosquitoes.
13. Olivia Judson. “A Bug’s Death.” The New York Times, September 25, 2003. http://www.nytimes.com/2003/09/25/opinion/a-bug-s-
death.html.
14. Gilda Grard, Mélanie Caron, Illich Manfred Mombo, Dieudonné Nkoghe, Statiana Mboui Ondo, Davy Jiolle, Didier Fontenille,
Christophe Paupy, and Eric Maurice Leroy. “Zika Virus in Gabon (Central Africa)–2007: A New Threat from Aedes albopictus?” PLOS
Neglected Tropical Diseases 8, no. 2 (2014): e2681.
15. Constância F.J. Ayres. “Identification of Zika Virus Vectors and Implications for Control.” The Lancet Infectious Diseases 16, no. 3
(2016): 278–279.

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Chapter 16 | Disease and Epidemiology 725

isolated to prevent transmission of the disease to others. Hospitals and other health-care facilities generally set up
special wards to isolate patients with particularly hazardous diseases such as tuberculosis or Ebola (Figure 16.15).
Depending on the setting, these wards may be equipped with special air-handling methods, and personnel may
implement special protocols to limit the risk of transmission, such as personal protective equipment or the use of
chemical disinfectant sprays upon entry and exit of medical personnel.
The duration of the quarantine depends on factors such as the incubation period of the disease and the evidence
suggestive of an infection. The patient may be released if signs and symptoms fail to materialize when expected or if
preventive treatment can be administered in order to limit the risk of transmission. If the infection is confirmed, the
patient may be compelled to remain in isolation until the disease is no longer considered contagious.
In the United States, public health authorities may only quarantine patients for certain diseases, such as cholera,
diphtheria, infectious tuberculosis, and strains of influenza capable of causing a pandemic. Individuals entering the
United States or moving between states may be quarantined by the CDC if they are suspected of having been exposed
to one of these diseases. Although the CDC routinely monitors entry points to the United States for crew or passengers
displaying illness, quarantine is rarely implemented.

Figure 16.15 (a) The Aeromedical Biological Containment System (ABCS) is a module designed by the CDC and
Department of Defense specifically for transporting highly contagious patients by air. (b) An isolation ward for Ebola
patients in Lagos, Nigeria. (credit a: modification of work by Centers for Disease Control and Prevention; credit b:
modification of work by CDC Global)

Healthcare-Associated (Nosocomial) Infections

Hospitals, retirement homes, and prisons attract the attention of epidemiologists because these settings are associated
with increased incidence of certain diseases. Higher rates of transmission may be caused by characteristics of the
environment itself, characteristics of the population, or both. Consequently, special efforts must be taken to limit the
risks of infection in these settings.
Infections acquired in health-care facilities, including hospitals, are called nosocomial infections or healthcare-
associated infections (HAI). HAIs are often connected with surgery or other invasive procedures that provide the
pathogen with access to the portal of infection. For an infection to be classified as an HAI, the patient must have
been admitted to the health-care facility for a reason other than the infection. In these settings, patients suffering from
primary disease are often afflicted with compromised immunity and are more susceptible to secondary infection and
opportunistic pathogens.
In 2011, more than 720,000 HAIs occurred in hospitals in the United States, according to the CDC. About 22%
of these HAIs occurred at a surgical site, and cases of pneumonia accounted for another 22%; urinary tract
infections accounted for an additional 13%, and primary bloodstream infections 10%.[16] Such HAIs often occur when

16. Centers for Disease Control and Prevention. “HAI Data and Statistics.” 2016. http://www.cdc.gov/hai/surveillance. Accessed Jan 2,
726 Chapter 16 | Disease and Epidemiology

pathogens are introduced to patients’ bodies through contaminated surgical or medical equipment, such as catheters
and respiratory ventilators. Health-care facilities seek to limit nosocomial infections through training and hygiene
protocols such as those described in Control of Microbial Growth.

• Give some reasons why HAIs occur.

16.4 Global Public Health

Learning Objectives
• Describe the entities involved in international public health and their activities
• Identify and differentiate between emerging and reemerging infectious diseases
A large number of international programs and agencies are involved in efforts to promote global public health. Among
their goals are developing infrastructure in health care, public sanitation, and public health capacity; monitoring
infectious disease occurrences around the world; coordinating communications between national public health
agencies in various countries; and coordinating international responses to major health crises. In large part, these
international efforts are necessary because disease-causing microorganisms know no national boundaries.

The World Health Organization (WHO)

International public health issues are coordinated by the World Health Organization (WHO), an agency of the
United Nations. Of its roughly $4 billion budget for 2015–16[17], about $1 billion was funded by member states
and the remaining $3 billion by voluntary contributions. In addition to monitoring and reporting on infectious
disease, WHO also develops and implements strategies for their control and prevention. WHO has had a number of
successful international public health campaigns. For example, its vaccination program against smallpox, begun in
the mid-1960s, resulted in the global eradication of the disease by 1980. WHO continues to be involved in infectious
disease control, primarily in the developing world, with programs targeting malaria, HIV/AIDS, and tuberculosis,
among others. It also runs programs to reduce illness and mortality that occur as a result of violence, accidents,
lifestyle-associated illnesses such as diabetes, and poor health-care infrastructure.
WHO maintains a global alert and response system that coordinates information from member nations. In the event
of a public health emergency or epidemic, it provides logistical support and coordinates international response to
the emergency. The United States contributes to this effort through the CDC. The CDC carries out international
monitoring and public health efforts, mainly in the service of protecting US public health in an increasingly connected
world. Similarly, the European Union maintains a Health Security Committee that monitors disease outbreaks within
its member countries and internationally, coordinating with WHO.

• Name the organizations that participate in international public health monitoring.

2016.
17. World Health Organization. “Programme Budget 2014–2015.” http://www.who.int/about/finances-accountability/budget/en.

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Chapter 16 | Disease and Epidemiology 727

Emerging and Reemerging Infectious Diseases

Both WHO and some national public health agencies such as the CDC monitor and prepare for emerging infectious
diseases. An emerging infectious disease is either new to the human population or has shown an increase in
prevalence in the previous twenty years. Whether the disease is new or conditions have changed to cause an increase
in frequency, its status as emerging implies the need to apply resources to understand and control its growing impact.
Emerging diseases may change their frequency gradually over time, or they may experience sudden epidemic growth.
The importance of vigilance was made clear during the Ebola hemorrhagic fever epidemic in western Africa through
2014–2015. Although health experts had been aware of the Ebola virus since the 1970s, an outbreak on such a large
scale had never happened before (Figure 16.16). Previous human epidemics had been small, isolated, and contained.
Indeed, the gorilla and chimpanzee populations of western Africa had suffered far worse from Ebola than the human
population. The pattern of small isolated human epidemics changed in 2014. Its high transmission rate, coupled with
cultural practices for treatment of the dead and perhaps its emergence in an urban setting, caused the disease to spread
rapidly, and thousands of people died. The international public health community responded with a large emergency
effort to treat patients and contain the epidemic.
Emerging diseases are found in all countries, both developed and developing (Table 16.2). Some nations are better
equipped to deal with them. National and international public health agencies watch for epidemics like the Ebola
outbreak in developing countries because those countries rarely have the health-care infrastructure and expertise to
deal with large outbreaks effectively. Even with the support of international agencies, the systems in western Africa
struggled to identify and care for the sick and control spread. In addition to the altruistic goal of saving lives and
assisting nations lacking in resources, the global nature of transportation means that an outbreak anywhere can spread
quickly to every corner of the planet. Managing an epidemic in one location—its source—is far easier than fighting
it on many fronts.
Ebola is not the only disease that needs to be monitored in the global environment. In 2015, WHO set priorities on
several emerging diseases that had a high probability of causing epidemics and that were poorly understood (and thus
urgently required research and development efforts).
A reemerging infectious disease is a disease that is increasing in frequency after a previous period of decline. Its
reemergence may be a result of changing conditions or old prevention regimes that are no longer working. Examples
of such diseases are drug-resistant forms of tuberculosis, bacterial pneumonia, and malaria. Drug-resistant strains
of the bacteria causing gonorrhea and syphilis are also becoming more widespread, raising concerns of untreatable
infections.
728 Chapter 16 | Disease and Epidemiology

Figure 16.16 Even before the Ebola epidemic of 2014–15, Ebola was considered an emerging disease because of
several smaller outbreaks between the mid-1990s and 2000s.

Some Emerging and Reemerging Infectious Diseases

Disease Pathogen Year Affected Regions Transmission
Discovered

AIDS HIV 1981 Worldwide Contact with infected

body fluids

Chikungunya Chikungunya 1952 Africa, Asia, India; spreading to Mosquito-borne

fever virus Europe and the Americas

Ebola virus Ebola virus 1976 Central and Western Africa Contact with infected
disease body fluids

H1N1 H1N1 virus 2009 Worldwide Droplet transmission

Influenza
(swine flu)

Lyme Borrelia 1981 Northern hemisphere From mammal

disease burgdorferi reservoirs to humans
bacterium by tick vectors

West Nile West Nile 1937 Africa, Australia, Canada to Mosquito-borne

virus disease virus Venezuela, Europe, Middle East,
Western Asia

Table 16.2

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Chapter 16 | Disease and Epidemiology 729

• Explain why it is important to monitor emerging infectious diseases.

• Explain how a bacterial disease could reemerge, even if it had previously been successfully treated and
controlled.

Micro Connections

SARS Outbreak and Identification

On November 16, 2002, the first case of a SARS outbreak was reported in Guangdong Province, China. The
patient exhibited influenza-like symptoms such as fever, cough, myalgia, sore throat, and shortness of breath.
As the number of cases grew, the Chinese government was reluctant to openly communicate information
about the epidemic with the World Health Organization (WHO) and the international community. The slow
reaction of Chinese public health officials to this new disease contributed to the spread of the epidemic
within and later outside China. In April 2003, the Chinese government finally responded with a huge public
health effort involving quarantines, medical checkpoints, and massive cleaning projects. Over 18,000 people
were quarantined in Beijing alone. Large funding initiatives were created to improve health-care facilities,
and dedicated outbreak teams were created to coordinate the response. By August 16, 2003, the last SARS
patients were released from a hospital in Beijing nine months after the first case was reported in China.
In the meantime, SARS spread to other countries on its way to becoming a global pandemic. Though the
infectious agent had yet to be identified, it was thought to be an influenza virus. The disease was named
SARS, an acronym for severe acute respiratory syndrome, until the etiologic agent could be identified. Travel
restrictions to Southeast Asia were enforced by many countries. By the end of the outbreak, there were
8,098 cases and 774 deaths worldwide. China and Hong Kong were hit hardest by the epidemic, but Taiwan,
Singapore, and Toronto, Canada, also saw significant numbers of cases.
Fortunately, timely public health responses in many countries effectively suppressed the outbreak and led to
its eventual containment. For example, the disease was introduced to Canada in February 2003 by an infected
traveler from Hong Kong, who died shortly after being hospitalized. By the end of March, hospital isolation
and home quarantine procedures were in place in the Toronto area, stringent anti-infection protocols were
introduced in hospitals, and the media were actively reporting on the disease. Public health officials tracked
down contacts of infected individuals and quarantined them. A total of 25,000 individuals were quarantined in
the city. Thanks to the vigorous response of the Canadian public health community, SARS was brought under
control in Toronto by June, a mere four months after it was introduced.
In 2003, WHO established a collaborative effort to identify the causative agent of SARS, which has now been
identified as a coronavirus that was associated with horseshoe bats. The genome of the SARS virus was
sequenced and published by researchers at the CDC and in Canada in May 2003, and in the same month
researchers in the Netherlands confirmed the etiology of the disease by fulfilling Koch’s postulates for the
SARS coronavirus. The last known case of SARS worldwide was reported in 2004.
730 Chapter 16 | Disease and Epidemiology

Link to Learning

This database (https://openstax.org/l/22dataoutinfdis) of reports chronicles

outbreaks of infectious disease around the world. It was on this system that the
first information about the SARS outbreak in China emerged.
The CDC publishes Emerging Infectious Diseases (https://openstax.org/l/
22CDCEmerinfdis) , a monthly journal available online.

Summary
16.1 The Language of Epidemiologists
• Epidemiology is the science underlying public health.
• Morbidity means being in a state of illness, whereas mortality refers to death; both morbidity rates and
mortality rates are of interest to epidemiologists.
• Incidence is the number of new cases (morbidity or mortality), usually expressed as a proportion, during a
specified time period; prevalence is the total number affected in the population, again usually expressed as a
proportion.
• Sporadic diseases only occur rarely and largely without a geographic focus. Endemic diseases occur at a
constant (and often low) level within a population. Epidemic diseases and pandemic diseases occur when an
outbreak occurs on a significantly larger than expected level, either locally or globally, respectively.
• Koch’s postulates specify the procedure for confirming a particular pathogen as the etiologic agent of a
particular disease. Koch’s postulates have limitations in application if the microbe cannot be isolated and
cultured or if there is no animal host for the microbe. In this case, molecular Koch’s postulates would be
utilized.
• In the United States, the Centers for Disease Control and Prevention monitors notifiable diseases and
publishes weekly updates in the Morbidity and Mortality Weekly Report.
16.2 Tracking Infectious Diseases
• Early pioneers of epidemiology such as John Snow, Florence Nightingale, and Joseph Lister, studied disease
at the population level and used data to disrupt disease transmission.
• Descriptive epidemiology studies rely on case analysis and patient histories to gain information about
outbreaks, frequently while they are still occurring.
• Retrospective epidemiology studies use historical data to identify associations with the disease state of
present cases. Prospective epidemiology studies gather data and follow cases to find associations with future
disease states.
• Analytical epidemiology studies are observational studies that are carefully designed to compare groups and
uncover associations between environmental or genetic factors and disease.
• Experimental epidemiology studies generate strong evidence of causation in disease or treatment by
manipulating subjects and comparing them with control subjects.
16.3 Modes of Disease Transmission
• Reservoirs of human disease can include the human and animal populations, soil, water, and inanimate
objects or materials.
• Contact transmission can be direct or indirect through physical contact with either an infected host (direct)
or contact with a fomite that an infected host has made contact with previously (indirect).
• Vector transmission occurs when a living organism carries an infectious agent on its body (mechanical) or as
an infection host itself (biological), to a new host.

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Chapter 16 | Disease and Epidemiology 731

• Vehicle transmission occurs when a substance, such as soil, water, or air, carries an infectious agent to a new
host.
• Healthcare-associated infections (HAI), or nosocomial infections, are acquired in a clinical setting.
Transmission is facilitated by medical interventions and the high concentration of susceptible,
immunocompromised individuals in clinical settings.
16.4 Global Public Health
• The World Health Organization (WHO) is an agency of the United Nations that collects and analyzes data
on disease occurrence from member nations. WHO also coordinates public health programs and responses to
international health emergencies.
• Emerging diseases are those that are new to human populations or that have been increasing in the past
two decades. Reemerging diseases are those that are making a resurgence in susceptible populations after
previously having been controlled in some geographic areas.

Review Questions
Multiple Choice 5. Which of the following would NOT be considered
1. Which is the most common type of biological vector an emerging disease?
of human disease? a. Ebola hemorrhagic fever
a. viruses b. West Nile virus fever/encephalitis
b. bacteria c. Zika virus disease
c. mammals d. Tuberculosis
d. arthropods 6. Which of the following would NOT be considered a
2. A mosquito bites a person who subsequently reemerging disease?
develops a fever and abdominal rash. What type of a. Drug-resistant tuberculosis
transmission would this be? b. Drug-resistant gonorrhea
a. mechanical vector transmission c. Malaria
b. biological vector transmission d. West Nile virus fever/encephalitis
c. direct contact transmission 7. Which of the following factors can lead to
d. vehicle transmission reemergence of a disease?
3. Cattle are allowed to pasture in a field that contains a. A mutation that allows it to infect humans
the farmhouse well, and the farmer’s family becomes ill b. A period of decline in vaccination rates
with a gastrointestinal pathogen after drinking the water. c. A change in disease reporting procedures
What type of transmission of infectious agents would d. Better education on the signs and symptoms of
this be? the disease
a. biological vector transmission 8. Why are emerging diseases with very few cases the
b. direct contact transmission focus of intense scrutiny?
c. indirect contact transmission a. They tend to be more deadly
d. vehicle transmission b. They are increasing and therefore not controlled
4. A blanket from a child with chickenpox is likely to c. They naturally have higher transmission rates
be contaminated with the virus that causes chickenpox d. They occur more in developed countries
(Varicella-zoster virus). What is the blanket called?
a. fomite
b. host
c. pathogen
d. vector
732 Chapter 16 | Disease and Epidemiology

Matching
9. Match each term with its description.
___sporadic disease A. the number of disease cases per 100,000 individuals

___endemic disease B. a disease in higher than expected numbers around the world

___pandemic disease C. the number of deaths from a disease for every 10,000 individuals

___morbidity rate D. a disease found occasionally in a region with cases occurring mainly in isolation from
each other

___mortality rate E. a disease found regularly in a region

10. Match each type of epidemiology study with its description.

___experimental A. examination of past case histories and medical test results conducted on patients in an
outbreak

___analytical B. examination of current case histories, interviews with patients and their contacts,
interpretation of medical test results; frequently conducted while outbreak is still in progress

___prospective C. use of a set of test subjects (human or animal) and control subjects that are treated the
same as the test subjects except for the specific treatment being studied

___descriptive D. observing groups of individuals to look for associations with disease

___retrospective E. a comparison of a cohort of individuals through the course of the study

11. Match each pioneer of epidemiology with his or her contribution.

___Florence Nightingale A. determined the source of a cholera outbreak in London

___Robert Koch B. showed that surgical wound infection rates could be dramatically reduced by using
carbolic acid to disinfect surgical tools, bandages, and surgical sites

___Joseph Lister C. compiled data on causes of mortality in soldiers, leading to innovations in military
medical care

___John Snow D. developed a methodology for conclusively determining the etiology of disease

Fill in the Blank

12. The ________ collects data and conducts epidemiologic studies in the United States.

13. ________occurs when an infected individual passes the infection on to other individuals, who pass it on to still
others, increasing the penetration of the infection into the susceptible population.

14. A batch of food contaminated with botulism exotoxin, consumed at a family reunion by most of the members of
a family, would be an example of a ________ outbreak.

15. A patient in the hospital with a urinary catheter develops a bladder infection. This is an example of a(n)
________ infection.

16. A ________ is an animal that can transfer infectious pathogens from one host to another.

17. The ________ collects data and conducts epidemiologic studies at the global level.

Short Answer
18. During an epidemic, why might the prevalence of a disease at a particular time not be equal to the sum of the
incidences of the disease?

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Chapter 16 | Disease and Epidemiology 733

19. In what publication would you find data on emerging/reemerging diseases in the United States?

20. What activity did John Snow conduct, other than mapping, that contemporary epidemiologists also use when
trying to understand how to control a disease?

21. Differentiate between droplet vehicle transmission and airborne transmission.

Critical Thinking
22. Why might an epidemiological population in a state not be the same size as the number of people in a state? Use
an example.

23. Many people find that they become ill with a cold after traveling by airplane. The air circulation systems of
commercial aircraft use HEPA filters that should remove any infectious agents that pass through them. What are the
possible reasons for increased incidence of colds after flights?

24. An Atlantic crossing by boat from England to New England took 60–80 days in the 18th century. In the late 19th
century the voyage took less than a week. How do you think these time differences for travel might have impacted
the spread of infectious diseases from Europe to the Americas, or vice versa?
734 Chapter 16 | Disease and Epidemiology

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Chapter 17 | Innate Nonspecific Host Defenses 735

Chapter 17

Innate Nonspecific Host Defenses

Figure 17.1 Varicella, or chickenpox, is caused by the highly contagious varicella-zoster virus. The characteristic
rash seen here is partly a result of inflammation associated with the body’s immune response to the virus.
Inflammation is a response mechanism of innate immunity that helps the body fight off a wide range of infections.
(credit: modification of work by Centers for Disease Control and Prevention)

Chapter Outline
17.1 Physical Defenses
17.2 Chemical Defenses
17.3 Cellular Defenses
17.4 Pathogen Recognition and Phagocytosis
17.5 Inflammation and Fever

Introduction
Despite relatively constant exposure to pathogenic microbes in the environment, humans do not generally suffer from
constant infection or disease. Under most circumstances, the body is able to defend itself from the threat of infection
thanks to a complex immune system designed to repel, kill, and expel disease-causing invaders. Immunity as a whole
can be described as two interrelated parts: nonspecific innate immunity, which is the subject of this chapter, and
specific adaptive host defenses, which are discussed in the next chapter.
The nonspecific innate immune response provides a first line of defense that can often prevent infections from gaining
a solid foothold in the body. These defenses are described as nonspecific because they do not target any specific
pathogen; rather, they defend against a wide range of potential pathogens. They are called innate because they are
built-in mechanisms of the human organism. Unlike the specific adaptive defenses, they are not acquired over time
and they have no “memory” (they do not improve after repeated exposures to specific pathogens).
Broadly speaking, nonspecific innate defenses provide an immediate (or very rapid) response against potential
pathogens. However, these responses are neither perfect nor impenetrable. They can be circumvented by pathogens
on occasion, and sometimes they can even cause damage to the body, contributing to the signs and symptoms of
736 Chapter 17 | Innate Nonspecific Host Defenses

infection (Figure 17.1).

17.1 Physical Defenses

Learning Objectives
• Describe the various physical barriers and mechanical defenses that protect the human body against infection
and disease
• Describe the role of microbiota as a first-line defense against infection and disease
Nonspecific innate immunity can be characterized as a multifaceted system of defenses that targets invading
pathogens in a nonspecific manner. In this chapter, we have divided the numerous defenses that make up this system
into three categories: physical defenses, chemical defenses, and cellular defenses. However, it is important to keep
in mind that these defenses do not function independently, and the categories often overlap. Table 17.1 provides an
overview of the nonspecific defenses discussed in this chapter.

Overview of Nonspecific Innate Immune Defenses

Physical barriers

Physical defenses Mechanical defenses

Microbiome

Chemicals and enzymes in body fluids

Antimicrobial peptides

Chemical defenses Plasma protein mediators

Cytokines

Inflammation-eliciting mediators

Granulocytes
Cellular defenses
Agranulocytes

Table 17.1

Physical defenses provide the body’s most basic form of nonspecific defense. They include physical barriers to

Clinical Focus

Part 1
Angela, a 25-year-old female patient in the emergency department, is having some trouble communicating
verbally because of shortness of breath. A nurse observes constriction and swelling of the airway and labored
breathing. The nurse asks Angela if she has a history of asthma or allergies. Angela shakes her head no, but
there is fear in her eyes. With some difficulty, she explains that her father died suddenly at age 27, when she
was just a little girl, of a similar respiratory attack. The underlying cause had never been identified.
• What are some possible causes of constriction and swelling of the airway?
• What causes swelling of body tissues in general?
Jump to the next Clinical Focus box.

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Chapter 17 | Innate Nonspecific Host Defenses 737

microbes, such as the skin and mucous membranes, as well as mechanical defenses that physically remove microbes
and debris from areas of the body where they might cause harm or infection. In addition, the microbiome provides
a measure of physical protection against disease, as microbes of the normal microbiota compete with pathogens for
nutrients and cellular binding sites necessary to cause infection.

Physical Barriers
Physical barriers play an important role in preventing microbes from reaching tissues that are susceptible to infection.
At the cellular level, barriers consist of cells that are tightly joined to prevent invaders from crossing through to
deeper tissue. For example, the endothelial cells that line blood vessels have very tight cell-to-cell junctions, blocking
microbes from gaining access to the bloodstream. Cell junctions are generally composed of cell membrane proteins
that may connect with the extracellular matrix or with complementary proteins from neighboring cells. Tissues in
various parts of the body have different types of cell junctions. These include tight junctions, desmosomes, and
gap junctions, as illustrated in Figure 17.2. Invading microorganisms may attempt to break down these substances
chemically, using enzymes such as proteases that can cause structural damage to create a point of entry for pathogens.

Figure 17.2 There are multiple types of cell junctions in human tissue, three of which are shown here. Tight
junctions rivet two adjacent cells together, preventing or limiting material exchange through the spaces between
them. Desmosomes have intermediate fibers that act like shoelaces, tying two cells together, allowing small materials
to pass through the resulting spaces. Gap junctions are channels between two cells that permit their communication
via signals. (credit: modification of work by Mariana Ruiz Villareal)

The Skin Barrier

One of the body’s most important physical barriers is the skin barrier, which is composed of three layers of closely
packed cells. The thin upper layer is called the epidermis. A second, thicker layer, called the dermis, contains hair
follicles, sweat glands, nerves, and blood vessels. A layer of fatty tissue called the hypodermis lies beneath the dermis
and contains blood and lymph vessels (Figure 17.3).
738 Chapter 17 | Innate Nonspecific Host Defenses

Figure 17.3 Human skin has three layers, the epidermis, the dermis, and the hypodermis, which provide a thick
barrier between microbes outside the body and deeper tissues. Dead skin cells on the surface of the epidermis are
continually shed, taking with them microbes on the skin’s surface. (credit: modification of work by National Institutes
of Health)

The topmost layer of skin, the epidermis, consists of cells that are packed with keratin. These dead cells remain as
a tightly connected, dense layer of protein-filled cell husks on the surface of the skin. The keratin makes the skin’s
surface mechanically tough and resistant to degradation by bacterial enzymes. Fatty acids on the skin’s surface create
a dry, salty, and acidic environment that inhibits the growth of some microbes and is highly resistant to breakdown by
bacterial enzymes. In addition, the dead cells of the epidermis are frequently shed, along with any microbes that may
be clinging to them. Shed skin cells are continually replaced with new cells from below, providing a new barrier that
will soon be shed in the same way.
Infections can occur when the skin barrier is compromised or broken. A wound can serve as a point of entry for
opportunistic pathogens, which can infect the skin tissue surrounding the wound and possibly spread to deeper tissues.

Case in Point

Every Rose Has its Thorn

Mike, a gardener from southern California, recently noticed a small red bump on his left forearm. Initially, he
did not think much of it, but soon it grew larger and then ulcerated (opened up), becoming a painful lesion that
extended across a large part of his forearm (Figure 17.4). He went to an urgent care facility, where a physician
asked about his occupation. When he said he was a landscaper, the physician immediately suspected a
case of sporotrichosis, a type of fungal infection known as rose gardener’s disease because it often afflicts
landscapers and gardening enthusiasts.
Under most conditions, fungi cannot produce skin infections in healthy individuals. Fungi grow filaments known
as hyphae, which are not particularly invasive and can be easily kept at bay by the physical barriers of the skin
and mucous membranes. However, small wounds in the skin, such as those caused by thorns, can provide an
opening for opportunistic pathogens like Sporothrix schenkii, a soil-dwelling fungus and the causative agent
of rose gardener’s disease. Once it breaches the skin barrier, S. schenkii can infect the skin and underlying
tissues, producing ulcerated lesions like Mike’s. Compounding matters, other pathogens may enter the infected

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Chapter 17 | Innate Nonspecific Host Defenses 739

tissue, causing secondary bacterial infections.

Luckily, rose gardener’s disease is treatable. Mike’s physician wrote him a prescription for some antifungal
drugs as well as a course of antibiotics to combat secondary bacterial infections. His lesions eventually healed,
and Mike returned to work with a new appreciation for gloves and protective clothing.

Figure 17.4 Rose gardener’s disease can occur when the fungus Sporothrix schenkii breaches the skin
through small cuts, such as might be inflicted by thorns. (credit left: modification of work by Elisa Self; credit
right: modification of work by Centers for Disease Control and Prevention)

Mucous Membranes
The mucous membranes lining the nose, mouth, lungs, and urinary and digestive tracts provide another nonspecific
barrier against potential pathogens. Mucous membranes consist of a layer of epithelial cells bound by tight junctions.
The epithelial cells secrete a moist, sticky substance called mucus, which covers and protects the more fragile
cell layers beneath it and traps debris and particulate matter, including microbes. Mucus secretions also contain
antimicrobial peptides.
In many regions of the body, mechanical actions serve to flush mucus (along with trapped or dead microbes) out of the
body or away from potential sites of infection. For example, in the respiratory system, inhalation can bring microbes,
dust, mold spores, and other small airborne debris into the body. This debris becomes trapped in the mucus lining the
respiratory tract, a layer known as the mucociliary blanket. The epithelial cells lining the upper parts of the respiratory
tract are called ciliated epithelial cells because they have hair-like appendages known as cilia. Movement of the cilia
propels debris-laden mucus out and away from the lungs. The expelled mucus is then swallowed and destroyed in
the stomach, or coughed up, or sneezed out (Figure 17.5). This system of removal is often called the mucociliary
escalator.
740 Chapter 17 | Innate Nonspecific Host Defenses

Figure 17.5 This scanning electron micrograph shows ciliated and nonciliated epithelial cells from the human
trachea. The mucociliary escalator pushes mucus away from the lungs, along with any debris or microorganisms that
may be trapped in the sticky mucus, and the mucus moves up to the esophagus where it can be removed by
swallowing.

The mucociliary escalator is such an effective barrier to microbes that the lungs, the lowermost (and most sensitive)
portion of the respiratory tract, were long considered to be a sterile environment in healthy individuals. Only recently
has research suggested that healthy lungs may have a small normal microbiota. Disruption of the mucociliary
escalator by the damaging effects of smoking or diseases such as cystic fibrosis can lead to increased colonization of
bacteria in the lower respiratory tract and frequent infections, which highlights the importance of this physical barrier
to host defenses.
Like the respiratory tract, the digestive tract is a portal of entry through which microbes enter the body, and the
mucous membranes lining the digestive tract provide a nonspecific physical barrier against ingested microbes. The
intestinal tract is lined with epithelial cells, interspersed with mucus-secreting goblet cells (Figure 17.6). This mucus
mixes with material received from the stomach, trapping foodborne microbes and debris. The mechanical action of
peristalsis, a series of muscular contractions in the digestive tract, moves the sloughed mucus and other material
through the intestines, rectum, and anus, excreting the material in feces.

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Chapter 17 | Innate Nonspecific Host Defenses 741

Figure 17.6 Goblet cells produce and secrete mucus. The arrows in this micrograph point to the mucus-secreting
goblet cells (magnification 1600⨯) in the intestinal epithelium. (credit micrograph: Micrograph provided by the
Regents of University of Michigan Medical School © 2012)

Endothelia
The epithelial cells lining the urogenital tract, blood vessels, lymphatic vessels, and certain other tissues are known
as endothelia. These tightly packed cells provide a particularly effective frontline barrier against invaders. The
endothelia of the blood-brain barrier, for example, protect the central nervous system (CNS), which consists of
the brain and the spinal cord. The CNS is one of the most sensitive and important areas of the body, as microbial
infection of the CNS can quickly lead to serious and often fatal inflammation. The cell junctions in the blood vessels
traveling through the CNS are some of the tightest and toughest in the body, preventing any transient microbes in the
bloodstream from entering the CNS. This keeps the cerebrospinal fluid that surrounds and bathes the brain and spinal
cord sterile under normal conditions.

• Describe how the mucociliary escalator functions.

• Name two places you would find endothelia.

Mechanical Defenses
In addition to physical barriers that keep microbes out, the body has a number of mechanical defenses that physically
remove pathogens from the body, preventing them from taking up residence. We have already discussed several
examples of mechanical defenses, including the shedding of skin cells, the expulsion of mucus via the mucociliary
escalator, and the excretion of feces through intestinal peristalsis. Other important examples of mechanical defenses
include the flushing action of urine and tears, which both serve to carry microbes away from the body. The flushing
action of urine is largely responsible for the normally sterile environment of the urinary tract, which includes the
742 Chapter 17 | Innate Nonspecific Host Defenses

kidneys, ureters, and urinary bladder. Urine passing out of the body washes out transient microorganisms, preventing
them from taking up residence. The eyes also have physical barriers and mechanical mechanisms for preventing
infections. The eyelashes and eyelids prevent dust and airborne microorganisms from reaching the surface of the eye.
Any microbes or debris that make it past these physical barriers may be flushed out by the mechanical action of
blinking, which bathes the eye in tears, washing debris away (Figure 17.7).

Figure 17.7 Tears flush microbes away from the surface of the eye. Urine washes microbes out of the urinary tract
as it passes through; as a result, the urinary system is normally sterile.

• Name two mechanical defenses that protect the eyes.

Microbiome
In various regions of the body, resident microbiota serve as an important first-line defense against invading pathogens.
Through their occupation of cellular binding sites and competition for available nutrients, the resident microbiota
prevent the critical early steps of pathogen attachment and proliferation required for the establishment of an infection.
For example, in the vagina, members of the resident microbiota compete with opportunistic pathogens like the yeast
Candida. This competition prevents infections by limiting the availability of nutrients, thus inhibiting the growth of
Candida, keeping its population in check. Similar competitions occur between the microbiota and potential pathogens
on the skin, in the upper respiratory tract, and in the gastrointestinal tract. As will be discussed later in this chapter,
the resident microbiota also contribute to the chemical defenses of the innate nonspecific host defenses.

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Chapter 17 | Innate Nonspecific Host Defenses 743

The importance of the normal microbiota in host defenses is highlighted by the increased susceptibility to infectious
diseases when the microbiota is disrupted or eliminated. Treatment with antibiotics can significantly deplete the
normal microbiota of the gastrointestinal tract, providing an advantage for pathogenic bacteria to colonize and cause
diarrheal infection. In the case of diarrhea caused by Clostridium difficile, the infection can be severe and potentially
lethal. One strategy for treating C. difficile infections is fecal transplantation, which involves the transfer of fecal
material from a donor (screened for potential pathogens) into the intestines of the recipient patient as a method of
restoring the normal microbiota and combating C. difficile infections.
Table 17.2 provides a summary of the physical defenses discussed in this section.

Physical Defenses of Nonspecific Innate Immunity

Defense Examples Function

Cellular Skin, mucous membranes, endothelial cells Deny entry to pathogens

barriers

Mechanical Shedding of skin cells, mucociliary sweeping, peristalsis, Remove pathogens from potential
defenses flushing action of urine and tears sites of infection

Microbiome Resident bacteria of the skin, upper respiratory tract, Compete with pathogens for cellular
gastrointestinal tract, and genitourinary tract binding sites and nutrients

Table 17.2

• List two ways resident microbiota defend against pathogens.

17.2 Chemical Defenses

Learning Objectives
• Describe how enzymes in body fluids provide protection against infection or disease
• List and describe the function of antimicrobial peptides, complement components, cytokines, and acute-phase
proteins
• Describe similarities and differences among classic, alternate, and lectin complement pathways
In addition to physical defenses, the innate nonspecific immune system uses a number of chemical mediators that
inhibit microbial invaders. The term “chemical mediators” encompasses a wide array of substances found in various
body fluids and tissues throughout the body. Chemical mediators may work alone or in conjunction with each other
to inhibit microbial colonization and infection.
Some chemical mediators are endogenously produced, meaning they are produced by human body cells; others are
produced exogenously, meaning that they are produced by certain microbes that are part of the microbiome. Some
mediators are produced continually, bathing the area in the antimicrobial substance; others are produced or activated
primarily in response to some stimulus, such as the presence of microbes.

Chemical and Enzymatic Mediators Found in Body Fluids

Fluids produced by the skin include examples of both endogenous and exogenous mediators. Sebaceous glands in
the dermis secrete an oil called sebum that is released onto the skin surface through hair follicles. This sebum is
744 Chapter 17 | Innate Nonspecific Host Defenses

an endogenous mediator, providing an additional layer of defense by helping seal off the pore of the hair follicle,
preventing bacteria on the skin’s surface from invading sweat glands and surrounding tissue (Figure 17.8). Certain
members of the microbiome, such as the bacterium Propionibacterium acnes and the fungus Malassezia, among
others, can use lipase enzymes to degrade sebum, using it as a food source. This produces oleic acid, which creates
a mildly acidic environment on the surface of the skin that is inhospitable to many pathogenic microbes. Oleic acid
is an example of an exogenously produced mediator because it is produced by resident microbes and not directly by
body cells.

Figure 17.8 Sebaceous glands secrete sebum, a chemical mediator that lubricates and protect the skin from
invading microbes. Sebum is also a food source for resident microbes that produce oleic acid, an exogenously
produced mediator. (credit micrograph: Micrograph provided by the Regents of University of Michigan Medical School
© 2012)

Environmental factors that affect the microbiota of the skin can have a direct impact on the production of chemical
mediators. Low humidity or decreased sebum production, for example, could make the skin less habitable for
microbes that produce oleic acid, thus making the skin more susceptible to pathogens normally inhibited by the skin’s
low pH. Many skin moisturizers are formulated to counter such effects by restoring moisture and essential oils to the
skin.
The digestive tract also produces a large number of chemical mediators that inhibit or kill microbes. In the oral
cavity, saliva contains mediators such as lactoperoxidase enzymes, and mucus secreted by the esophagus contains
the antibacterial enzyme lysozyme. In the stomach, highly acidic gastric fluid kills most microbes. In the lower
digestive tract, the intestines have pancreatic and intestinal enzymes, antibacterial peptides (cryptins), bile produced
from the liver, and specialized Paneth cells that produce lysozyme. Together, these mediators are able to eliminate
most pathogens that manage to survive the acidic environment of the stomach.
In the urinary tract, urine flushes microbes out of the body during urination. Furthermore, the slight acidity of urine
(the average pH is about 6) inhibits the growth of many microbes and potential pathogens in the urinary tract.
The female reproductive system employs lactate, an exogenously produced chemical mediator, to inhibit microbial
growth. The cells and tissue layers composing the vagina produce glycogen, a branched and more complex polymer
of glucose. Lactobacilli in the area ferment glycogen to produce lactate, lowering the pH in the vagina and inhibiting
transient microbiota, opportunistic pathogens like Candida (a yeast associated with vaginal infections), and other
pathogens responsible for sexually transmitted diseases.
In the eyes, tears contain the chemical mediators lysozyme and lactoferrin, both of which are capable of eliminating
microbes that have found their way to the surface of the eyes. Lysozyme cleaves the bond between NAG and NAM

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Chapter 17 | Innate Nonspecific Host Defenses 745

in peptidoglycan, a component of the cell wall in bacteria. It is more effective against gram-positive bacteria, which
lack the protective outer membrane associated with gram-negative bacteria. Lactoferrin inhibits microbial growth by
chemically binding and sequestering iron. This effectually starves many microbes that require iron for growth.
In the ears, cerumen (earwax) exhibits antimicrobial properties due to the presence of fatty acids, which lower the pH
to between 3 and 5.
The respiratory tract uses various chemical mediators in the nasal passages, trachea, and lungs. The mucus produced
in the nasal passages contains a mix of antimicrobial molecules similar to those found in tears and saliva (e.g.,
lysozyme, lactoferrin, lactoperoxidase). Secretions in the trachea and lungs also contain lysozyme and lactoferrin, as
well as a diverse group of additional chemical mediators, such as the lipoprotein complex called surfactant, which has
antibacterial properties.

• Explain the difference between endogenous and exogenous mediators

• Describe how pH affects antimicrobial defenses

Antimicrobial Peptides
The antimicrobial peptides (AMPs) are a special class of nonspecific cell-derived mediators with broad-spectrum
antimicrobial properties. Some AMPs are produced routinely by the body, whereas others are primarily produced (or
produced in greater quantities) in response to the presence of an invading pathogen. Research has begun exploring
how AMPs can be used in the diagnosis and treatment of disease.
AMPs may induce cell damage in microorganisms in a variety of ways, including by inflicting damage to membranes,
destroying DNA and RNA, or interfering with cell-wall synthesis. Depending on the specific antimicrobial
mechanism, a particular AMP may inhibit only certain groups of microbes (e.g., gram-positive or gram-negative
bacteria) or it may be more broadly effective against bacteria, fungi, protozoa, and viruses. Many AMPs are found on
the skin, but they can also be found in other regions of the body.
A family of AMPs called defensins can be produced by epithelial cells throughout the body as well as by cellular
defenses such as macrophages and neutrophils (see Cellular Defenses). Defensins may be secreted or act inside
host cells; they combat microorganisms by damaging their plasma membranes. AMPs called bacteriocins are
produced exogenously by certain members of the resident microbiota within the gastrointestinal tract. The genes
coding for these types of AMPs are often carried on plasmids and can be passed between different species within the
resident microbiota through lateral or horizontal gene transfer.
There are numerous other AMPs throughout the body. The characteristics of a few of the more significant AMPs are
summarized in Table 17.3.

Characteristics of Selected Antimicrobial Peptides (AMPs)

AMP Secreted by Body site Pathogens Mode of action
inhibited

Bacteriocins Resident microbiota Gastrointestinal Bacteria Disrupt membrane

tract

Cathelicidin Epithelial cells, Skin Bacteria and Disrupts membrane

macrophages, and other fungi
cell types

Table 17.3
746 Chapter 17 | Innate Nonspecific Host Defenses

Characteristics of Selected Antimicrobial Peptides (AMPs)

AMP Secreted by Body site Pathogens Mode of action
inhibited

Defensins Epithelial cells, Throughout the Fungi, bacteria, Disrupt membrane

macrophages, neutrophils body and many viruses

Dermicidin Sweat glands Skin Bacteria and Disrupts membrane

fungi integrity and ion
channels

Histatins Salivary glands Oral cavity Fungi Disrupt intracellular

function

Table 17.3

• Why are antimicrobial peptides (AMPs) considered nonspecific defenses?

Plasma Protein Mediators

Many nonspecific innate immune factors are found in plasma, the fluid portion of blood. Plasma contains electrolytes,
sugars, lipids, and proteins, each of which helps to maintain homeostasis (i.e., stable internal body functioning), and
contains the proteins involved in the clotting of blood. Additional proteins found in blood plasma, such as acute-phase
proteins, complement proteins, and cytokines, are involved in the nonspecific innate immune response.

Micro Connections

Plasma versus Serum

There are two terms for the fluid portion of blood: plasma and serum. How do they differ if they are both fluid
and lack cells? The fluid portion of blood left over after coagulation (blood cell clotting) has taken place is
serum. Although molecules such as many vitamins, electrolytes, certain sugars, complement proteins, and
antibodies are still present in serum, clotting factors are largely depleted. Plasma, conversely, still contains
all the clotting elements. To obtain plasma from blood, an anticoagulant must be used to prevent clotting.
Examples of anticoagulants include heparin and ethylene diamine tetraacetic acid (EDTA). Because clotting is
inhibited, once obtained, the sample must be gently spun down in a centrifuge. The heavier, denser blood cells
form a pellet at the bottom of a centrifuge tube, while the fluid plasma portion, which is lighter and less dense,
remains above the cell pellet.

Acute-Phase Proteins
The acute-phase proteins are another class of antimicrobial mediators. Acute-phase proteins are primarily produced
in the liver and secreted into the blood in response to inflammatory molecules from the immune system. Examples
of acute-phase proteins include C-reactive protein, serum amyloid A, ferritin, transferrin, fibrinogen, and mannose-
binding lectin. Each of these proteins has a different chemical structure and inhibits or destroys microbes in some way
(Table 17.4).

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Chapter 17 | Innate Nonspecific Host Defenses 747

Some Acute-Phase Proteins and Their Functions

C-reactive protein
Coats bacteria (opsonization), preparing them for ingestion by phagocytes
Serum amyloid A

Ferritin
Bind and sequester iron, thereby inhibiting the growth of pathogens
Transferrin

Fibrinogen Involved in formation of blood clots that trap bacterial pathogens

Mannose-binding lectin Activates complement cascade

Table 17.4

The Complement System

The complement system is a group of plasma protein mediators that can act as an innate nonspecific defense while
also serving to connect innate and adaptive immunity (discussed in the next chapter). The complement system is
composed of more than 30 proteins (including C1 through C9) that normally circulate as precursor proteins in blood.
These precursor proteins become activated when stimulated or triggered by a variety of factors, including the presence
of microorganisms. Complement proteins are considered part of innate nonspecific immunity because they are always
present in the blood and tissue fluids, allowing them to be activated quickly. Also, when activated through the
alternative pathway (described later in this section), complement proteins target pathogens in a nonspecific manner.
The process by which circulating complement precursors become functional is called complement activation. This
process is a cascade that can be triggered by one of three different mechanisms, known as the alternative, classical,
and lectin pathways.
The alternative pathway is initiated by the spontaneous activation of the complement protein C3. The hydrolysis of
C3 produces two products, C3a and C3b. When no invader microbes are present, C3b is very quickly degraded in
a hydrolysis reaction using the water in the blood. However, if invading microbes are present, C3b attaches to the
surface of these microbes. Once attached, C3b will recruit other complement proteins in a cascade (Figure 17.9).
The classical pathway provides a more efficient mechanism of activating the complement cascade, but it depends
upon the production of antibodies by the specific adaptive immune defenses. To initiate the classical pathway, a
specific antibody must first bind to the pathogen to form an antibody-antigen complex. This activates the first protein
in the complement cascade, the C1 complex. The C1 complex is a multipart protein complex, and each component
participates in the full activation of the overall complex. Following recruitment and activation of the C1 complex, the
remaining classical pathway complement proteins are recruited and activated in a cascading sequence (Figure 17.9).
The lectin activation pathway is similar to the classical pathway, but it is triggered by the binding of mannose-binding
lectin, an acute-phase protein, to carbohydrates on the microbial surface. Like other acute-phase proteins, lectins are
produced by liver cells and are commonly upregulated in response to inflammatory signals received by the body
during an infection (Figure 17.9).
748 Chapter 17 | Innate Nonspecific Host Defenses

Figure 17.9 The three complement activation pathways have different triggers, as shown here, but all three result in
the activation of the complement protein C3, which produces C3a and C3b. The latter binds to the surface of the
target cell and then works with other complement proteins to cleave C5 into C5a and C5b. C5b also binds to the cell
surface and then recruits C6 through C9; these molecules form a ring structure called the membrane attack complex
(MAC), which punches through the cell membrane of the invading pathogen, causing it to swell and burst.

Although each complement activation pathway is initiated in a different way, they all provide the same protective
outcomes: opsonization, inflammation, chemotaxis, and cytolysis. The term opsonization refers to the coating of a
pathogen by a chemical substance (called an opsonin) that allows phagocytic cells to recognize, engulf, and destroy
it more easily. Opsonins from the complement cascade include C1q, C3b, and C4b. Additional important opsonins
include mannose-binding proteins and antibodies. The complement fragments C3a and C5a are well-characterized
anaphylatoxins with potent proinflammatory functions. Anaphylatoxins activate mast cells, causing degranulation
and the release of inflammatory chemical signals, including mediators that cause vasodilation and increased vascular
permeability. C5a is also one of the most potent chemoattractants for neutrophils and other white blood cells, cellular
defenses that will be discussed in the next section.
The complement proteins C6, C7, C8, and C9 assemble into a membrane attack complex (MAC), which allows
C9 to polymerize into pores in the membranes of gram-negative bacteria. These pores allow water, ions, and other
molecules to move freely in and out of the targeted cells, eventually leading to cell lysis and death of the pathogen
(Figure 17.9). However, the MAC is only effective against gram-negative bacteria; it cannot penetrate the thick layer
of peptidoglycan associated with cell walls of gram-positive bacteria. Since the MAC does not pose a lethal threat to
gram-positive bacterial pathogens, complement-mediated opsonization is more important for their clearance.

Cytokines
Cytokines are soluble proteins that act as communication signals between cells. In a nonspecific innate immune
response, various cytokines may be released to stimulate production of chemical mediators or other cell functions,
such as cell proliferation, cell differentiation, inhibition of cell division, apoptosis, and chemotaxis.
When a cytokine binds to its target receptor, the effect can vary widely depending on the type of cytokine and the type
of cell or receptor to which it has bound. The function of a particular cytokine can be described as autocrine, paracrine,
or endocrine (Figure 17.10). In autocrine function, the same cell that releases the cytokine is the recipient of the
signal; in other words, autocrine function is a form of self-stimulation by a cell. In contrast, paracrine function
involves the release of cytokines from one cell to other nearby cells, stimulating some response from the recipient
cells. Last, endocrine function occurs when cells release cytokines into the bloodstream to be carried to target cells
much farther away.

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Chapter 17 | Innate Nonspecific Host Defenses 749

Figure 17.10 Autocrine, paracrine, and endocrine actions describe which cells are targeted by cytokines and how
far the cytokines must travel to bind to their intended target cells’ receptors.

Three important classes of cytokines are the interleukins, chemokines, and interferons. The interleukins were
originally thought to be produced only by leukocytes (white blood cells) and to only stimulate leukocytes, thus
the reasons for their name. Although interleukins are involved in modulating almost every function of the immune
system, their role in the body is not restricted to immunity. Interleukins are also produced by and stimulate a variety
of cells unrelated to immune defenses.
The chemokines are chemotactic factors that recruit leukocytes to sites of infection, tissue damage, and inflammation.
In contrast to more general chemotactic factors, like complement factor C5a, chemokines are very specific in the
subsets of leukocytes they recruit.
Interferons are a diverse group of immune signaling molecules and are especially important in our defense against
viruses. Type I interferons (interferon-α and interferon-β) are produced and released by cells infected with virus.
These interferons stimulate nearby cells to stop production of mRNA, destroy RNA already produced, and reduce
protein synthesis. These cellular changes inhibit viral replication and production of mature virus, slowing the spread
of the virus. Type I interferons also stimulate various immune cells involved in viral clearance to more aggressively
attack virus-infected cells. Type II interferon (interferon-γ) is an important activator of immune cells (Figure 17.11).
750 Chapter 17 | Innate Nonspecific Host Defenses

Figure 17.11 Interferons are cytokines released by a cell infected with a virus. Interferon-α and interferon-β signal
uninfected neighboring cells to inhibit mRNA synthesis, destroy RNA, and reduce protein synthesis (top arrow).
Interferon-α and interferon-β also promote apoptosis in cells infected with the virus (middle arrow). Interferon-γ alerts
neighboring immune cells to an attack (bottom arrow). Although interferons do not cure the cell releasing them or
other infected cells, which will soon die, their release may prevent additional cells from becoming infected, thus
stemming the infection.

Inflammation-Eliciting Mediators
Many of the chemical mediators discussed in this section contribute in some way to inflammation and fever, which
are nonspecific immune responses discussed in more detail in Inflammation and Fever. Cytokines stimulate the
production of acute-phase proteins such as C-reactive protein and mannose-binding lectin in the liver. These acute-
phase proteins act as opsonins, activating complement cascades through the lectin pathway.
Some cytokines also bind mast cells and basophils, inducing them to release histamine, a proinflammatory
compound. Histamine receptors are found on a variety of cells and mediate proinflammatory events, such as
bronchoconstriction (tightening of the airways) and smooth muscle contraction.
In addition to histamine, mast cells may release other chemical mediators, such as leukotrienes. Leukotrienes
are lipid-based proinflammatory mediators that are produced from the metabolism of arachidonic acid in the
cell membrane of leukocytes and tissue cells. Compared with the proinflammatory effects of histamine, those of
leukotrienes are more potent and longer lasting. Together, these chemical mediators can induce coughing, vomiting,
and diarrhea, which serve to expel pathogens from the body.
Certain cytokines also stimulate the production of prostaglandins, chemical mediators that promote the inflammatory
effects of kinins and histamines. Prostaglandins can also help to set the body temperature higher, leading to fever,
which promotes the activities of white blood cells and slightly inhibits the growth of pathogenic microbes (see
Inflammation and Fever).
Another inflammatory mediator, bradykinin, contributes to edema, which occurs when fluids and leukocytes leak
out of the bloodstream and into tissues. It binds to receptors on cells in the capillary walls, causing the capillaries to
dilate and become more permeable to fluids.

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Chapter 17 | Innate Nonspecific Host Defenses 751

• What do the three complement activation pathways have in common?

• Explain autocrine, paracrine, and endocrine signals.
• Name two important inflammation-eliciting mediators.

Clinical Focus

Part 2
To relieve the constriction of her airways, Angela is immediately treated with antihistamines and administered
corticosteroids through an inhaler, and then monitored for a period of time. Though her condition does not
worsen, the drugs do not seem to be alleviating her condition. She is admitted to the hospital for further
observation, testing, and treatment.
Following admission, a clinician conducts allergy testing to try to determine if something in her environment
might be triggering an allergic inflammatory response. A doctor orders blood analysis to check for levels of
particular cytokines. A sputum sample is also taken and sent to the lab for microbial staining, culturing, and
identification of pathogens that could be causing an infection.
• Which aspects of the innate immune system could be contributing to Angela’s airway constriction?
• Why was Angela treated with antihistamines?
• Why would the doctor be interested in levels of cytokines in Angela’s blood?
Jump to the next Clinical Focus box. Go back to the previous Clinical Focus box.

Table 17.5 provides a summary of the chemical defenses discussed in this section.

Chemical Defenses of Nonspecific Innate Immunity

Defense Examples Function

Chemicals Sebum from sebaceous glands Provides oil barrier protecting hair follicle pores from
and enzymes pathogens
in body fluids
Oleic acid from sebum and skin Lowers pH to inhibit pathogens
microbiota

Lysozyme in secretions Kills bacteria by attacking cell wall

Acid in stomach, urine, and vagina Inhibits or kills bacteria

Digestive enzymes and bile Kill bacteria

Lactoferrin and transferrin Bind and sequester iron, inhibiting bacterial growth

Surfactant in lungs Kills bacteria

Antimicrobial Defensins, bacteriocins, Kill bacteria by attacking membranes or interfering with

peptides dermicidin, cathelicidin, histatins, cell functions

Table 17.5
752 Chapter 17 | Innate Nonspecific Host Defenses

Chemical Defenses of Nonspecific Innate Immunity

Defense Examples Function

Plasma Acute-phase proteins (C-reactive Inhibit the growth of bacteria and assist in the trapping
protein protein, serum amyloid A, ferritin, and killing of bacteria
mediators fibrinogen, transferrin, and
mannose-binding lectin)

Complements C3b and C4b Opsonization of pathogens to aid phagocytosis

Complement C5a Chemoattractant for phagocytes

Complements C3a and C5a Proinflammatory anaphylatoxins

Cytokines Interleukins Stimulate and modulate most functions of immune

system

Chemokines Recruit white blood cells to infected area

Interferons Alert cells to viral infection, induce apoptosis of virus-

infected cells, induce antiviral defenses in infected and
nearby uninfected cells, stimulate immune cells to attack
virus-infected cells

Inflammation- Histamine Promotes vasodilation, bronchoconstriction, smooth

eliciting muscle contraction, increased secretion and mucus
mediators production

Leukotrienes Promote inflammation; stronger and longer lasting than

histamine

Prostaglandins Promote inflammation and fever

Bradykinin Increases vasodilation and vascular permeability,

leading to edema

Table 17.5

17.3 Cellular Defenses

Learning Objectives
• Identify and describe the components of blood
• Explain the process by which the formed elements of blood are formed (hematopoiesis)
• Describe the characteristics of formed elements found in peripheral blood, as well as their respective functions
within the innate immune system
In the previous section, we discussed some of the chemical mediators found in plasma, the fluid portion of blood. The
nonfluid portion of blood consists of various types of formed elements, so called because they are all formed from the
same stem cells found in bone marrow. The three major categories of formed elements are: red blood cells (RBCs),
also called erythrocytes; platelets, also called thrombocytes; and white blood cells (WBCs), also called leukocytes.
Red blood cells are primarily responsible for carrying oxygen to tissues. Platelets are cellular fragments that
participate in blood clot formation and tissue repair. Several different types of WBCs participate in various
nonspecific mechanisms of innate and adaptive immunity. In this section, we will focus primarily on the innate
mechanisms of various types of WBCs.

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Chapter 17 | Innate Nonspecific Host Defenses 753

Hematopoiesis
All of the formed elements of blood are derived from pluripotent hematopoietic stem cells (HSCs) in the bone
marrow. As the HSCs make copies of themselves in the bone marrow, individual cells receive different cues from
the body that control how they develop and mature. As a result, the HSCs differentiate into different types of blood
cells that, once mature, circulate in peripheral blood. This process of differentiation, called hematopoiesis, is shown
in more detail in Figure 17.12.
In terms of sheer numbers, the vast majority of HSCs become erythrocytes. Much smaller numbers become
leukocytes and platelets. Leukocytes can be further subdivided into granulocytes, which are characterized by
numerous granules visible in the cytoplasm, and agranulocytes, which lack granules. Figure 17.13 provides an
overview of the various types of formed elements, including their relative numbers, primary function, and lifespans.

Figure 17.12 All the formed elements of the blood arise by differentiation of hematopoietic stem cells in the bone
marrow.
754 Chapter 17 | Innate Nonspecific Host Defenses

Figure 17.13 Formed elements of blood include erythrocytes (red blood cells), leukocytes (white blood cells), and
platelets.

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Chapter 17 | Innate Nonspecific Host Defenses 755

Granulocytes
The various types of granulocytes can be distinguished from one another in a blood smear by the appearance of
their nuclei and the contents of their granules, which confer different traits, functions, and staining properties. The
neutrophils, also called polymorphonuclear neutrophils (PMNs), have a nucleus with three to five lobes and small,
numerous, lilac-colored granules. Each lobe of the nucleus is connected by a thin strand of material to the other lobes.
The eosinophils have fewer lobes in the nucleus (typically 2–3) and larger granules that stain reddish-orange. The
basophils have a two-lobed nucleus and large granules that stain dark blue or purple (Figure 17.14).

Figure 17.14 Granulocytes can be distinguished by the number of lobes in their nuclei and the staining properties of
their granules. (credit “neutrophil” micrograph: modification of work by Ed Uthman)

Neutrophils (PMNs)
Neutrophils (PMNs) are frequently involved in the elimination and destruction of extracellular bacteria. They are
capable of migrating through the walls of blood vessels to areas of bacterial infection and tissue damage, where
they seek out and kill infectious bacteria. PMN granules contain a variety of defensins and hydrolytic enzymes
that help them destroy bacteria through phagocytosis (described in more detail in Pathogen Recognition and
Phagocytosis) In addition, when many neutrophils are brought into an infected area, they can be stimulated to
release toxic molecules into the surrounding tissue to better clear infectious agents. This is called degranulation.
Another mechanism used by neutrophils is neutrophil extracellular traps (NETs), which are extruded meshes of
chromatin that are closely associated with antimicrobial granule proteins and components. Chromatin is DNA with
associated proteins (usually histone proteins, around which DNA wraps for organization and packing within a cell).
By creating and releasing a mesh or lattice-like structure of chromatin that is coupled with antimicrobial proteins,
the neutrophils can mount a highly concentrated and efficient attack against nearby pathogens. Proteins frequently
associated with NETs include lactoferrin, gelatinase, cathepsin G, and myeloperoxidase. Each has a different means
of promoting antimicrobial activity, helping neutrophils eliminate pathogens. The toxic proteins in NETs may kill
some of the body’s own cells along with invading pathogens. However, this collateral damage can be repaired after
the danger of the infection has been eliminated.
As neutrophils fight an infection, a visible accumulation of leukocytes, cellular debris, and bacteria at the site of
infection can be observed. This buildup is what we call pus (also known as purulent or suppurative discharge
or drainage). The presence of pus is a sign that the immune defenses have been activated against an infection;
756 Chapter 17 | Innate Nonspecific Host Defenses

historically, some physicians believed that inducing pus formation could actually promote the healing of wounds.
The practice of promoting “laudable pus” (by, for instance, wrapping a wound in greasy wool soaked in wine) dates
back to the ancient physician Galen in the 2nd century AD, and was practiced in variant forms until the 17th century
(though it was not universally accepted). Today, this method is no longer practiced because we now know that it is
not effective. Although a small amount of pus formation can indicate a strong immune response, artificially inducing
pus formation does not promote recovery.

Eosinophils
Eosinophils are granulocytes that protect against protozoa and helminths; they also play a role in allergic reactions.
The granules of eosinophils, which readily absorb the acidic reddish dye eosin, contain histamine, degradative
enzymes, and a compound known as major basic protein (MBP) (Figure 17.14). MBP binds to the surface
carbohydrates of parasites, and this binding is associated with disruption of the cell membrane and membrane
permeability.

Basophils
Basophils have cytoplasmic granules of varied size and are named for their granules’ ability to absorb the basic
dye methylene blue (Figure 17.14). Their stimulation and degranulation can result from multiple triggering events.
Activated complement fragments C3a and C5a, produced in the activation cascades of complement proteins, act as
anaphylatoxins by inducing degranulation of basophils and inflammatory responses. This cell type is important in
allergic reactions and other responses that involve inflammation. One of the most abundant components of basophil
granules is histamine, which is released along with other chemical factors when the basophil is stimulated. These
chemicals can be chemotactic and can help to open the gaps between cells in the blood vessels. Other mechanisms for
basophil triggering require the assistance of antibodies, as discussed in B Lymphocytes and Humoral Immunity.

Mast Cells
Hematopoiesis also gives rise to mast cells, which appear to be derived from the same common myeloid progenitor
cell as neutrophils, eosinophils, and basophils. Functionally, mast cells are very similar to basophils, containing many
of the same components in their granules (e.g., histamine) and playing a similar role in allergic responses and other
inflammatory reactions. However, unlike basophils, mast cells leave the circulating blood and are most frequently
found residing in tissues. They are often associated with blood vessels and nerves or found close to surfaces that
interface with the external environment, such as the skin and mucous membranes in various regions of the body
(Figure 17.15).

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Chapter 17 | Innate Nonspecific Host Defenses 757

Figure 17.15 Mast cells function similarly to basophils by inducing and promoting inflammatory responses. (a) This
figure shows mast cells in blood. In a blood smear, they are difficult to differentiate from basophils (b). Unlike
basophils, mast cells migrate from the blood into various tissues. (credit right: modification of work by Greenland JR,
Xu X, Sayah DM, Liu FC, Jones KD, Looney MR, Caughey GH)

• Describe the granules and nuclei of neutrophils, eosinophils, basophils, and mast cells.
• Name three antimicrobial mechanisms of neutrophils

Clinical Focus

Part 3
Angela’s tests come back negative for all common allergens, and her sputum samples contain no abnormal
presence of pathogenic microbes or elevated levels of members of the normal respiratory microbiota. She
does, however, have elevated levels of inflammatory cytokines in her blood.
The swelling of her airway has still not responded to treatment with antihistamines or corticosteroids. Additional
blood work shows that Angela has a mildly elevated white blood cell count but normal antibody levels. Also,
she has a lower-than-normal level of the complement protein C4.
• What does this new information reveal about the cause of Angela’s constricted airways?
• What are some possible conditions that could lead to low levels of complement proteins?
Jump to the next Clinical Focus box. Go back to the previous Clinical Focus box.

Agranulocytes
As their name suggests, agranulocytes lack visible granules in the cytoplasm. Agranulocytes can be categorized as
lymphocytes or monocytes (Figure 17.13). Among the lymphocytes are natural killer cells, which play an important
role in nonspecific innate immune defenses. Lymphocytes also include the B cells and T cells, which are discussed
in the next chapter because they are central players in the specific adaptive immune defenses. The monocytes
differentiate into macrophages and dendritic cells, which are collectively referred to as the mononuclear phagocyte
system.
758 Chapter 17 | Innate Nonspecific Host Defenses

Natural Killer Cells

Most lymphocytes are primarily involved in the specific adaptive immune response, and thus will be discussed
in the following chapter. An exception is the natural killer cells (NK cells); these mononuclear lymphocytes use
nonspecific mechanisms to recognize and destroy cells that are abnormal in some way. Cancer cells and cells infected
with viruses are two examples of cellular abnormalities that are targeted by NK cells. Recognition of such cells
involves a complex process of identifying inhibitory and activating molecular markers on the surface of the target cell.
Molecular markers that make up the major histocompatibility complex (MHC) are expressed by healthy cells as an
indication of “self.” This will be covered in more detail in next chapter. NK cells are able to recognize normal MHC
markers on the surface of healthy cells, and these MHC markers serve as an inhibitory signal preventing NK cell
activation. However, cancer cells and virus-infected cells actively diminish or eliminate expression of MHC markers
on their surface. When these MHC markers are diminished or absent, the NK cell interprets this as an abnormality
and a cell in distress. This is one part of the NK cell activation process (Figure 17.16). NK cells are also activated by
binding to activating molecular molecules on the target cell. These activating molecular molecules include “altered
self” or “nonself” molecules. When a NK cell recognizes a decrease in inhibitory normal MHC molecules and an
increase in activating molecules on the surface of a cell, the NK cell will be activated to eliminate the cell in distress.

Figure 17.16 Natural killer (NK) cells are inhibited by the presence of the major histocompatibility cell (MHC)
receptor on healthy cells. Cancer cells and virus-infected cells have reduced expression of MHC and increased
expression of activating molecules. When a NK cell recognizes decreased MHC and increased activating molecules,
it will kill the abnormal cell.

Once a cell has been recognized as a target, the NK cell can use several different mechanisms to kill its target.
For example, it may express cytotoxic membrane proteins and cytokines that stimulate the target cell to undergo
apoptosis, or controlled cell suicide. NK cells may also use perforin-mediated cytotoxicity to induce apoptosis in

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Chapter 17 | Innate Nonspecific Host Defenses 759

target cells. This mechanism relies on two toxins released from granules in the cytoplasm of the NK cell: perforin,
a protein that creates pores in the target cell, and granzymes, proteases that enter through the pores into the target
cell’s cytoplasm, where they trigger a cascade of protein activation that leads to apoptosis. The NK cell binds to the
abnormal target cell, releases its destructive payload, and detaches from the target cell. While the target cell undergoes
apoptosis, the NK cell synthesizes more perforin and proteases to use on its next target.
NK cells contain these toxic compounds in granules in their cytoplasm. When stained, the granules are azurophilic
and can be visualized under a light microscope (Figure 17.17). Even though they have granules, NK cells are
not considered granulocytes because their granules are far less numerous than those found in true granulocytes.
Furthermore, NK cells have a different lineage than granulocytes, arising from lymphoid rather than myeloid stem
cells (Figure 17.12).

Figure 17.17 Natural killer cell with perforin-containing granules. (credit: modification of work by Rolstad B)

Monocytes
The largest of the white blood cells, monocytes have a nucleus that lacks lobes, and they also lack granules in the
cytoplasm (Figure 17.18). Nevertheless, they are effective phagocytes, engulfing pathogens and apoptotic cells to
help fight infection.
When monocytes leave the bloodstream and enter a specific body tissue, they differentiate into tissue-specific
phagocytes called macrophages and dendritic cells. They are particularly important residents of lymphoid tissue,
as well as nonlymphoid sites and organs. Macrophages and dendritic cells can reside in body tissues for significant
lengths of time. Macrophages in specific body tissues develop characteristics suited to the particular tissue. Not only
do they provide immune protection for the tissue in which they reside but they also support normal function of their
neighboring tissue cells through the production of cytokines. Macrophages are given tissue-specific names, and a few
examples of tissue-specific macrophages are listed in Table 17.6. Dendritic cells are important sentinels residing
in the skin and mucous membranes, which are portals of entry for many pathogens. Monocytes, macrophages, and
dendritic cells are all highly phagocytic and important promoters of the immune response through their production
and release of cytokines. These cells provide an essential bridge between innate and adaptive immune responses, as
discussed in the next section as well as the next chapter.
760 Chapter 17 | Innate Nonspecific Host Defenses

Figure 17.18 Monocytes are large, agranular white blood cells with a nucleus that lacks lobes. When monocytes
leave the bloodstream, they differentiate and become macrophages with tissue-specific properties. (credit left:
modification of work by Armed Forces Institute of Pathology; credit right: modification of work by Centers for Disease
Control and Prevention)

Macrophages Found in Various Body Tissues

Tissue Macrophage

Brain and central nervous system Microglial cells

Liver Kupffer cells

Lungs Alveolar macrophages (dust cells)

Peritoneal cavity Peritoneal macrophages

Table 17.6

• Describe the signals that activate natural killer cells.

• What is the difference between monocytes and macrophages?

17.4 Pathogen Recognition and Phagocytosis

Learning Objectives
• Explain how leukocytes migrate from peripheral blood into infected tissues
• Explain the mechanisms by which leukocytes recognize pathogens
• Explain the process of phagocytosis and the mechanisms by which phagocytes destroy and degrade pathogens
Several of the cell types discussed in the previous section can be described as phagocytes—cells whose main function
is to seek, ingest, and kill pathogens. This process, called phagocytosis, was first observed in starfish in the 1880s by
Nobel Prize-winning zoologist Ilya Metchnikoff (1845–1916), who made the connection to white blood cells (WBCs)

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Chapter 17 | Innate Nonspecific Host Defenses 761

in humans and other animals. At the time, Pasteur and other scientists believed that WBCs were spreading pathogens
rather than killing them (which is true for some diseases, such as tuberculosis). But in most cases, phagocytes provide
a strong, swift, and effective defense against a broad range of microbes, making them a critical component of innate
nonspecific immunity. This section will focus on the mechanisms by which phagocytes are able to seek, recognize,
and destroy pathogens.

Extravasation (Diapedesis) of Leukocytes

Some phagocytes are leukocytes (WBCs) that normally circulate in the bloodstream. To reach pathogens located
in infected tissue, leukocytes must pass through the walls of small capillary blood vessels within tissues. This
process, called extravasation, or diapedesis, is initiated by complement factor C5a, as well as cytokines released
into the immediate vicinity by resident macrophages and tissue cells responding to the presence of the infectious
agent (Figure 17.19). Similar to C5a, many of these cytokines are proinflammatory and chemotactic, and they
bind to cells of small capillary blood vessels, initiating a response in the endothelial cells lining the inside of the
blood vessel walls. This response involves the upregulation and expression of various cellular adhesion molecules
and receptors. Leukocytes passing through will stick slightly to the adhesion molecules, slowing down and rolling
along the blood vessel walls near the infected area. When they reach a cellular junction, they will bind to even
more of these adhesion molecules, flattening out and squeezing through the cellular junction in a process known as
transendothelial migration. This mechanism of “rolling adhesion” allows leukocytes to exit the bloodstream and
enter the infected areas, where they can begin phagocytosing the invading pathogens.
Note that extravasation does not occur in arteries or veins. These blood vessels are surrounded by thicker, multilayer
protective walls, in contrast to the thin single-cell-layer walls of capillaries. Furthermore, the blood flow in arteries is
too turbulent to allow for rolling adhesion. Also, some leukocytes tend to respond to an infection more quickly than
others. The first to arrive typically are neutrophils, often within hours of a bacterial infection. By contract, monocytes
may take several days to leave the bloodstream and differentiate into macrophages.
762 Chapter 17 | Innate Nonspecific Host Defenses

Figure 17.19 Damaged cells and macrophages that have ingested pathogens release cytokines that are
proinflammatory and chemotactic for leukocytes. In addition, activation of complement at the site of infection results in
production of the chemotactic and proinflammatory C5a. Leukocytes exit the blood vessel and follow the
chemoattractant signal of cytokines and C5a to the site of infection. Granulocytes such as neutrophils release
chemicals that destroy pathogens. They are also capable of phagocytosis and intracellular killing of bacterial
pathogens.

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Chapter 17 | Innate Nonspecific Host Defenses 763

Link to Learning

Watch the following videos on leukocyte extravasation (https://openstax.org/

l/22leukextrvid) and leukocyte rolling (https://openstax.org/l/22leukrollvid)
to learn more.

• Explain the role of adhesion molecules in the process of extravasation.

Pathogen Recognition
As described in the previous section, opsonization of pathogens by antibody; complement factors C1q, C3b, and
C4b; and lectins can assist phagocytic cells in recognition of pathogens and attachment to initiate phagocytosis.
However, not all pathogen recognition is opsonin dependent. Phagocytes can also recognize molecular structures that
are common to many groups of pathogenic microbes. Such structures are called pathogen-associated molecular
patterns (PAMPs). Common PAMPs include the following:
• peptidoglycan, found in bacterial cell walls;
• flagellin, a protein found in bacterial flagella;
• lipopolysaccharide (LPS) from the outer membrane of gram-negative bacteria;
• lipopeptides, molecules expressed by most bacteria; and
• nucleic acids such as viral DNA or RNA.
Like numerous other PAMPs, these substances are integral to the structure of broad classes of microbes.
The structures that allow phagocytic cells to detect PAMPs are called pattern recognition receptors (PRRs). One
group of PRRs is the toll-like receptors (TLRs), which bind to various PAMPs and communicate with the nucleus
of the phagocyte to elicit a response. Many TLRs (and other PRRs) are located on the surface of a phagocyte, but
some can also be found embedded in the membranes of interior compartments and organelles (Figure 17.20). These
interior PRRs can be useful for the binding and recognition of intracellular pathogens that may have gained access
to the inside of the cell before phagocytosis could take place. Viral nucleic acids, for example, might encounter an
interior PRR, triggering production of the antiviral cytokine interferon.
In addition to providing the first step of pathogen recognition, the interaction between PAMPs and PRRs on
macrophages provides an intracellular signal that activates the phagocyte, causing it to transition from a dormant
state of readiness and slow proliferation to a state of hyperactivity, proliferation, production/secretion of cytokines,
and enhanced intracellular killing. PRRs on macrophages also respond to chemical distress signals from damaged
or stressed cells. This allows macrophages to extend their responses beyond protection from infectious diseases to a
broader role in the inflammatory response initiated from injuries or other diseases.
764 Chapter 17 | Innate Nonspecific Host Defenses

Figure 17.20 Phagocytic cells contain pattern recognition receptors (PRRs) capable of recognizing various
pathogen-associated molecular patterns (PAMPs). These PRRs can be found on the plasma membrane or in internal
phagosomes. When a PRR recognizes a PAMP, it sends a signal to the nucleus that activates genes involved in
phagocytosis, cellular proliferation, production and secretion of antiviral interferons and proinflammatory cytokines,
and enhanced intracellular killing.

• Name four pathogen-associated molecular patterns (PAMPs).

• Describe the process of phagocyte activation.

Pathogen Degradation
Once pathogen recognition and attachment occurs, the pathogen is engulfed in a vesicle and brought into the internal
compartment of the phagocyte in a process called phagocytosis (Figure 17.21). PRRs can aid in phagocytosis by
first binding to the pathogen’s surface, but phagocytes are also capable of engulfing nearby items even if they are not
bound to specific receptors. To engulf the pathogen, the phagocyte forms a pseudopod that wraps around the pathogen
and then pinches it off into a membrane vesicle called a phagosome. Acidification of the phagosome (pH decreases to
the range of 4–5) provides an important early antibacterial mechanism. The phagosome containing the pathogen fuses
with one or more lysosomes, forming a phagolysosome. Formation of the phagolysosome enhances the acidification,
which is essential for activation of pH-dependent digestive lysosomal enzymes and production of hydrogen peroxide
and toxic reactive oxygen species. Lysosomal enzymes such as lysozyme, phospholipase, and proteases digest the
pathogen. Other enzymes are involved a respiratory burst. During the respiratory burst, phagocytes will increase their
uptake and consumption of oxygen, but not for energy production. The increased oxygen consumption is focused on
the production of superoxide anion, hydrogen peroxide, hydroxyl radicals, and other reactive oxygen species that are
antibacterial.
In addition to the reactive oxygen species produced by the respiratory burst, reactive nitrogen compounds with

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Chapter 17 | Innate Nonspecific Host Defenses 765

cytotoxic (cell-killing) potential can also form. For example, nitric oxide can react with superoxide to form
peroxynitrite, a highly reactive nitrogen compound with degrading capabilities similar to those of the reactive oxygen
species. Some phagocytes even contain an internal storehouse of microbicidal defensin proteins (e.g., neutrophil
granules). These destructive forces can be released into the area around the cell to degrade microbes externally.
Neutrophils, especially, can be quite efficient at this secondary antimicrobial mechanism.
Once degradation is complete, leftover waste products are excreted from the cell in an exocytic vesicle. However, it is
important to note that not all remains of the pathogen are excreted as waste. Macrophages and dendritic cells are also
antigen-presenting cells involved in the specific adaptive immune response. These cells further process the remains
of the degraded pathogen and present key antigens (specific pathogen proteins) on their cellular surface. This is an
important step for stimulation of some adaptive immune responses, as will be discussed in more detail in the next
chapter.

Figure 17.21 The stages of phagocytosis include the engulfment of a pathogen, the formation of a phagosome, the
digestion of the pathogenic particle in the phagolysosome, and the expulsion of undigested materials from the cell.

Link to Learning

Visit this link (https://openstax.org/l/22phagpathvid) to view a phagocyte

chasing and engulfing a pathogen.

• What is the difference between a phagosome and a lysosome?

Micro Connections

When Phagocytosis Fails

Although phagocytosis successfully destroys many pathogens, some are able to survive and even exploit
766 Chapter 17 | Innate Nonspecific Host Defenses

this defense mechanism to multiply in the body and cause widespread infection. Protozoans of the genus
Leishmania are one example. These obligate intracellular parasites are flagellates transmitted to humans by
the bite of a sand fly. Infections cause serious and sometimes disfiguring sores and ulcers in the skin and
other tissues (Figure 17.22). Worldwide, an estimated 1.3 million people are newly infected with leishmaniasis
annually.[1]
Salivary peptides from the sand fly activate host macrophages at the site of their bite. The classic or
alternate pathway for complement activation ensues with C3b opsonization of the parasite. Leishmania cells
are phagocytosed, lose their flagella, and multiply in a form known as an amastigote (Leishman-Donovan
body) within the phagolysosome. Although many other pathogens are destroyed in the phagolysosome,
survival of the Leishmania amastigotes is maintained by the presence of surface lipophosphoglycan and
acid phosphatase. These substances inhibit the macrophage respiratory burst and lysosomal enzymes. The
parasite then multiplies inside the cell and lyses the infected macrophage, releasing the amastigotes to infect
other macrophages within the same host. Should another sand fly bite an infected person, it might ingest
amastigotes and then transmit them to another individual through another bite.
There are several different forms of leishmaniasis. The most common is a localized cutaneous form of the
illness caused by L. tropica, which typically resolves spontaneously over time but with some significant
lymphocyte infiltration and permanent scarring. A mucocutaneous form of the disease, caused by L. viannia
brasilienfsis, produces lesions in the tissue of the nose and mouth and can be life threatening. A visceral form
of the illness can be caused by several of the different Leishmania species. It affects various organ systems
and causes abnormal enlargement of the liver and spleen. Irregular fevers, anemia, liver dysfunction, and
weight loss are all signs and symptoms of visceral leishmaniasis. If left untreated, it is typically fatal.

Figure 17.22 (a) Cutaneous leishmaniasis is a disfiguring disease caused by the intracellular flagellate
Leishmania tropica, transmitted by the bite of a sand fly. (b) This light micrograph of a sample taken from a
skin lesion shows a large cell, which is a macrophage infected with L. tropica amastigotes (arrows). The
amastigotes have lost their flagella but their nuclei are visible. Soon the amastigotes will lyse the macrophage
and be engulfed by other phagocytes, spreading the infection. (credit a: modification of work by Otis Historical
Archives of “National Museum of Health & Medicine”; credit b: modification of work by Centers for Disease
Control and Prevention)

1. World Health Organization. “Leishmaniasis.” 2016. http://www.who.int/mediacentre/factsheets/fs375/en/.

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Chapter 17 | Innate Nonspecific Host Defenses 767

17.5 Inflammation and Fever

Learning Objectives
• Identify the signs of inflammation and fever and explain why they occur
• Explain the advantages and risks posed by inflammatory responses
The inflammatory response, or inflammation, is triggered by a cascade of chemical mediators and cellular responses
that may occur when cells are damaged and stressed or when pathogens successfully breach the physical barriers
of the innate immune system. Although inflammation is typically associated with negative consequences of injury
or disease, it is a necessary process insofar as it allows for recruitment of the cellular defenses needed to eliminate
pathogens, remove damaged and dead cells, and initiate repair mechanisms. Excessive inflammation, however, can
result in local tissue damage and, in severe cases, may even become deadly.

Acute Inflammation
An early, if not immediate, response to tissue injury is acute inflammation. Immediately following an injury,
vasoconstriction of blood vessels will occur to minimize blood loss. The amount of vasoconstriction is related to the
amount of vascular injury, but it is usually brief. Vasoconstriction is followed by vasodilation and increased vascular
permeability, as a direct result of the release of histamine from resident mast cells. Increased blood flow and vascular
permeability can dilute toxins and bacterial products at the site of injury or infection. They also contribute to the five
observable signs associated with the inflammatory response: erythema (redness), edema (swelling), heat, pain, and
altered function. Vasodilation and increased vascular permeability are also associated with an influx of phagocytes
at the site of injury and/or infection. This can enhance the inflammatory response because phagocytes may release
proinflammatory chemicals when they are activated by cellular distress signals released from damaged cells, by
PAMPs, or by opsonins on the surface of pathogens. Activation of the complement system can further enhance the
inflammatory response through the production of the anaphylatoxin C5a. Figure 17.23 illustrates a typical case of
acute inflammation at the site of a skin wound.

Figure 17.23 (a) Mast cells detect injury to nearby cells and release histamine, initiating an inflammatory response.
(b) Histamine increases blood flow to the wound site, and increased vascular permeability allows fluid, proteins,
phagocytes, and other immune cells to enter infected tissue. These events result in the swelling and reddening of the
injured site, and the increased blood flow to the injured site causes it to feel warm. Inflammation is also associated
with pain due to these events stimulating nerve pain receptors in the tissue. The interaction of phagocyte PRRs with
cellular distress signals and PAMPs and opsonins on the surface of pathogens leads to the release of more
proinflammatory chemicals, enhancing the inflammatory response.

During the period of inflammation, the release of bradykinin causes capillaries to remain dilated, flooding tissues with
768 Chapter 17 | Innate Nonspecific Host Defenses

fluids and leading to edema. Increasing numbers of neutrophils are recruited to the area to fight pathogens. As the
fight rages on, pus forms from the accumulation of neutrophils, dead cells, tissue fluids, and lymph. Typically, after a
few days, macrophages will help to clear out this pus. Eventually, tissue repair can begin in the wounded area.

Chronic Inflammation
When acute inflammation is unable to clear an infectious pathogen, chronic inflammation may occur. This often
results in an ongoing (and sometimes futile) lower-level battle between the host organism and the pathogen. The
wounded area may heal at a superficial level, but pathogens may still be present in deeper tissues, stimulating ongoing
inflammation. Additionally, chronic inflammation may be involved in the progression of degenerative neurological
diseases such as Alzheimer’s and Parkinson’s, heart disease, and metastatic cancer.
Chronic inflammation may lead to the formation of granulomas, pockets of infected tissue walled off and surrounded
by WBCs. Macrophages and other phagocytes wage an unsuccessful battle to eliminate the pathogens and dead
cellular materials within a granuloma. One example of a disease that produces chronic inflammation is tuberculosis,
which results in the formation of granulomas in lung tissues. A tubercular granuloma is called a tubercle (Figure
17.24). Tuberculosis will be covered in more detail in Bacterial Infections of the Respiratory Tract.
Chronic inflammation is not just associated with bacterial infections. Chronic inflammation can be an important cause
of tissue damage from viral infections. The extensive scarring observed with hepatitis C infections and liver cirrhosis
is the result of chronic inflammation.

Figure 17.24 A tubercle is a granuloma in the lung tissue of a patient with tuberculosis. In this micrograph, white
blood cells (stained purple) have walled off a pocket of tissue infected with Mycobacterium tuberculosis. Granulomas
also occur in many other forms of disease. (credit: modification of work by Piotrowski WJ, Górski P, Duda-Szymańska
J, Kwiatkowska S)

• Name the five signs of inflammation.

• Is a granuloma an acute or chronic form of inflammation? Explain.

Micro Connections

Chronic Edema
In addition to granulomas, chronic inflammation can also result in long-term edema. A condition known
as lymphatic filariasis (also known as elephantiasis) provides an extreme example. Lymphatic filariasis is
caused by microscopic nematodes (parasitic worms) whose larvae are transmitted between human hosts

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Chapter 17 | Innate Nonspecific Host Defenses 769

by mosquitoes. Adult worms live in the lymphatic vessels, where their presence stimulates infiltration by
lymphocytes, plasma cells, eosinophils, and thrombocytes (a condition known as lymphangitis). Because of the
chronic nature of the illness, granulomas, fibrosis, and blocking of the lymphatic system may eventually occur.
Over time, these blockages may worsen with repeated infections over decades, leading to skin thickened
with edema and fibrosis. Lymph (extracellular tissue fluid) may spill out of the lymphatic areas and back into
tissues, causing extreme swelling (Figure 17.25). Secondary bacterial infections commonly follow. Because it
is a disease caused by a parasite, eosinophilia (a dramatic rise in the number of eosinophils in the blood) is
characteristic of acute infection. However, this increase in antiparasite granulocytes is not sufficient to clear the
infection in many cases.
Lymphatic filariasis affects an estimated 120 million people worldwide, mostly concentrated in Africa and
Asia.[2] Improved sanitation and mosquito control can reduce transmission rates.

Figure 17.25 Elephantiasis (chronic edema) of the legs due to filariasis. (credit: modification of work by
Centers for Disease Control and Prevention)

Fever
A fever is an inflammatory response that extends beyond the site of infection and affects the entire body, resulting
in an overall increase in body temperature. Body temperature is normally regulated and maintained by the
hypothalamus, an anatomical section of the brain that functions to maintain homeostasis in the body. However,
certain bacterial or viral infections can result in the production of pyrogens, chemicals that effectively alter the
“thermostat setting” of the hypothalamus to elevate body temperature and cause fever. Pyrogens may be exogenous
or endogenous. For example, the endotoxin lipopolysaccharide (LPS), produced by gram-negative bacteria, is an
exogenous pyrogen that may induce the leukocytes to release endogenous pyrogens such as interleukin-1 (IL-1), IL-6,
interferon-γ (IFN-γ), and tumor necrosis factor (TNF). In a cascading effect, these molecules can then lead to the
release of prostaglandin E2 (PGE2) from other cells, resetting the hypothalamus to initiate fever (Figure 17.26).

2. Centers for Disease Control and Prevention. “Parasites–Lymphatic Filiariasis.” 2016. http://www.cdc.gov/parasites/lymphaticfilariasis/
gen_info/faqs.html.
770 Chapter 17 | Innate Nonspecific Host Defenses

Figure 17.26 The role of the hypothalamus in the inflammatory response. Macrophages recognize pathogens in an
area and release cytokines that trigger inflammation. The cytokines also send a signal up the vagus nerve to the
hypothalamus.

Like other forms of inflammation, a fever enhances the innate immune defenses by stimulating leukocytes to kill
pathogens. The rise in body temperature also may inhibit the growth of many pathogens since human pathogens are
mesophiles with optimum growth occurring around 35 °C (95 °F). In addition, some studies suggest that fever may
also stimulate release of iron-sequestering compounds from the liver, thereby starving out microbes that rely on iron
for growth.[3]
During fever, the skin may appear pale due to vasoconstriction of the blood vessels in the skin, which is mediated
by the hypothalamus to divert blood flow away from extremities, minimizing the loss of heat and raising the core
temperature. The hypothalamus will also stimulate shivering of muscles, another effective mechanism of generating
heat and raising the core temperature.
The crisis phase occurs when the fever breaks. The hypothalamus stimulates vasodilation, resulting in a return of
blood flow to the skin and a subsequent release of heat from the body. The hypothalamus also stimulates sweating,
which cools the skin as the sweat evaporates.
Although a low-level fever may help an individual overcome an illness, in some instances, this immune response
can be too strong, causing tissue and organ damage and, in severe cases, even death. The inflammatory response to
bacterial superantigens is one scenario in which a life-threatening fever may develop. Superantigens are bacterial or
viral proteins that can cause an excessive activation of T cells from the specific adaptive immune defense, as well as
an excessive release of cytokines that overstimulates the inflammatory response. For example, Staphylococcus aureus
and Streptococcus pyogenes are capable of producing superantigens that cause toxic shock syndrome and scarlet
fever, respectively. Both of these conditions can be associated with very high, life-threatening fevers in excess of 42
°C (108 °F).

• Explain the difference between exogenous and endogenous pyrogens.

• How does a fever inhibit pathogens?

3. N. Parrow et al. “Sequestration and Scavenging of Iron in Infection.” Infection and Immunity 81 no. 10 (2013):3503–3514

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Chapter 17 | Innate Nonspecific Host Defenses 771

Clinical Focus

Resolution
Given her father’s premature death, Angela’s doctor suspects that she has hereditary angioedema, a genetic
disorder that compromises the function of C1 inhibitor protein. Patients with this genetic abnormality may have
occasional episodes of swelling in various parts of the body. In Angela’s case, the swelling has occurred in the
respiratory tract, leading to difficulty breathing. Swelling may also occur in the gastrointestinal tract, causing
abdominal cramping, diarrhea, and vomiting, or in the muscles of the face or limbs. This swelling may be
nonresponsive to steroid treatment and is often misdiagnosed as an allergy.
Because there are three types of hereditary angioedema, the doctor orders a more specific blood test to look
for levels of C1-INH, as well as a functional assay of Angela’s C1 inhibitors. The results suggest that Angela
has type I hereditary angioedema, which accounts for 80%–85% of all cases. This form of the disorder is
caused by a deficiency in C1 esterase inhibitors, the proteins that normally help suppress activation of the
complement system. When these proteins are deficient or nonfunctional, overstimulation of the system can
lead to production of inflammatory anaphylatoxins, which results in swelling and fluid buildup in tissues.
There is no cure for hereditary angioedema, but timely treatment with purified and concentrated C1-INH from
blood donors can be effective, preventing tragic outcomes like the one suffered by Angela’s father. A number
of therapeutic drugs, either currently approved or in late-stage human trials, may also be considered as options
for treatment in the near future. These drugs work by inhibiting inflammatory molecules or the receptors for
inflammatory molecules.
Thankfully, Angela’s condition was quickly diagnosed and treated. Although she may experience additional
episodes in the future, her prognosis is good and she can expect to live a relatively normal life provided she
seeks treatment at the onset of symptoms.
Go back to the previous Clinical Focus box.

Summary
17.1 Physical Defenses
• Nonspecific innate immunity provides a first line of defense against infection by nonspecifically blocking
entry of microbes and targeting them for destruction or removal from the body.
• The physical defenses of innate immunity include physical barriers, mechanical actions that remove microbes
and debris, and the microbiome, which competes with and inhibits the growth of pathogens.
• The skin, mucous membranes, and endothelia throughout the body serve as physical barriers that prevent
microbes from reaching potential sites of infection. Tight cell junctions in these tissues prevent microbes from
passing through.
• Microbes trapped in dead skin cells or mucus are removed from the body by mechanical actions such
as shedding of skin cells, mucociliary sweeping, coughing, peristalsis, and flushing of bodily fluids (e.g.,
urination, tears)
• The resident microbiota provide a physical defense by occupying available cellular binding sites and
competing with pathogens for available nutrients.
17.2 Chemical Defenses
• Numerous chemical mediators produced endogenously and exogenously exhibit nonspecific antimicrobial
functions.
• Many chemical mediators are found in body fluids such as sebum, saliva, mucus, gastric and intestinal fluids,
urine, tears, cerumen, and vaginal secretions.
• Antimicrobial peptides (AMPs) found on the skin and in other areas of the body are largely produced
in response to the presence of pathogens. These include dermcidin, cathelicidin, defensins, histatins, and
772 Chapter 17 | Innate Nonspecific Host Defenses

bacteriocins.
• Plasma contains various proteins that serve as chemical mediators, including acute-phase proteins,
complement proteins, and cytokines.
• The complement system involves numerous precursor proteins that circulate in plasma. These proteins
become activated in a cascading sequence in the presence of microbes, resulting in the opsonization of
pathogens, chemoattraction of leukocytes, induction of inflammation, and cytolysis through the formation of
a membrane attack complex (MAC).
• Cytokines are proteins that facilitate various nonspecific responses by innate immune cells, including
production of other chemical mediators, cell proliferation, cell death, and differentiation.
• Cytokines play a key role in the inflammatory response, triggering production of inflammation-eliciting
mediators such as acute-phase proteins, histamine, leukotrienes, prostaglandins, and bradykinin.
17.3 Cellular Defenses
• The formed elements of the blood include red blood cells (erythrocytes), white blood cells (leukocytes), and
platelets (thrombocytes). Of these, leukocytes are primarily involved in the immune response.
• All formed elements originate in the bone marrow as stem cells (HSCs) that differentiate through
hematopoiesis.
• Granulocytes are leukocytes characterized by a lobed nucleus and granules in the cytoplasm. These include
neutrophils (PMNs), eosinophils, and basophils.
• Neutrophils are the leukocytes found in the largest numbers in the bloodstream and they primarily fight
bacterial infections.
• Eosinophils target parasitic infections. Eosinophils and basophils are involved in allergic reactions. Both
release histamine and other proinflammatory compounds from their granules upon stimulation.
• Mast cells function similarly to basophils but can be found in tissues outside the bloodstream.
• Natural killer (NK) cells are lymphocytes that recognize and kill abnormal or infected cells by releasing
proteins that trigger apoptosis.
• Monocytes are large, mononuclear leukocytes that circulate in the bloodstream. They may leave the
bloodstream and take up residence in body tissues, where they differentiate and become tissue-specific
macrophages and dendritic cells.
17.4 Pathogen Recognition and Phagocytosis
• Phagocytes are cells that recognize pathogens and destroy them through phagocytosis.
• Recognition often takes place by the use of phagocyte receptors that bind molecules commonly found on
pathogens, known as pathogen-associated molecular patterns (PAMPs).
• The receptors that bind PAMPs are called pattern recognition receptors, or PRRs. Toll-like receptors
(TLRs) are one type of PRR found on phagocytes.
• Extravasation of white blood cells from the bloodstream into infected tissue occurs through the process of
transendothelial migration.
• Phagocytes degrade pathogens through phagocytosis, which involves engulfing the pathogen, killing and
digesting it within a phagolysosome, and then excreting undigested matter.
17.5 Inflammation and Fever
• Inflammation results from the collective response of chemical mediators and cellular defenses to an injury or
infection.
• Acute inflammation is short lived and localized to the site of injury or infection. Chronic inflammation
occurs when the inflammatory response is unsuccessful, and may result in the formation of granulomas (e.g.,
with tuberculosis) and scarring (e.g., with hepatitis C viral infections and liver cirrhosis).
• The five cardinal signs of inflammation are erythema, edema, heat, pain, and altered function. These largely
result from innate responses that draw increased blood flow to the injured or infected tissue.

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Chapter 17 | Innate Nonspecific Host Defenses 773

• Fever is a system-wide sign of inflammation that raises the body temperature and stimulates the immune
response.
• Both inflammation and fever can be harmful if the inflammatory response is too severe.

Review Questions
Multiple Choice 6. Which of the following chemical mediators is
1. Which of the following best describes the innate secreted onto the surface of the skin?
nonspecific immune system? a. cerumen
a. a targeted and highly specific response to a b. sebum
single pathogen or molecule c. gastric acid
b. a generalized and nonspecific set of defenses d. prostaglandin
against a class or group of pathogens 7. Identify the complement activation pathway that is
c. a set of barrier mechanisms that adapts to triggered by the binding of an acute-phase protein to a
specific pathogens after repeated exposure pathogen.
d. the production of antibody molecules against a. classical
pathogens b. alternate
2. Which of the following constantly sheds dead cells c. lectin
along with any microbes that may be attached to those d. cathelicidin
cells? 8. Histamine, leukotrienes, prostaglandins, and
a. epidermis bradykinin are examples of which of the following?
b. dermis a. chemical mediators primarily found in the
c. hypodermis digestive system
d. mucous membrane b. chemical mediators that promote inflammation
3. Which of the following uses a particularly dense c. antimicrobial peptides found on the skin
suite of tight junctions to prevent microbes from d. complement proteins that form MACs
entering the underlying tissue? 9. White blood cells are also referred to as which of the
a. the mucociliary escalator following?
b. the epidermis a. platelets
c. the blood-brain barrier b. erythrocytes
d. the urethra c. leukocytes
4. Which of the following serve as chemical signals d. megakaryocytes
between cells and stimulate a wide range of nonspecific 10. Hematopoiesis occurs in which of the following?
defenses? a. liver
a. cytokines b. bone marrow
b. antimicrobial peptides c. kidneys
c. complement proteins d. central nervous system
d. antibodies
11. Granulocytes are which type of cell?
5. Bacteriocins and defensins are types of which of the a. lymphocyte
following? b. erythrocyte
a. leukotrienes c. megakaryocyte
b. cytokines d. leukocyte
c. inflammation-eliciting mediators
d. antimicrobial peptides
774 Chapter 17 | Innate Nonspecific Host Defenses

12. PAMPs would be found on the surface of which of

the following?
a. pathogen
b. phagocyte
c. skin cell
d. blood vessel wall

13. ________ on phagocytes bind to PAMPs on

bacteria, which triggers the uptake and destruction of the
bacterial pathogens?
a. PRRs
b. AMPs
c. PAMPs
d. PMNs

14. Which of the following best characterizes the mode

of pathogen recognition for opsonin-dependent
phagocytosis?
a. Opsonins produced by a pathogen attract
phagocytes through chemotaxis.
b. A PAMP on the pathogen’s surface is recognized
by a phagocyte’s toll-like receptors.
c. A pathogen is first coated with a molecule such
as a complement protein, which allows it to be
recognized by phagocytes.
d. A pathogen is coated with a molecule such as a
complement protein that immediately lyses the
cell.

15. Which refers to swelling as a result of

inflammation?
a. erythema
b. edema
c. granuloma
d. vasodilation

16. Which type of inflammation occurs at the site of an

injury or infection?
a. acute
b. chronic
c. endogenous
d. exogenous

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Chapter 17 | Innate Nonspecific Host Defenses 775

Matching
17. Match each cell type with its description.
___natural killer A. stains with basic dye methylene blue, has large amounts of histamine in granules, and
cell facilitates allergic responses and inflammation

___basophil B. stains with acidic dye eosin, has histamine and major basic protein in granules, and
facilitates responses to protozoa and helminths

___macrophage C. recognizes abnormal cells, binds to them, and releases perforin and granzyme molecules,
which induce apoptosis

___eosinophil D. large agranular phagocyte that resides in tissues such as the brain and lungs

18. Match each cellular defense with the infection it would most likely target.
___natural killer cell A. virus-infected cell

___neutrophil B. tapeworm in the intestines

___eosinophil C. bacteria in a skin lesion

Fill in the Blank

19. The muscular contraction of the intestines that results in movement of material through the digestive tract is
called ________.

20. ______ are the hair-like appendages of cells lining parts of the respiratory tract that sweep debris away from the
lungs.

21. Secretions that bathe and moisten the interior of the intestines are produced by _______ cells.

22. ________ are antimicrobial peptides produced by members of the normal microbiota.

23. ________ is the fluid portion of a blood sample that has been drawn in the presence of an anticoagulant
compound.

24. The process by which cells are drawn or attracted to an area by a microbe invader is known as ________.

25. Platelets are also called ________.

26. The cell in the bone marrow that gives rise to all other blood cell types is the ________.

27. PMNs are another name for ________.

28. Kupffer cells residing in the liver are a type of ________.

29. _____________ are similar to basophils, but reside in tissues rather than circulating in the blood.

30. ________, also known as diapedesis, refers to the exit from the bloodstream of neutrophils and other circulating
leukocytes.

31. Toll-like receptors are examples of ________.

32. A(n) ________ is a walled-off area of infected tissue that exhibits chronic inflammation.

33. The ________ is the part of the body responsible for regulating body temperature.

34. Heat and redness, or ________, occur when the small blood vessels in an inflamed area dilate (open up), bringing
more blood much closer to the surface of the skin.
776 Chapter 17 | Innate Nonspecific Host Defenses

Short Answer
35. Differentiate a physical barrier from a mechanical removal mechanism and give an example of each.

36. Identify some ways that pathogens can breach the physical barriers of the innate immune system.

37. Differentiate the main activation methods of the classic, alternative, and lectin complement cascades.

38. What are the four protective outcomes of complement activation?

39. Explain the difference between plasma and the formed elements of the blood.

40. List three ways that a neutrophil can destroy an infectious bacterium.

41. Briefly summarize the events leading up to and including the process of transendothelial migration.

42. Differentiate exogenous and endogenous pyrogens, and provide an example of each.

Critical Thinking
43. Neutrophils can sometimes kill human cells along with pathogens when they release the toxic contents of their
granules into the surrounding tissue. Likewise, natural killer cells target human cells for destruction. Explain why it
is advantageous for the immune system to have cells that can kill human cells as well as pathogens.

44. Refer to Figure 17.13. In a blood smear taken from a healthy patient, which type of leukocyte would you expect
to observe in the highest numbers?

45. If a gram-negative bacterial infection reaches the bloodstream, large quantities of LPS can be released into the
blood, resulting in a syndrome called septic shock. Death due to septic shock is a real danger. The overwhelming
immune and inflammatory responses that occur with septic shock can cause a perilous drop in blood pressure;
intravascular blood clotting; development of thrombi and emboli that block blood vessels, leading to tissue death;
failure of multiple organs; and death of the patient. Identify and characterize two to three therapies that might be
useful in stopping the dangerous events and outcomes of septic shock once it has begun, given what you have learned
about inflammation and innate immunity in this chapter.

46. In Lubeck, Germany, in 1930, a group of 251 infants was accidentally administered a tainted vaccine for
tuberculosis that contained live Mycobacterium tuberculosis. This vaccine was administered orally, directly exposing
the infants to the deadly bacterium. Many of these infants contracted tuberculosis, and some died. However, 44 of the
infants never contracted tuberculosis. Based on your knowledge of the innate immune system, what innate defenses
might have inhibited M. tuberculosis enough to prevent these infants from contracting the disease?

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Chapter 18 | Adaptive Specific Host Defenses 777

Chapter 18

Adaptive Specific Host Defenses

Figure 18.1 Polio was once a common disease with potentially serious consequences, including paralysis.
Vaccination has all but eliminated the disease from most countries around the world. An iron-lung ward, such as the
one shown in this 1953 photograph, housed patients paralyzed from polio and unable to breathe for themselves.

Chapter Outline
18.1 Overview of Specific Adaptive Immunity
18.2 Major Histocompatibility Complexes and Antigen-Presenting Cells
18.3 T Lymphocytes and Cellular Immunity
18.4 B Lymphocytes and Humoral Immunity
18.5 Vaccines

Introduction
People living in developed nations and born in the 1960s or later may have difficulty understanding the once heavy
burden of devastating infectious diseases. For example, smallpox, a deadly viral disease, once destroyed entire
civilizations but has since been eradicated. Thanks to the vaccination efforts by multiple groups, including the World
Health Organization, Rotary International, and the United Nations Children’s Fund (UNICEF), smallpox has not
been diagnosed in a patient since 1977. Polio is another excellent example. This crippling viral disease paralyzed
patients, who were often kept alive in “iron lung wards” as recently as the 1950s (Figure 18.1). Today, vaccination
against polio has nearly eradicated the disease. Vaccines have also reduced the prevalence of once-common infectious
diseases such as chickenpox, German measles, measles, mumps, and whooping cough. The success of these and other
vaccines is due to the very specific and adaptive host defenses that are the focus of this chapter.
Innate Nonspecific Host Defenses described innate immunity against microbial pathogens. Higher animals,
such as humans, also possess an adaptive immune defense, which is highly specific for individual microbial
pathogens. This specific adaptive immunity is acquired through active infection or vaccination and serves as an
important defense against pathogens that evade the defenses of innate immunity.
778 Chapter 18 | Adaptive Specific Host Defenses

18.1 Overview of Specific Adaptive Immunity

Learning Objectives
• Define memory, primary response, secondary response, and specificity
• Distinguish between humoral and cellular immunity
• Differentiate between antigens, epitopes, and haptens
• Describe the structure and function of antibodies and distinguish between the different classes of antibodies
Adaptive immunity is defined by two important characteristics: specificity and memory. Specificity refers to the
adaptive immune system’s ability to target specific pathogens, and memory refers to its ability to quickly respond to
pathogens to which it has previously been exposed. For example, when an individual recovers from chickenpox, the
body develops a memory of the infection that will specifically protect it from the causative agent, the varicella-zoster
virus, if it is exposed to the virus again later.
Specificity and memory are achieved by essentially programming certain cells involved in the immune response to
respond rapidly to subsequent exposures of the pathogen. This programming occurs as a result of the first exposure to
a pathogen or vaccine, which triggers a primary response. Subsequent exposures result in a secondary response that
is faster and stronger as a result of the body’s memory of the first exposure (Figure 18.2). This secondary response,
however, is specific to the pathogen in question. For example, exposure to one virus (e.g., varicella-zoster virus) will
not provide protection against other viral diseases (e.g., measles, mumps, or polio).
Adaptive specific immunity involves the actions of two distinct cell types: B lymphocytes (B cells) and T
lymphocytes (T cells). Although B cells and T cells arise from a common hematopoietic stem cell differentiation
pathway (see Figure 17.12), their sites of maturation and their roles in adaptive immunity are very different.
B cells mature in the bone marrow and are responsible for the production of glycoproteins called antibodies, or
immunoglobulins. Antibodies are involved in the body’s defense against pathogens and toxins in the extracellular
environment. Mechanisms of adaptive specific immunity that involve B cells and antibody production are referred to
as humoral immunity. The maturation of T cells occurs in the thymus. T cells function as the central orchestrator
of both innate and adaptive immune responses. They are also responsible for destruction of cells infected with
intracellular pathogens. The targeting and destruction of intracellular pathogens by T cells is called cell-mediated
immunity, or cellular immunity.

Clinical Focus

Part 1
Olivia, a one-year old infant, is brought to the emergency room by her parents, who report her symptoms:
excessive crying, irritability, sensitivity to light, unusual lethargy, and vomiting. A physician feels swollen lymph
nodes in Olivia’s throat and armpits. In addition, the area of the abdomen over the spleen is swollen and tender.
• What do these symptoms suggest?
• What tests might be ordered to try to diagnose the problem?
Jump to the next Clinical Focus box.

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Chapter 18 | Adaptive Specific Host Defenses 779

Figure 18.2 This graph illustrates the primary and secondary immune responses related to antibody production after
an initial and secondary exposure to an antigen. Notice that the secondary response is faster and provides a much
higher concentration of antibody.

• List the two defining characteristics of adaptive immunity.

• Explain the difference between a primary and secondary immune response.
• How do humoral and cellular immunity differ?

Antigens
Activation of the adaptive immune defenses is triggered by pathogen-specific molecular structures called antigens.
Antigens are similar to the pathogen-associated molecular patterns (PAMPs) discussed in Pathogen Recognition
and Phagocytosis; however, whereas PAMPs are molecular structures found on numerous pathogens, antigens are
unique to a specific pathogen. The antigens that stimulate adaptive immunity to chickenpox, for example, are unique
to the varicella-zoster virus but significantly different from the antigens associated with other viral pathogens.
The term antigen was initially used to describe molecules that stimulate the production of antibodies; in fact, the term
comes from a combination of the words antibody and generator, and a molecule that stimulates antibody production
is said to be antigenic. However, the role of antigens is not limited to humoral immunity and the production of
antibodies; antigens also play an essential role in stimulating cellular immunity, and for this reason antigens are
sometimes more accurately referred to as immunogens. In this text, however, we will typically refer to them as
antigens.
Pathogens possess a variety of structures that may contain antigens. For example, antigens from bacterial cells may
be associated with their capsules, cell walls, fimbriae, flagella, or pili. Bacterial antigens may also be associated with
extracellular toxins and enzymes that they secrete. Viruses possess a variety of antigens associated with their capsids,
envelopes, and the spike structures they use for attachment to cells.
Antigens may belong to any number of molecular classes, including carbohydrates, lipids, nucleic acids, proteins,
and combinations of these molecules. Antigens of different classes vary in their ability to stimulate adaptive immune
defenses as well as in the type of response they stimulate (humoral or cellular). The structural complexity of an
antigenic molecule is an important factor in its antigenic potential. In general, more complex molecules are more
effective as antigens. For example, the three-dimensional complex structure of proteins make them the most effective
and potent antigens, capable of stimulating both humoral and cellular immunity. In comparison, carbohydrates are
780 Chapter 18 | Adaptive Specific Host Defenses

less complex in structure and therefore less effective as antigens; they can only stimulate humoral immune defenses.
Lipids and nucleic acids are the least antigenic molecules, and in some cases may only become antigenic when
combined with proteins or carbohydrates to form glycolipids, lipoproteins, or nucleoproteins.
One reason the three-dimensional complexity of antigens is so important is that antibodies and T cells do not
recognize and interact with an entire antigen but with smaller exposed regions on the surface of antigens called
epitopes. A single antigen may possess several different epitopes (Figure 18.3), and different antibodies may bind
to different epitopes on the same antigen (Figure 18.4). For example, the bacterial flagellum is a large, complex
protein structure that can possess hundreds or even thousands of epitopes with unique three-dimensional structures.
Moreover, flagella from different bacterial species (or even strains of the same species) contain unique epitopes that
can only be bound by specific antibodies.
An antigen’s size is another important factor in its antigenic potential. Whereas large antigenic structures like flagella
possess multiple epitopes, some molecules are too small to be antigenic by themselves. Such molecules, called
haptens, are essentially free epitopes that are not part of the complex three-dimensional structure of a larger antigen.
For a hapten to become antigenic, it must first attach to a larger carrier molecule (usually a protein) to produce
a conjugate antigen. The hapten-specific antibodies produced in response to the conjugate antigen are then able
to interact with unconjugated free hapten molecules. Haptens are not known to be associated with any specific
pathogens, but they are responsible for some allergic responses. For example, the hapten urushiol, a molecule found
in the oil of plants that cause poison ivy, causes an immune response that can result in a severe rash (called contact
dermatitis). Similarly, the hapten penicillin can cause allergic reactions to drugs in the penicillin class.

Figure 18.3 An antigen is a macromolecule that reacts with components of the immune system. A given antigen
may contain several motifs that are recognized by immune cells.

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Chapter 18 | Adaptive Specific Host Defenses 781

Figure 18.4 A typical protein antigen has multiple epitopes, shown by the ability of three different antibodies to bind
to different epitopes of the same antigen.

• What is the difference between an antigen and an epitope?

• What factors affect an antigen’s antigenic potential?
• Why are haptens typically not antigenic, and how do they become antigenic?

Antibodies
Antibodies (also called immunoglobulins) are glycoproteins that are present in both the blood and tissue fluids. The
basic structure of an antibody monomer consists of four protein chains held together by disulfide bonds (Figure
18.5). A disulfide bond is a covalent bond between the sulfhydryl R groups found on two cysteine amino acids.
The two largest chains are identical to each other and are called the heavy chains. The two smaller chains are also
identical to each other and are called the light chains. Joined together, the heavy and light chains form a basic Y-
shaped structure.
The two ‘arms’ of the Y-shaped antibody molecule are known as the Fab region, for “fragment of antigen binding.”
The far end of the Fab region is the variable region, which serves as the site of antigen binding. The amino acid
sequence in the variable region dictates the three-dimensional structure, and thus the specific three-dimensional
epitope to which the Fab region is capable of binding. Although the epitope specificity of the Fab regions is identical
for each arm of a single antibody molecule, this region displays a high degree of variability between antibodies with
different epitope specificities. Binding to the Fab region is necessary for neutralization of pathogens, agglutination or
782 Chapter 18 | Adaptive Specific Host Defenses

aggregation of pathogens, and antibody-dependent cell-mediated cytotoxicity.

The constant region of the antibody molecule includes the trunk of the Y and lower portion of each arm of the Y.
The trunk of the Y is also called the Fc region, for “fragment of crystallization,” and is the site of complement factor
binding and binding to phagocytic cells during antibody-mediated opsonization.

Figure 18.5 (a) The typical four-chain structure of a generic antibody monomer. (b) The corresponding three-
dimensional structure of the antibody IgG. (credit b: modification of work by Tim Vickers)

• Describe the different functions of the Fab region and the Fc region.

Antibody Classes
The constant region of an antibody molecule determines its class, or isotype. The five classes of antibodies are IgG,
IgM, IgA, IgD, and IgE. Each class possesses unique heavy chains designated by Greek letters γ, μ, α, δ, and ε,
respectively. Antibody classes also exhibit important differences in abundance in serum, arrangement, body sites of
action, functional roles, and size (Figure 18.6).
IgG is a monomer that is by far the most abundant antibody in human blood, accounting for about 80% of total serum
antibody. IgG penetrates efficiently into tissue spaces, and is the only antibody class with the ability to cross the
placental barrier, providing passive immunity to the developing fetus during pregnancy. IgG is also the most versatile
antibody class in terms of its role in the body’s defense against pathogens.
IgM is initially produced in a monomeric membrane-bound form that serves as an antigen-binding receptor on B
cells. The secreted form of IgM assembles into a pentamer with five monomers of IgM bound together by a protein
structure called the J chain. Although the location of the J chain relative to the Fc regions of the five monomers
prevents IgM from performing some of the functions of IgG, the ten available Fab sites associated with a pentameric
IgM make it an important antibody in the body’s arsenal of defenses. IgM is the first antibody produced and secreted
by B cells during the primary and secondary immune responses, making pathogen-specific IgM a valuable diagnostic
marker during active or recent infections.
IgA accounts for about 13% of total serum antibody, and secretory IgA is the most common and abundant antibody
class found in the mucus secretions that protect the mucous membranes. IgA can also be found in other secretions
such as breast milk, tears, and saliva. Secretory IgA is assembled into a dimeric form with two monomers joined by a
protein structure called the secretory component. One of the important functions of secretory IgA is to trap pathogens

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Chapter 18 | Adaptive Specific Host Defenses 783

in mucus so that they can later be eliminated from the body.

Similar to IgM, IgD is a membrane-bound monomer found on the surface of B cells, where it serves as an antigen-
binding receptor. However, IgD is not secreted by B cells, and only trace amounts are detected in serum. These trace
amounts most likely come from the degradation of old B cells and the release of IgD molecules from their cytoplasmic
membranes.
IgE is the least abundant antibody class in serum. Like IgG, it is secreted as a monomer, but its role in adaptive
immunity is restricted to anti-parasitic defenses. The Fc region of IgE binds to basophils and mast cells. The
Fab region of the bound IgE then interacts with specific antigen epitopes, causing the cells to release potent pro-
inflammatory mediators. The inflammatory reaction resulting from the activation of mast cells and basophils aids in
the defense against parasites, but this reaction is also central to allergic reactions (see Diseases of the Immune
System.

Figure 18.6
784 Chapter 18 | Adaptive Specific Host Defenses

• What part of an antibody molecule determines its class?

• What class of antibody is involved in protection against parasites?
• Describe the difference in structure between IgM and IgG.

Antigen-Antibody Interactions
Different classes of antibody play important roles in the body’s defense against pathogens. These functions include
neutralization of pathogens, opsonization for phagocytosis, agglutination, complement activation, and antibody-
dependent cell-mediated cytotoxicity. For most of these functions, antibodies also provide an important link between
adaptive specific immunity and innate nonspecific immunity.
Neutralization involves the binding of certain antibodies (IgG, IgM, or IgA) to epitopes on the surface of pathogens
or toxins, preventing their attachment to cells. For example, Secretory IgA can bind to specific pathogens and block
initial attachment to intestinal mucosal cells. Similarly, specific antibodies can bind to certain toxins, blocking them
from attaching to target cells and thus neutralizing their toxic effects. Viruses can be neutralized and prevented from
infecting a cell by the same mechanism (Figure 18.7).
As described in Chemical Defenses, opsonization is the coating of a pathogen with molecules, such as complement
factors, C-reactive protein, and serum amyloid A, to assist in phagocyte binding to facilitate phagocytosis. IgG
antibodies also serve as excellent opsonins, binding their Fab sites to specific epitopes on the surface of pathogens.
Phagocytic cells such as macrophages, dendritic cells, and neutrophils have receptors on their surfaces that recognize
and bind to the Fc portion of the IgG molecules; thus, IgG helps such phagocytes attach to and engulf the pathogens
they have bound (Figure 18.8).
Agglutination or aggregation involves the cross-linking of pathogens by antibodies to create large aggregates
(Figure 18.9). IgG has two Fab antigen-binding sites, which can bind to two separate pathogen cells, clumping them
together. When multiple IgG antibodies are involved, large aggregates can develop; these aggregates are easier for
the kidneys and spleen to filter from the blood and easier for phagocytes to ingest for destruction. The pentameric
structure of IgM provides ten Fab binding sites per molecule, making it the most efficient antibody for agglutination.

Figure 18.7 Neutralization involves the binding of specific antibodies to antigens found on bacteria, viruses, and
toxins, preventing them from attaching to target cells.

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Chapter 18 | Adaptive Specific Host Defenses 785

Figure 18.8 Antibodies serve as opsonins and inhibit infection by tagging pathogens for destruction by
macrophages, dendritic cells, and neutrophils. These phagocytic cells use Fc receptors to bind to IgG-opsonized
pathogens and initiate the first step of attachment before phagocytosis.

Figure 18.9 Antibodies, especially IgM antibodies, agglutinate bacteria by binding to epitopes on two or more
bacteria simultaneously. When multiple pathogens and antibodies are present, aggregates form when the binding
sites of antibodies bind with separate pathogens.

Another important function of antibodies is activation of the complement cascade. As discussed in the previous
chapter, the complement system is an important component of the innate defenses, promoting the inflammatory
response, recruiting phagocytes to site of infection, enhancing phagocytosis by opsonization, and killing gram-
negative bacterial pathogens with the membrane attack complex (MAC). Complement activation can occur through
three different pathways (see Figure 17.9), but the most efficient is the classical pathway, which requires the initial
binding of IgG or IgM antibodies to the surface of a pathogen cell, allowing for recruitment and activation of the C1
complex.
Yet another important function of antibodies is antibody-dependent cell-mediated cytotoxicity (ADCC), which
enhances killing of pathogens that are too large to be phagocytosed. This process is best characterized for natural
killer cells (NK cells), as shown in Figure 18.10, but it can also involve macrophages and eosinophils. ADCC occurs
786 Chapter 18 | Adaptive Specific Host Defenses

when the Fab region of an IgG antibody binds to a large pathogen; Fc receptors on effector cells (e.g., NK cells) then
bind to the Fc region of the antibody, bringing them into close proximity with the target pathogen. The effector cell
then secretes powerful cytotoxins (e.g., perforin and granzymes) that kill the pathogen.

Figure 18.10 In this example of ADCC, antibodies bind to a large pathogenic cell that is too big for phagocytosis and
then bind to Fc receptors on the membrane of a natural killer cell. This interaction brings the NK cell into close
proximity, where it can kill the pathogen through release of lethal extracellular cytotoxins.

• Where is IgA normally found?

• Which class of antibody crosses the placenta, providing protection to the fetus?
• Compare the mechanisms of opsonization and antibody-dependent cell-mediated cytotoxicity.

18.2 Major Histocompatibility Complexes and Antigen-

Presenting Cells
Learning Objectives
• Identify cells that express MHC I and/or MHC II molecules and describe the structures and cellular location of
MHC I and MHC II molecules
• Identify the cells that are antigen-presenting cells
• Describe the process of antigen processing and presentation with MHC I and MHC II
As discussed in Cellular Defenses, major histocompatibility complex (MHC) molecules are expressed on the
surface of healthy cells, identifying them as normal and “self” to natural killer (NK) cells. MHC molecules also play
an important role in the presentation of foreign antigens, which is a critical step in the activation of T cells and thus
an important mechanism of the adaptive immune system.

Major Histocompatibility Complex Molecules

The major histocompatibility complex (MHC) is a collection of genes coding for MHC molecules found on the
surface of all nucleated cells of the body. In humans, the MHC genes are also referred to as human leukocyte antigen
(HLA) genes. Mature red blood cells, which lack a nucleus, are the only cells that do not express MHC molecules on
their surface.

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Chapter 18 | Adaptive Specific Host Defenses 787

There are two classes of MHC molecules involved in adaptive immunity, MHC I and MHC II (Figure 18.11).
MHC I molecules are found on all nucleated cells; they present normal self-antigens as well as abnormal or nonself
pathogens to the effector T cells involved in cellular immunity. In contrast, MHC II molecules are only found on
macrophages, dendritic cells, and B cells; they present abnormal or nonself pathogen antigens for the initial activation
of T cells.
Both types of MHC molecules are transmembrane glycoproteins that assemble as dimers in the cytoplasmic
membrane of cells, but their structures are quite different. MHC I molecules are composed of a longer α protein chain
coupled with a smaller β2 microglobulin protein, and only the α chain spans the cytoplasmic membrane. The α chain
of the MHC I molecule folds into three separate domains: α1, α2 and α3. MHC II molecules are composed of two
protein chains (an α and a β chain) that are approximately similar in length. Both chains of the MHC II molecule
possess portions that span the plasma membrane, and each chain folds into two separate domains: α1 and α2, and β1,
and β2. In order to present abnormal or non-self-antigens to T cells, MHC molecules have a cleft that serves as the
antigen-binding site near the “top” (or outermost) portion of the MHC-I or MHC-II dimer. For MHC I, the antigen-
binding cleft is formed by the α1 and α2 domains, whereas for MHC II, the cleft is formed by the α1 and β1 domains
(Figure 18.11).

Figure 18.11 MHC I are found on all nucleated body cells, and MHC II are found on macrophages, dendritic cells,
and B cells (along with MHC I). The antigen-binding cleft of MHC I is formed by domains α 1 and α2. The antigen-
binding cleft of MHC II is formed by domains α1 and β1.

• Compare the structures of the MHC I and MHC II molecules.

Antigen-Presenting Cells (APCs)

All nucleated cells in the body have mechanisms for processing and presenting antigens in association with MHC
molecules. This signals the immune system, indicating whether the cell is normal and healthy or infected with an
intracellular pathogen. However, only macrophages, dendritic cells, and B cells have the ability to present antigens
specifically for the purpose of activating T cells; for this reason, these types of cells are sometimes referred to as
antigen-presenting cells (APCs).
While all APCs play a similar role in adaptive immunity, there are some important differences to consider.
Macrophages and dendritic cells are phagocytes that ingest and kill pathogens that penetrate the first-line barriers (i.e.,
skin and mucous membranes). B cells, on the other hand, do not function as phagocytes but play a primary role in
788 Chapter 18 | Adaptive Specific Host Defenses

the production and secretion of antibodies. In addition, whereas macrophages and dendritic cells recognize pathogens
through nonspecific receptor interactions (e.g., PAMPs, toll-like receptors, and receptors for opsonizing complement
or antibody), B cells interact with foreign pathogens or their free antigens using antigen-specific immunoglobulin as
receptors (monomeric IgD and IgM). When the immunoglobulin receptors bind to an antigen, the B cell internalizes
the antigen by endocytosis before processing and presentting the antigen to T cells.

Antigen Presentation with MHC II Molecules

MHC II molecules are only found on the surface of APCs. Macrophages and dendritic cells use similar mechanisms
for processing and presentation of antigens and their epitopes in association with MHC II; B cells use somewhat
different mechanisms that will be described further in B Lymphocytes and Humoral Immunity. For now, we
will focus on the steps of the process as they pertain to dendritic cells.
After a dendritic cell recognizes and attaches to a pathogen cell, the pathogen is internalized by phagocytosis and is
initially contained within a phagosome. Lysosomes containing antimicrobial enzymes and chemicals fuse with the
phagosome to create a phagolysosome, where degradation of the pathogen for antigen processing begins. Proteases
(protein-degrading) are especially important in antigen processing because only protein antigen epitopes are presented
to T cells by MHC II (Figure 18.12).
APCs do not present all possible epitopes to T cells; only a selection of the most antigenic or immunodominant
epitopes are presented. The mechanism by which epitopes are selected for processing and presentation by an APC
is complicated and not well understood; however, once the most antigenic, immunodominant epitopes have been
processed, they associate within the antigen-binding cleft of MHC II molecules and are translocated to the cell surface
of the dendritic cell for presentation to T cells.

Figure 18.12 A dendritic cell phagocytoses a bacterial cell and brings it into a phagosome. Lysosomes fuse with the
phagosome to create a phagolysosome, where antimicrobial chemicals and enzymes degrade the bacterial cell.
Proteases process bacterial antigens, and the most antigenic epitopes are selected and presented on the cell’s
surface in conjunction with MHC II molecules. T cells recognize the presented antigens and are thus activated.

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Chapter 18 | Adaptive Specific Host Defenses 789

• What are the three kinds of APCs?

• What role to MHC II molecules play in antigen presentation?
• What is the role of antigen presentation in adaptive immunity?

Antigen Presentation with MHC I Molecules

MHC I molecules, found on all normal, healthy, nucleated cells, signal to the immune system that the cell is a
normal “self” cell. In a healthy cell, proteins normally found in the cytoplasm are degraded by proteasomes (enzyme
complexes responsible for degradation and processing of proteins) and processed into self-antigen epitopes; these
self-antigen epitopes bind within the MHC I antigen-binding cleft and are then presented on the cell surface. Immune
cells, such as NK cells, recognize these self-antigens and do not target the cell for destruction. However, if a cell
becomes infected with an intracellular pathogen (e.g., a virus), protein antigens specific to the pathogen are processed
in the proteasomes and bind with MHC I molecules for presentation on the cell surface. This presentation of pathogen-
specific antigens with MHC I signals that the infected cell must be targeted for destruction along with the pathogen.
Before elimination of infected cells can begin, APCs must first activate the T cells involved in cellular immunity. If
an intracellular pathogen directly infects the cytoplasm of an APC, then the processing and presentation of antigens
can occur as described (in proteasomes and on the cell surface with MHC I). However, if the intracellular pathogen
does not directly infect APCs, an alternative strategy called cross-presentation is utilized. In cross-presentation,
antigens are brought into the APC by mechanisms normally leading to presentation with MHC II (i.e., through
phagocytosis), but the antigen is presented on an MHC I molecule for CD8 T cells. The exact mechanisms by which
cross-presentation occur are not yet well understood, but it appears that cross-presentation is primarily a function of
dendritic cells and not macrophages or B cells.

• Compare and contrast antigen processing and presentation associated with MHC I and MHC II molecules.
• What is cross-presentation, and when is it likely to occur?

18.3 T Lymphocytes and Cellular Immunity

Learning Objectives
• Describe the process of T-cell maturation and thymic selection
• Explain the genetic events that lead to diversity of T-cell receptors
• Compare and contrast the various classes and subtypes of T cells in terms of activation and function
• Explain the mechanism by which superantigens effect unregulated T-cell activation
As explained in Overview of Specific Adaptive Immunity, the antibodies involved in humoral immunity often
bind pathogens and toxins before they can attach to and invade host cells. Thus, humoral immunity is primarily
concerned with fighting pathogens in extracellular spaces. However, pathogens that have already gained entry to host
cells are largely protected from the humoral antibody-mediated defenses. Cellular immunity, on the other hand, targets
and eliminates intracellular pathogens through the actions of T lymphocytes, or T cells (Figure 18.13). T cells also
play a more central role in orchestrating the overall adaptive immune response (humoral as well as cellular) along
with the cellular defenses of innate immunity.
790 Chapter 18 | Adaptive Specific Host Defenses

Figure 18.13 This scanning electron micrograph shows a T lymphocyte, which is responsible for the cell-mediated
immune response. The spike-like membrane structures increase surface area, allowing for greater interaction with
other cell types and their signals. (credit: modification of work by NCI)

T Cell Production and Maturation

T cells, like all other white blood cells involved in innate and adaptive immunity, are formed from multipotent
hematopoietic stem cells (HSCs) in the bone marrow (see Figure 17.12). However, unlike the white blood cells
of innate immunity, eventual T cells differentiate first into lymphoid stem cells that then become small, immature
lymphocytes, sometimes called lymphoblasts. The first steps of differentiation occur in the red marrow of bones
(Figure 18.14), after which immature T lymphocytes enter the bloodstream and travel to the thymus for the final
steps of maturation (Figure 18.15). Once in the thymus, the immature T lymphocytes are referred to as thymocytes.
The maturation of thymocytes within the thymus can be divided into tree critical steps of positive and negative
selection, collectively referred to as thymic selection. The first step of thymic selection occurs in the cortex of the
thymus and involves the development of a functional T-cell receptor (TCR) that is required for activation by APCs.
Thymocytes with defective TCRs are removed by negative selection through the induction of apoptosis (programmed
controlled cell death). The second step of thymic selection also occurs in the cortex and involves the positive selection
of thymocytes that will interact appropriately with MHC molecules. Thymocytes that can interact appropriately with
MHC molecules receive a positive stimulation that moves them further through the process of maturation, whereas
thymocytes that do not interact appropriately are not stimulated and are eliminated by apoptosis. The third and
final step of thymic selection occurs in both the cortex and medulla and involves negative selection to remove self-
reacting thymocytes, those that react to self-antigens, by apoptosis. This final step is sometimes referred to as central
tolerance because it prevents self-reacting T cells from reaching the bloodstream and potentially causing autoimmune
disease, which occurs when the immune system attacks healthy “self” cells.
Despite central tolerance, some self-reactive T cells generally escape the thymus and enter the peripheral bloodstream.
Therefore, a second line of defense called peripheral tolerance is needed to protect against autoimmune disease.
Peripheral tolerance involves mechanisms of anergy and inhibition of self-reactive T cells by regulatory T cells.
Anergy refers to a state of nonresponsiveness to antigen stimulation. In the case of self-reactive T cells that escape
the thymus, lack of an essential co-stimulatory signal required for activation causes anergy and prevents autoimmune
activation. Regulatory T cells participate in peripheral tolerance by inhibiting the activation and function of self-
reactive T cells and by secreting anti-inflammatory cytokines.
It is not completely understood what events specifically direct maturation of thymocytes into regulatory T cells.
Current theories suggest the critical events may occur during the third step of thymic selection, when most self-

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Chapter 18 | Adaptive Specific Host Defenses 791

reactive T cells are eliminated. Regulatory T cells may receive a unique signal that is below the threshold required
to target them for negative selection and apoptosis. Consequently, these cells continue to mature and then exit the
thymus, armed to inhibit the activation of self-reactive T cells.
It has been estimated that the three steps of thymic selection eliminate 98% of thymocytes. The remaining 2% that
exit the thymus migrate through the bloodstream and lymphatic system to sites of secondary lymphoid organs/tissues,
such as the lymph nodes, spleen, and tonsils (Figure 18.15), where they await activation through the presentation of
specific antigens by APCs. Until they are activated, they are known as mature naïve T cells.

Figure 18.14 (a) Red bone marrow can be found in the head of the femur (thighbone) and is also present in the flat
bones of the body, such as the ilium and the scapula. (b) Red bone marrow is the site of production and differentiation
of many formed elements of blood, including erythrocytes, leukocytes, and platelets. The yellow bone marrow is
populated primarily with adipose cells.

Figure 18.15 The thymus is a bi-lobed, H-shaped glandular organ that is located just above the heart. It is
surrounded by a fibrous capsule of connective tissue. The darkly staining cortex and the lighter staining medulla of
individual lobules are clearly visible in the light micrograph of the thymus of a newborn (top right, LM × 100). (credit
micrograph: modification of micrograph provided by the Regents of University of Michigan Medical School © 2012)
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• What anatomical sites are involved in T cell production and maturation?

• What are the three steps involved in thymic selection?
• Why are central tolerance and peripheral tolerance important? What do they prevent?

Classes of T Cells
T cells can be categorized into three distinct classes: helper T cells, regulatory T cells, and cytotoxic T cells. These
classes are differentiated based on their expression of certain surface molecules, their mode of activation, and their
functional roles in adaptive immunity (Table 18.1).
All T cells produce cluster of differentiation (CD) molecules, cell surface glycoproteins that can be used to
identify and distinguish between the various types of white blood cells. Although T cells can produce a variety of
CD molecules, CD4 and CD8 are the two most important used for differentiation of the classes. Helper T cells
and regulatory T cells are characterized by the expression of CD4 on their surface, whereas cytotoxic T cells are
characterized by the expression of CD8.
Classes of T cells can also be distinguished by the specific MHC molecules and APCs with which they interact for
activation. Helper T cells and regulatory T cells can only be activated by APCs presenting antigens associated with
MHC II. In contrast, cytotoxic T cells recognize antigens presented in association with MHC I, either by APCs or by
nucleated cells infected with an intracellular pathogen.
The different classes of T cells also play different functional roles in the immune system. Helper T cells serve as
the central orchestrators that help activate and direct functions of humoral and cellular immunity. In addition, helper
T cells enhance the pathogen-killing functions of macrophages and NK cells of innate immunity. In contrast, the
primary role of regulatory T cells is to prevent undesirable and potentially damaging immune responses. Their role
in peripheral tolerance, for example, protects against autoimmune disorders, as discussed earlier. Finally, cytotoxic T
cells are the primary effector cells for cellular immunity. They recognize and target cells that have been infected by
intracellular pathogens, destroying infected cells along with the pathogens inside.

Classes of T Cells
Class Surface Activation Functions
CD
Molecules

Helper T CD4 APCs presenting antigens associated Orchestrate humoral and cellular
cells with MHC II immunity

Involved in the activation of

macrophages and NK cells

Regulatory CD4 APCs presenting antigens associated Involved in peripheral tolerance and
T cells with MHC II prevention of autoimmune responses

Cytotoxic CD8 APCs or infected nucleated cells Destroy cells infected with intracellular
T cells presenting antigens associated with pathogens
MHC I

Table 18.1

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Chapter 18 | Adaptive Specific Host Defenses 793

• What are the unique functions of the three classes of T cells?

• Which T cells can be activated by antigens presented by cells other than APCs?

T-Cell Receptors
For both helper T cells and cytotoxic T cells, activation is a complex process that requires the interactions of multiple
molecules and exposure to cytokines. The T-cell receptor (TCR) is involved in the first step of pathogen epitope
recognition during the activation process.
The TCR comes from the same receptor family as the antibodies IgD and IgM, the antigen receptors on the B
cell membrane surface, and thus shares common structural elements. Similar to antibodies, the TCR has a variable
region and a constant region, and the variable region provides the antigen-binding site (Figure 18.16). However,
the structure of TCR is smaller and less complex than the immunoglobulin molecules (Figure 18.5). Whereas
immunoglobulins have four peptide chains and Y-shaped structures, the TCR consists of just two peptide chains (α
and β chains), both of which span the cytoplasmic membrane of the T cell.
TCRs are epitope-specific, and it has been estimated that 25 million T cells with unique epitope-binding TCRs are
required to protect an individual against a wide range of microbial pathogens. Because the human genome only
contains about 25,000 genes, we know that each specific TCR cannot be encoded by its own set of genes. This raises
the question of how such a vast population of T cells with millions of specific TCRs can be achieved. The answer is
a process called genetic rearrangement, which occurs in the thymus during the first step of thymic selection.
The genes that code for the variable regions of the TCR are divided into distinct gene segments called variable (V),
diversity (D), and joining (J) segments. The genes segments associated with the α chain of the TCR consist 70 or
more different Vα segments and 61 different Jα segments. The gene segments associated with the β chain of the TCR
consist of 52 different Vβ segments, two different Dβ segments, and 13 different Jβ segments. During the development
of the functional TCR in the thymus, genetic rearrangement in a T cell brings together one Vα segment and one Jα
segment to code for the variable region of the α chain. Similarly, genetic rearrangement brings one of the Vβ segments
together with one of the Dβ segments and one of thetJβ segments to code for the variable region of the β chain. All
the possible combinations of rearrangements between different segments of V, D, and J provide the genetic diversity
required to produce millions of TCRs with unique epitope-specific variable regions.
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Figure 18.16 A T-cell receptor spans the cytoplasmic membrane and projects variable binding regions into the
extracellular space to bind processed antigens associated with MHC I or MHC II molecules.

• What are the similarities and differences between TCRs and immunoglobulins?
• What process is used to provide millions of unique TCR binding sites?

Activation and Differentiation of Helper T Cells

Helper T cells can only be activated by APCs presenting processed foreign epitopes in association with MHC II. The
first step in the activation process is TCR recognition of the specific foreign epitope presented within the MHC II
antigen-binding cleft. The second step involves the interaction of CD4 on the helper T cell with a region of the MHC
II molecule separate from the antigen-binding cleft. This second interaction anchors the MHC II-TCR complex and
ensures that the helper T cell is recognizing both the foreign (“nonself”) epitope and “self” antigen of the APC; both
recognitions are required for activation of the cell. In the third step, the APC and T cell secrete cytokines that activate
the helper T cell. The activated helper T cell then proliferates, dividing by mitosis to produce clonal naïve helper T
cells that differentiate into subtypes with different functions (Figure 18.17).

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Chapter 18 | Adaptive Specific Host Defenses 795

Figure 18.17 This illustration depicts the activation of a naïve (unactivated) helper T cell by an antigen-presenting
cell and the subsequent proliferation and differentiation of the activated T cell into different subtypes.

Activated helper T cells can differentiate into one of four distinct subtypes, summarized in Table 18.2. The
differentiation process is directed by APC-secreted cytokines. Depending on which APC-secreted cytokines interact
with an activated helper T cell, the cell may differentiate into a T helper 1 (TH1) cell, a T helper 2 (TH2) cell, or
a memory helper T cell. The two types of helper T cells are relatively short-lived effector cells, meaning that they
perform various functions of the immediate immune response. In contrast, memory helper T cells are relatively long
lived; they are programmed to “remember” a specific antigen or epitope in order to mount a rapid, strong, secondary
response to subsequent exposures.
TH1 cells secrete their own cytokines that are involved in stimulating and orchestrating other cells involved in
adaptive and innate immunity. For example, they stimulate cytotoxic T cells, enhancing their killing of infected cells
and promoting differentiation into memory cytotoxic T cells. TH1 cells also stimulate macrophages and neutrophils
to become more effective in their killing of intracellular bacteria. They can also stimulate NK cells to become more
effective at killing target cells.
TH2 cells play an important role in orchestrating the humoral immune response through their secretion of cytokines
that activate B cells and direct B cell differentiation and antibody production. Various cytokines produced by TH2
cells orchestrate antibody class switching, which allows B cells to switch between the production of IgM, IgG,
IgA, and IgE as needed to carry out specific antibody functions and to provide pathogen-specific humoral immune
responses.
A third subtype of helper T cells called TH17 cells was discovered through observations that immunity to some
infections is not associated with TH1 or TH2 cells. TH17 cells and the cytokines they produce appear to be specifically
responsible for the body’s defense against chronic mucocutaneous infections. Patients who lack sufficient TH17 cells
in the mucosa (e.g., HIV patients) may be more susceptible to bacteremia and gastrointestinal infections. [1]

1. Blaschitz C., Raffatellu M. “Th17 cytokines and the gut mucosal barrier.” J Clin Immunol. 2010 Mar; 30(2):196-203. doi: 10.1007/
s10875-010-9368-7.
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Subtypes of Helper T Cells

Subtype Functions

TH1 cells Stimulate cytotoxic T cells and produce memory cytotoxic T cells

Stimulate macrophages and neutrophils (PMNs) for more effective intracellular killing of
pathogens

Stimulate NK cells to kill more effectively

TH2 cells Stimulate B cell activation and differentiation into plasma cells and memory B cells

Direct antibody class switching in B cells

TH17 cells Stimulate immunity to specific infections such as chronic mucocutaneous infections

Memory helper T “Remember” a specific pathogen and mount a strong, rapid secondary response upon re-
cells exposure

Table 18.2

Activation and Differentiation of Cytotoxic T Cells

Cytotoxic T cells (also referred to as cytotoxic T lymphocytes, or CTLs) are activated by APCs in a three-step process
similar to that of helper T cells. The key difference is that the activation of cytotoxic T cells involves recognition
of an antigen presented with MHC I (as opposed to MHC II) and interaction of CD8 (as opposed to CD4) with the
receptor complex. After the successful co-recognition of foreign epitope and self-antigen, the production of cytokines
by the APC and the cytotoxic T cell activate clonal proliferation and differentiation. Activated cytotoxic T cells can
differentiate into effector cytotoxic T cells that target pathogens for destruction or memory cells that are ready to
respond to subsequent exposures.
As noted, proliferation and differentiation of cytotoxic T cells is also stimulated by cytokines secreted from TH1 cells
activated by the same foreign epitope. The co-stimulation that comes from these TH1 cells is provided by secreted
cytokines. Although it is possible for activation of cytotoxic T cells to occur without stimulation from TH1 cells, the
activation is not as effective or long-lasting.
Once activated, cytotoxic T cells serve as the effector cells of cellular immunity, recognizing and kill cells infected
with intracellular pathogens through a mechanism very similar to that of NK cells. However, whereas NK cells
recognize nonspecific signals of cell stress or abnormality, cytotoxic T cells recognize infected cells through antigen
presentation of pathogen-specific epitopes associated with MHC I. Once an infected cell is recognized, the TCR of
the cytotoxic T cell binds to the epitope and releases perforin and granzymes that destroy the infected cell (Figure
18.18). Perforin is a protein that creates pores in the target cell, and granzymes are proteases that enter the pores
and induce apoptosis. This mechanism of programmed cell death is a controlled and efficient means of destroying
and removing infected cells without releasing the pathogens inside to infect neighboring cells, as might occur if the
infected cells were simply lysed.

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Chapter 18 | Adaptive Specific Host Defenses 797

Figure 18.18 This figure illustrates the activation of a naïve (unactivated) cytotoxic T cell (CTL) by an antigen-
presenting MHC I molecule on an infected body cell. Once activated, the CTL releases perforin and granzymes that
invade the infected cell and induce controlled cell death, or apoptosis.

Link to Learning

In this video (https://www.openstax.org/l/22cytoTcellapop) , you can see a

cytotoxic T cell inducing apoptosis in a target cell.

• Compare and contrast the activation of helper T cells and cytotoxic T cells.
• What are the different functions of helper T cell subtypes?
• What is the mechanism of CTL-mediated destruction of infected cells?

Superantigens and Unregulated Activation of T Cells

When T cell activation is controlled and regulated, the result is a protective response that is effective in combating
infections. However, if T cell activation is unregulated and excessive, the result can be a life-threatening. Certain
bacterial and viral pathogens produce toxins known as superantigens (see Virulence Factors of Bacterial and
Viral Pathogens) that can trigger such an unregulated response. Known bacterial superantigens include toxic shock
syndrome toxin (TSST), staphylococcal enterotoxins, streptococcal pyrogenic toxins, streptococcal superantigen, and
the streptococcal mitogenic exotoxin. Viruses known to produce superantigens include Epstein-Barr virus (human
herpesvirus 4), cytomegalovirus (human herpesvirus 5), and others.
798 Chapter 18 | Adaptive Specific Host Defenses

The mechanism of T cell activation by superantigens involves their simultaneous binding to MHC II molecules of
APCs and the variable region of the TCR β chain. This binding occurs outside of the antigen-binding cleft of MHC II,
so the superantigen will bridge together and activate MHC II and TCR without specific foreign epitope recognition
(Figure 18.19). The result is an excessive, uncontrolled release of cytokines, often called a cytokine storm, which
stimulates an excessive inflammatory response. This can lead to a dangerous decrease in blood pressure, shock, multi-
organ failure, and potentially, death.

Figure 18.19 (a) The macrophage in this figure is presenting a foreign epitope that does not match the TCR of the T
cell. Because the T cell does not recognize the epitope, it is not activated. (b) The macrophage in this figure is
presenting a superantigen that is not recognized by the TCR of the T cell, yet the superantigen still is able to bridge
and bind the MHC II and TCR molecules. This nonspecific, uncontrolled activation of the T cell results in an excessive
release of cytokines that activate other T cells and cause excessive inflammation. (credit: modification of work by
“Microbiotic”/YouTube)

• What are examples of superantigens?

• How does a superantigen activate a helper T cell?
• What effect does a superantigen have on a T cell?

Case in Point

Superantigens
Melissa, an otherwise healthy 22-year-old woman, is brought to the emergency room by her concerned
boyfriend. She complains of a sudden onset of high fever, vomiting, diarrhea, and muscle aches. In her initial
interview, she tells the attending physician that she is on hormonal birth control and also is two days into the
menstruation portion of her cycle. She is on no other medications and is not abusing any drugs or alcohol. She
is not a smoker. She is not diabetic and does not currently have an infection of any kind to her knowledge.
While waiting in the emergency room, Melissa’s blood pressure begins to drop dramatically and her mental
state deteriorates to general confusion. The physician believes she is likely suffering from toxic shock
syndrome (TSS). TSS is caused by the toxin TSST-1, a superantigen associated with Staphylococcus aureus,

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Chapter 18 | Adaptive Specific Host Defenses 799

and improper tampon use is a common cause of infections leading to TSS. The superantigen inappropriately
stimulates widespread T cell activation and excessive cytokine release, resulting in a massive and systemic
inflammatory response that can be fatal.
Vaginal or cervical swabs may be taken to confirm the presence of the microbe, but these tests are not critical
to perform based on Melissa’s symptoms and medical history. The physician prescribes rehydration, supportive
therapy, and antibiotics to stem the bacterial infection. She also prescribes drugs to increase Melissa’s blood
pressure. Melissa spends three days in the hospital undergoing treatment; in addition, her kidney function is
monitored because of the high risk of kidney failure associated with TSS. After 72 hours, Melissa is well enough
to be discharged to continue her recovery at home.
• In what way would antibiotic therapy help to combat a superantigen?

Clinical Focus

Part 2
Olivia’s swollen lymph nodes, abdomen, and spleen suggest a strong immune response to a systemic infection
in progress. In addition, little Olivia is reluctant to turn her head and appears to be experiencing severe neck
pain. The physician orders a complete blood count, blood culture, and lumbar puncture. The cerebrospinal
fluid (CSF) obtained appears cloudy and is further evaluated by Gram stain assessment and culturing for
potential bacterial pathogens. The complete blood count indicates elevated numbers of white blood cells in
Olivia’s bloodstream. The white blood cell increases are recorded at 28.5 K/µL (normal range: 6.0–17.5 K/µL).
The neutrophil percentage was recorded as 60% (normal range: 23–45%). Glucose levels in the CSF were
registered at 30 mg/100 mL (normal range: 50–80 mg/100 mL). The WBC count in the CSF was 1,163/mm3
(normal range: 5–20/mm3).
• Based on these results, do you have a preliminary diagnosis?
• What is a recommended treatment based on this preliminary diagnosis?
Jump to the next Clinical Focus box. Go back to the previous Clinical Focus box.

18.4 B Lymphocytes and Humoral Immunity

Learning Objectives
• Describe the production and maturation of B cells
• Compare the structure of B-cell receptors and T-cell receptors
• Compare T-dependent and T-independent activation of B cells
• Compare the primary and secondary antibody responses
Humoral immunity refers to mechanisms of the adaptive immune defenses that are mediated by antibodies secreted by
B lymphocytes, or B cells. This section will focus on B cells and discuss their production and maturation, receptors,
and mechanisms of activation.

B Cell Production and Maturation

Like T cells, B cells are formed from multipotent hematopoietic stem cells (HSCs) in the bone marrow and follow
a pathway through lymphoid stem cell and lymphoblast (see Figure 17.12). Unlike T cells, however, lymphoblasts
800 Chapter 18 | Adaptive Specific Host Defenses

destined to become B cells do not leave the bone marrow and travel to the thymus for maturation. Rather, eventual B
cells continue to mature in the bone marrow.
The first step of B cell maturation is an assessment of the functionality of their antigen-binding receptors. This occurs
through positive selection for B cells with normal functional receptors. A mechanism of negative selection is then
used to eliminate self-reacting B cells and minimize the risk of autoimmunity. Negative selection of self-reacting B
cells can involve elimination by apoptosis, editing or modification of the receptors so they are no longer self-reactive,
or induction of anergy in the B cell. Immature B cells that pass the selection in the bone marrow then travel to the
spleen for their final stages of maturation. There they become naïve mature B cells, i.e., mature B cells that have not
yet been activated.

• Compare the maturation of B cells with the maturation of T cells.

B-Cell Receptors
Like T cells, B cells possess antigen-specific receptors with diverse specificities. Although they rely on T cells for
optimum function, B cells can be activated without help from T cells. B-cell receptors (BCRs) for naïve mature
B cells are membrane-bound monomeric forms of IgD and IgM. They have two identical heavy chains and two
identical light chains connected by disulfide bonds into a basic “Y” shape (Figure 18.20). The trunk of the Y-shaped
molecule, the constant region of the two heavy chains, spans the B cell membrane. The two antigen-binding sites
exposed to the exterior of the B cell are involved in the binding of specific pathogen epitopes to initiate the activation
process. It is estimated that each naïve mature B cell has upwards of 100,000 BCRs on its membrane, and each of
these BCRs has an identical epitope-binding specificity.
In order to be prepared to react to a wide range of microbial epitopes, B cells, like T cells, use genetic rearrangement
of hundreds of gene segments to provide the necessary diversity of receptor specificities. The variable region of the
BCR heavy chain is made up of V, D, and J segments, similar to the β chain of the TCR. The variable region of the
BCR light chain is made up of V and J segments, similar to the α chain of the TCR. Genetic rearrangement of all
possible combinations of V-J-D (heavy chain) and V-J (light chain) provides for millions of unique antigen-binding
sites for the BCR and for the antibodies secreted after activation.
One important difference between BCRs and TCRs is the way they can interact with antigenic epitopes. Whereas
TCRs can only interact with antigenic epitopes that are presented within the antigen-binding cleft of MHC I or MHC
II, BCRs do not require antigen presentation with MHC; they can interact with epitopes on free antigens or with
epitopes displayed on the surface of intact pathogens. Another important difference is that TCRs only recognize
protein epitopes, whereas BCRs can recognize epitopes associated with different molecular classes (e.g., proteins,
polysaccharides, lipopolysaccharides).
Activation of B cells occurs through different mechanisms depending on the molecular class of the antigen. Activation
of a B cell by a protein antigen requires the B cell to function as an APC, presenting the protein epitopes with MHC II
to helper T cells. Because of their dependence on T cells for activation of B cells, protein antigens are classified as T-
dependent antigens. In contrast, polysaccharides, lipopolysaccharides, and other nonprotein antigens are considered
T-independent antigens because they can activate B cells without antigen processing and presentation to T cells.

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Chapter 18 | Adaptive Specific Host Defenses 801

Figure 18.20 B-cell receptors are embedded in the membranes of B cells. The variable regions of all of the
receptors on a single cell bind the same specific antigen.

• What types of molecules serve as the BCR?

• What are the differences between TCRs and BCRs with respect to antigen recognition?
• Which molecule classes are T-dependent antigens and which are T-independent antigens?

T Cell-Independent Activation of B cells

Activation of B cells without the cooperation of helper T cells is referred to as T cell-independent activation and
occurs when BCRs interact with T-independent antigens. T-independent antigens (e.g., polysaccharide capsules,
lipopolysaccharide) have repetitive epitope units within their structure, and this repetition allows for the cross-linkage
of multiple BCRs, providing the first signal for activation (Figure 18.21). Because T cells are not involved, the
second signal has to come from other sources, such as interactions of toll-like receptors with PAMPs or interactions
with factors from the complement system.
Once a B cell is activated, it undergoes clonal proliferation and daughter cells differentiate into plasma cells.
Plasma cells are antibody factories that secrete large quantities of antibodies. After differentiation, the surface BCRs
disappear and the plasma cell secretes pentameric IgM molecules that have the same antigen specificity as the BCRs
(Figure 18.21).
The T cell-independent response is short-lived and does not result in the production of memory B cells. Thus it will
not result in a secondary response to subsequent exposures to T-independent antigens.
802 Chapter 18 | Adaptive Specific Host Defenses

Figure 18.21 T-independent antigens have repeating epitopes that can induce B cell recognition and activation
without involvement from T cells. A second signal, such as interaction of TLRs with PAMPs (not shown), is also
required for activation of the B cell. Once activated, the B cell proliferates and differentiates into antibody-secreting
plasma cells.

• What are the two signals required for T cell-independent activation of B cells?
• What is the function of a plasma cell?

T Cell-Dependent Activation of B cells

T cell-dependent activation of B cells is more complex than T cell-independent activation, but the resulting immune
response is stronger and develops memory. T cell-dependent activation can occur either in response to free protein
antigens or to protein antigens associated with an intact pathogen. Interaction between the BCRs on a naïve mature
B cell and a free protein antigen stimulate internalization of the antigen, whereas interaction with antigens associated
with an intact pathogen initiates the extraction of the antigen from the pathogen before internalization. Once
internalized inside the B cell, the protein antigen is processed and presented with MHC II. The presented antigen is
then recognized by helper T cells specific to the same antigen. The TCR of the helper T cell recognizes the foreign
antigen, and the T cell’s CD4 molecule interacts with MHC II on the B cell. The coordination between B cells and
helper T cells that are specific to the same antigen is referred to as linked recognition.
Once activated by linked recognition, TH2 cells produce and secrete cytokines that activate the B cell and cause
proliferation into clonal daughter cells. After several rounds of proliferation, additional cytokines provided by the
TH2 cells stimulate the differentiation of activated B cell clones into memory B cells, which will quickly respond
to subsequent exposures to the same protein epitope, and plasma cells that lose their membrane BCRs and initially
secrete pentameric IgM (Figure 18.22).
After initial secretion of IgM, cytokines secreted by TH2 cells stimulate the plasma cells to switch from IgM
production to production of IgG, IgA, or IgE. This process, called class switching or isotype switching, allows plasma
cells cloned from the same activated B cell to produce a variety of antibody classes with the same epitope specificity.
Class switching is accomplished by genetic rearrangement of gene segments encoding the constant region, which
determines an antibody’s class. The variable region is not changed, so the new class of antibody retains the original
epitope specificity.

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Chapter 18 | Adaptive Specific Host Defenses 803

Figure 18.22 In T cell-dependent activation of B cells, the B cell recognizes and internalizes an antigen and
presents it to a helper T cell that is specific to the same antigen. The helper T cell interacts with the antigen presented
by the B cell, which activates the T cell and stimulates the release of cytokines that then activate the B cell. Activation
of the B cell triggers proliferation and differentiation into B cells and plasma cells.

• What steps are required for T cell-dependent activation of B cells?

• What is antibody class switching and why is it important?

Primary and Secondary Responses

T cell-dependent activation of B cells plays an important role in both the primary and secondary responses associated
with adaptive immunity. With the first exposure to a protein antigen, a T cell-dependent primary antibody response
occurs. The initial stage of the primary response is a lag period, or latent period, of approximately 10 days, during
which no antibody can be detected in serum. This lag period is the time required for all of the steps of the primary
804 Chapter 18 | Adaptive Specific Host Defenses

response, including naïve mature B cell binding of antigen with BCRs, antigen processing and presentation, helper T
cell activation, B cell activation, and clonal proliferation. The end of the lag period is characterized by a rise in IgM
levels in the serum, as TH2 cells stimulate B cell differentiation into plasma cells. IgM levels reach their peak around
14 days after primary antigen exposure; at about this same time, TH2 stimulates antibody class switching, and IgM
levels in serum begin to decline. Meanwhile, levels of IgG increase until they reach a peak about three weeks into the
primary response (Figure 18.23).
During the primary response, some of the cloned B cells are differentiated into memory B cells programmed to
respond to subsequent exposures. This secondary response occurs more quickly and forcefully than the primary
response. The lag period is decreased to only a few days and the production of IgG is significantly higher than
observed for the primary response (Figure 18.23). In addition, the antibodies produced during the secondary
response are more effective and bind with higher affinity to the targeted epitopes. Plasma cells produced during
secondary responses live longer than those produced during the primary response, so levels of specific antibody
remain elevated for a longer period of time.

Figure 18.23 Compared to the primary response, the secondary antibody response occurs more quickly and
produces antibody levels that are higher and more sustained. The secondary response mostly involves IgG.

• What events occur during the lag period of the primary antibody response?
• Why do antibody levels remain elevated longer during the secondary antibody response?

18.5 Vaccines
Learning Objectives
• Compare the various kinds of artificial immunity
• Differentiate between variolation and vaccination
• Describe different types of vaccines and explain their respective advantages and disadvantages
For many diseases, prevention is the best form of treatment, and few strategies for disease prevention are as effective

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Chapter 18 | Adaptive Specific Host Defenses 805

as vaccination. Vaccination is a form of artificial immunity. By artificially stimulating the adaptive immune defenses,
a vaccine triggers memory cell production similar to that which would occur during a primary response. In so doing,
the patient is able to mount a strong secondary response upon exposure to the pathogen—but without having to first
suffer through an initial infection. In this section, we will explore several different kinds of artificial immunity along
with various types of vaccines and the mechanisms by which they induce artificial immunity.

Classifications of Adaptive Immunity

All forms of adaptive immunity can be described as either active or passive. Active immunity refers to the activation
of an individual’s own adaptive immune defenses, whereas passive immunity refers to the transfer of adaptive
immune defenses from another individual or animal. Active and passive immunity can be further subdivided based
on whether the protection is acquired naturally or artificially.
Natural active immunity is adaptive immunity that develops after natural exposure to a pathogen (Figure 18.24).
Examples would include the lifelong immunity that develops after recovery from a chickenpox or measles infection
(although an acute infection is not always necessary to activate adaptive immunity). The length of time that an
individual is protected can vary substantially depending upon the pathogen and antigens involved. For example,
activation of adaptive immunity by protein spike structures during an intracellular viral infection can activate lifelong
immunity, whereas activation by carbohydrate capsule antigens during an extracellular bacterial infection may
activate shorter-term immunity.
Natural passive immunity involves the natural passage of antibodies from a mother to her child before and after
birth. IgG is the only antibody class that can cross the placenta from mother’s blood to the fetal blood supply. Placental
transfer of IgG is an important passive immune defense for the infant, lasting up to six months after birth. Secretory
IgA can also be transferred from mother to infant through breast milk.
Artificial passive immunity refers to the transfer of antibodies produced by a donor (human or animal) to another
individual. This transfer of antibodies may be done as a prophylactic measure (i.e., to prevent disease after exposure
to a pathogen) or as a strategy for treating an active infection. For example, artificial passive immunity is commonly
used for post-exposure prophylaxis against rabies, hepatitis A, hepatitis B, and chickenpox (in high risk individuals).
Active infections treated by artificial passive immunity include cytomegalovirus infections in immunocompromised
patients and Ebola virus infections. In 1995, eight patients in the Democratic Republic of the Congo with active Ebola
infections were treated with blood transfusions from patients who were recovering from Ebola. Only one of the eight
patients died (a 12.5% mortality rate), which was much lower than the expected 80% mortality rate for Ebola in
untreated patients.[2] Artificial passive immunity is also used for the treatment of diseases caused by bacterial toxins,
including tetanus, botulism, and diphtheria.
Artificial active immunity is the foundation for vaccination. It involves the activation of adaptive immunity through
the deliberate exposure of an individual to weakened or inactivated pathogens, or preparations consisting of key
pathogen antigens.

2. K. Mupapa, M. Massamba, K. Kibadi, K. Kivula, A. Bwaka, M. Kipasa, R. Colebunders, J. J. Muyembe-Tamfum. “Treatment of Ebola
Hemorrhagic Fever with Blood Transfusions from Convalescent Patients.” Journal of Infectious Diseases 179 Suppl. (1999): S18–S23.
806 Chapter 18 | Adaptive Specific Host Defenses

Figure 18.24 The four classifications of immunity. (credit top left photo: modification of work by USDA; credit top
right photo: modification of work by “Michaelberry”/Wikimedia; credit bottom left photo: modification of work by
Centers for Disease Control and Prevention; credit bottom right photo: modification of work by Friskila Silitonga,
Indonesia, Centers for Disease Control and Prevention)

• What is the difference between active and passive immunity?

• What kind of immunity is conferred by a vaccine?

Herd Immunity
The four kinds of immunity just described result from an individual’s adaptive immune system. For any given
disease, an individual may be considered immune or susceptible depending on his or her ability to mount an effective
immune response upon exposure. Thus, any given population is likely to have some individuals who are immune and
other individuals who are susceptible. If a population has very few susceptible individuals, even those susceptible
individuals will be protected by a phenomenon called herd immunity. Herd immunity has nothing to do with an
individual’s ability to mount an effective immune response; rather, it occurs because there are too few susceptible
individuals in a population for the disease to spread effectively.
Vaccination programs create herd immunity by greatly reducing the number of susceptible individuals in a population.
Even if some individuals in the population are not vaccinated, as long as a certain percentage is immune (either
naturally or artificially), the few susceptible individuals are unlikely to be exposed to the pathogen. However, because
new individuals are constantly entering populations (for example, through birth or relocation), vaccination programs
are necessary to maintain herd immunity.

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Chapter 18 | Adaptive Specific Host Defenses 807

Eye on Ethics

Vaccination: Obligation or Choice

A growing number of parents are choosing not to vaccinate their children. They are dubbed “antivaxxers,” and
the majority of them believe that vaccines are a cause of autism (or other disease conditions), a link that has
now been thoroughly disproven. Others object to vaccines on religious or moral grounds (e.g., the argument
that Gardasil vaccination against HPV may promote sexual promiscuity), on personal ethical grounds (e.g., a
conscientious objection to any medical intervention), or on political grounds (e.g., the notion that mandatory
vaccinations are a violation of individual liberties).[3]
It is believed that this growing number of unvaccinated individuals has led to new outbreaks of whooping cough
and measles. We would expect that herd immunity would protect those unvaccinated in our population, but
herd immunity can only be maintained if enough individuals are being vaccinated.
Vaccination is clearly beneficial for public health. But from the individual parent’s perspective the view can
be murkier. Vaccines, like all medical interventions, have associated risks, and while the risks of vaccination
may be extremely low compared to the risks of infection, parents may not always understand or accept the
consensus of the medical community. Do such parents have a right to withhold vaccination from their children?
Should they be allowed to put their children—and society at large—at risk?
Many governments insist on childhood vaccinations as a condition for entering public school, but it has become
easy in most states to opt out of the requirement or to keep children out of the public system. Since the 1970s,
West Virginia and Mississippi have had in place a stringent requirement for childhood vaccination, without
exceptions, and neither state has had a case of measles since the early 1990s. California lawmakers recently
passed a similar law in response to a measles outbreak in 2015, making it much more difficult for parents to
opt out of vaccines if their children are attending public schools. Given this track record and renewed legislative
efforts, should other states adopt similarly strict requirements?
What role should health-care providers play in promoting or enforcing universal vaccination? Studies have
shown that many parents’ minds can be changed in response to information delivered by health-care workers,
but is it the place of health-care workers to try to persuade parents to have their children vaccinated? Some
health-care providers are understandably reluctant to treat unvaccinated patients. Do they have the right to
refuse service to patients who decline vaccines? Do insurance companies have the right to deny coverage to
antivaxxers? These are all ethical questions that policymakers may be forced to address as more parents skirt
vaccination norms.

Variolation and Vaccination

Thousands of years ago, it was first recognized that individuals who survived a smallpox infection were immune to
subsequent infections. The practice of inoculating individuals to actively protect them from smallpox appears to have
originated in the 10th century in China, when the practice of variolation was described (Figure 18.25). Variolation
refers to the deliberate inoculation of individuals with infectious material from scabs or pustules of smallpox victims.
Infectious materials were either injected into the skin or introduced through the nasal route. The infection that
developed was usually milder than naturally acquired smallpox, and recovery from the milder infection provided
protection against the more serious disease.
Although the majority of individuals treated by variolation developed only mild infections, the practice was not
without risks. More serious and sometimes fatal infections did occur, and because smallpox was contagious,

3. Elizabeth Yale. “Why Anti-Vaccination Movements Can Never Be Tamed.” Religion & Politics, July 22, 2014.
http://religionandpolitics.org/2014/07/22/why-anti-vaccination-movements-can-never-be-tamed.
808 Chapter 18 | Adaptive Specific Host Defenses

infections resulting from variolation could lead to epidemics. Even so, the practice of variolation for smallpox
prevention spread to other regions, including India, Africa, and Europe.

Figure 18.25 Variolation for smallpox originated in the Far East and the practice later spread to Europe and Africa.
This Japanese relief depicts a patient receiving a smallpox variolation from the physician Ogata Shunsaku
(1748–1810).

Although variolation had been practiced for centuries, the English physician Edward Jenner (1749–1823) is generally
credited with developing the modern process of vaccination. Jenner observed that milkmaids who developed cowpox,
a disease similar to smallpox but milder, were immune to the more serious smallpox. This led Jenner to hypothesize
that exposure to a less virulent pathogen could provide immune protection against a more virulent pathogen, providing
a safer alternative to variolation. In 1796, Jenner tested his hypothesis by obtaining infectious samples from a
milkmaid’s active cowpox lesion and injecting the materials into a young boy (Figure 18.26). The boy developed a
mild infection that included a low-grade fever, discomfort in his axillae (armpit) and loss of appetite. When the boy
was later infected with infectious samples from smallpox lesions, he did not contract smallpox.[4] This new approach
was termed vaccination, a name deriving from the use of cowpox (Latin vacca meaning “cow”) to protect against
smallpox. Today, we know that Jenner’s vaccine worked because the cowpox virus is genetically and antigenically
related to the Variola viruses that caused smallpox. Exposure to cowpox antigens resulted in a primary response and
the production of memory cells that identical or related epitopes of Variola virus upon a later exposure to smallpox.
The success of Jenner’s smallpox vaccination led other scientists to develop vaccines for other diseases. Perhaps the
most notable was Louis Pasteur, who developed vaccines for rabies, cholera, and anthrax. During the 20th and 21st
centuries, effective vaccines were developed to prevent a wide range of diseases caused by viruses (e.g., chickenpox
and shingles, hepatitis, measles, mumps, polio, and yellow fever) and bacteria (e.g., diphtheria, pneumococcal
pneumonia, tetanus, and whooping cough,).

4. N. J. Willis. “Edward Jenner and the Eradication of Smallpox.” Scottish Medical Journal 42 (1997): 118–121.

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Chapter 18 | Adaptive Specific Host Defenses 809

Figure 18.26 (a) A painting of Edward Jenner depicts a cow and a milkmaid in the background. (b) Lesions on a
patient infected with cowpox, a zoonotic disease caused by a virus closely related to the one that causes smallpox.
(credit b: modification of work by the Centers for Disease Control and Prevention)

• What is the difference between variolation and vaccination for smallpox?

• Explain why vaccination is less risky than variolation.

Classes of Vaccines
For a vaccine to provide protection against a disease, it must expose an individual to pathogen-specific antigens
that will stimulate a protective adaptive immune response. By its very nature, this entails some risk. As with any
pharmaceutical drug, vaccines have the potential to cause adverse effects. However, the ideal vaccine causes no severe
adverse effects and poses no risk of contracting the disease that it is intended to prevent. Various types of vaccines
have been developed with these goals in mind. These different classes of vaccines are described in the next section
and summarized in Table 18.3.

Live Attenuated Vaccines

Live attenuated vaccines expose an individual to a weakened strain of a pathogen with the goal of establishing
a subclinical infection that will activate the adaptive immune defenses. Pathogens are attenuated to decrease their
virulence using methods such as genetic manipulation (to eliminate key virulence factors) or long-term culturing in
an unnatural host or environment (to promote mutations and decrease virulence).
By establishing an active infection, live attenuated vaccines stimulate a more comprehensive immune response than
some other types of vaccines. Live attenuated vaccines activate both cellular and humoral immunity and stimulate the
development of memory for long-lasting immunity. In some cases, vaccination of one individual with a live attenuated
pathogen can even lead to natural transmission of the attenuated pathogen to other individuals. This can cause the
other individuals to also develop an active, subclinical infection that activates their adaptive immune defenses.
Disadvantages associated with live attenuated vaccines include the challenges associated with long-term storage and
transport as well as the potential for a patient to develop signs and symptoms of disease during the active infection
(particularly in immunocompromised patients). There is also a risk of the attenuated pathogen reverting back to full
virulence. Table 18.3 lists examples live attenuated vaccines.
810 Chapter 18 | Adaptive Specific Host Defenses

Inactivated Vaccines
Inactivated vaccines contain whole pathogens that have been killed or inactivated with heat, chemicals, or radiation.
For inactivated vaccines to be effective, the inactivation process must not affect the structure of key antigens on the
pathogen.
Because the pathogen is killed or inactive, inactivated vaccines do not produce an active infection, and the resulting
immune response is weaker and less comprehensive than that provoked by a live attenuated vaccine. Typically the
response involves only humoral immunity, and the pathogen cannot be transmitted to other individuals. In addition,
inactivated vaccines usually require higher doses and multiple boosters, possibly causing inflammatory reactions at
the site of injection.
Despite these disadvantages, inactivated vaccines do have the advantages of long-term storage stability and ease of
transport. Also, there is no risk of causing severe active infections. However, inactivated vaccines are not without
their side effects. Table 18.3 lists examples of inactivated vaccines.

Subunit Vaccines
Whereas live attenuated and inactive vaccines expose an individual to a weakened or dead pathogen, subunit
vaccines only expose the patient to the key antigens of a pathogen—not whole cells or viruses. Subunit vaccines can
be produced either by chemically degrading a pathogen and isolating its key antigens or by producing the antigens
through genetic engineering. Because these vaccines contain only the essential antigens of a pathogen, the risk of side
effects is relatively low. Table 18.3 lists examples of subunit vaccines.

Toxoid Vaccines
Like subunit vaccines, toxoid vaccines do not introduce a whole pathogen to the patient; they contain inactivated
bacterial toxins, called toxoids. Toxoid vaccines are used to prevent diseases in which bacterial toxins play an
important role in pathogenesis. These vaccines activate humoral immunity that neutralizes the toxins. Table 18.3
lists examples of toxoid vaccines.

Conjugate Vaccines
A conjugate vaccine is a type of subunit vaccine that consists of a protein conjugated to a capsule polysaccharide.
Conjugate vaccines have been developed to enhance the efficacy of subunit vaccines against pathogens that have
protective polysaccharide capsules that help them evade phagocytosis, causing invasive infections that can lead
to meningitis and other serious conditions. The subunit vaccines against these pathogens introduce T-independent
capsular polysaccharide antigens that result in the production of antibodies that can opsonize the capsule and thus
combat the infection; however, children under the age of two years do not respond effectively to these vaccines.
Children do respond effectively when vaccinated with the conjugate vaccine, in which a protein with T-dependent
antigens is conjugated to the capsule polysaccharide. The conjugated protein-polysaccharide antigen stimulates
production of antibodies against both the protein and the capsule polysaccharide. Table 18.3 lists examples of
conjugate vaccines.

Classes of Vaccines
Class Description Advantages Disadvantages Examples

Live Weakened strain of Cellular and Difficult to store and Chickenpox, German measles,
attenuated whole pathogen humoral transport measles, mumps, tuberculosis,
immunity typhoid fever, yellow fever

Long-lasting Risk of infection in

immunity immunocompromised
patients

Table 18.3

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Chapter 18 | Adaptive Specific Host Defenses 811

Classes of Vaccines
Class Description Advantages Disadvantages Examples

Transmission Risk of reversion

to contacts

Inactivated Whole pathogen Ease of Weaker immunity Cholera, hepatitis A, influenza,

killed or inactivated storage and (humoral only) plague, rabies
with heat, transport
chemicals, or
radiation No risk of Higher doses and
severe active more boosters
infection required

Subunit Immunogenic Lower risk of Limited longevity Anthrax, hepatitis B, influenza,

antigens side effects meningitis, papillomavirus,
Multiple doses pneumococcal pneumonia,
required whooping cough
No protection against
antigenic variation

Toxoid Inactivated bacterial Humoral Does not prevent Botulism, diphtheria, pertussis,
toxin immunity to infection tetanus
neutralize
toxin

Conjugate Capsule T-dependent Costly to produce Meningitis

polysaccharide response to (Haemophilus influenzae,
conjugated to capsule No protection against Streptococcus pneumoniae,
protein antigenic variation Neisseria meningitides)
Better May interfere with
response in other vaccines
young
children

Table 18.3

• What is the risk associated with a live attenuated vaccine?

• Why is a conjugated vaccine necessary in some cases?

Micro Connections

DNA Vaccines
DNA vaccines represent a relatively new and promising approach to vaccination. A DNA vaccine is produced
by incorporating genes for antigens into a recombinant plasmid vaccine. Introduction of the DNA vaccine into
a patient leads to uptake of the recombinant plasmid by some of the patient’s cells, followed by transcription
and translation of antigens and presentation of these antigens with MHC I to activate adaptive immunity. This
results in the stimulation of both humoral and cellular immunity without the risk of active disease associated
with live attenuated vaccines.
812 Chapter 18 | Adaptive Specific Host Defenses

Although most DNA vaccines for humans are still in development, it is likely that they will become more
prevalent in the near future as researchers are working on engineering DNA vaccines that will activate adaptive
immunity against several different pathogens at once. First-generation DNA vaccines tested in the 1990s
looked promising in animal models but were disappointing when tested in human subjects. Poor cellular uptake
of the DNA plasmids was one of the major problems impacting their efficacy. Trials of second-generation DNA
vaccines have been more promising thanks to new techniques for enhancing cellular uptake and optimizing
antigens. DNA vaccines for various cancers and viral pathogens such as HIV, HPV, and hepatitis B and C are
currently in development.
Some DNA vaccines are already in use. In 2005, a DNA vaccine against West Nile virus was approved for
use in horses in the United States. Canada has also approved a DNA vaccine to protect fish from infectious
hematopoietic necrosis virus.[5] A DNA vaccine against Japanese encephalitis virus was approved for use in
humans in 2010 in Australia.[6]

Clinical Focus

Resolution
Based on Olivia’s symptoms, her physician made a preliminary diagnosis of bacterial meningitis without waiting
for positive identification from the blood and CSF samples sent to the lab. Olivia was admitted to the hospital
and treated with intravenous broad-spectrum antibiotics and rehydration therapy. Over the next several days,
her condition began to improve, and new blood samples and lumbar puncture samples showed an absence
of microbes in the blood and CSF with levels of white blood cells returning to normal. During this time, the lab
produced a positive identification of Neisseria meningitidis, the causative agent of meningococcal meningitis,
in her original CSF sample.
N. meningitidis produces a polysaccharide capsule that serves as a virulence factor. N. meningitidis tends to
affect infants after they begin to lose the natural passive immunity provided by maternal antibodies. At one year
of age, Olivia’s maternal IgG antibodies would have disappeared, and she would not have developed memory
cells capable of recognizing antigens associated with the polysaccharide capsule of the N. meningitidis. As
a result, her adaptive immune system was unable to produce protective antibodies to combat the infection,
and without antibiotics she may not have survived. Olivia’s infection likely would have been avoided altogether
had she been vaccinated. A conjugate vaccine to prevent meningococcal meningitis is available and approved
for infants as young as two months of age. However, current vaccination schedules in the United States
recommend that the vaccine be administered at age 11–12 with a booster at age 16.
Go back to the previous Clinical Focus box.

5. M. Alonso and J. C. Leong. “Licensed DNA Vaccines Against Infectious Hematopoietic Necrosis Virus (IHNV).” Recent Patents on
DNA & Gene Sequences (Discontinued) 7 no. 1 (2013): 62–65, issn 1872-2156/2212-3431. doi 10.2174/1872215611307010009.
6. S.B. Halstead and S. J. Thomas. “New Japanese Encephalitis Vaccines: Alternatives to Production in Mouse Brain.” Expert Review of
Vaccines 10 no. 3 (2011): 355–64.

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Chapter 18 | Adaptive Specific Host Defenses 813

Link to Learning

In countries with developed public health systems, many vaccines are routinely
administered to children and adults. Vaccine schedules are changed periodically,
based on new information and research results gathered by public health
agencies. In the United States, the CDC publishes schedules and other
updated information (https://www.openstax.org/l/22CDCVacSched) about
vaccines.

Summary
18.1 Overview of Specific Adaptive Immunity
• Adaptive immunity is an acquired defense against foreign pathogens that is characterized by specificity and
memory. The first exposure to an antigen stimulates a primary response, and subsequent exposures stimulate
a faster and strong secondary response.
• Adaptive immunity is a dual system involving humoral immunity (antibodies produced by B cells) and
cellular immunity (T cells directed against intracellular pathogens).
• Antigens, also called immunogens, are molecules that activate adaptive immunity. A single antigen possesses
smaller epitopes, each capable of inducing a specific adaptive immune response.
• An antigen’s ability to stimulate an immune response depends on several factors, including its molecular class,
molecular complexity, and size.
• Antibodies (immunoglobulins) are Y-shaped glycoproteins with two Fab sites for binding antigens and an Fc
portion involved in complement activation and opsonization.
• The five classes of antibody are IgM, IgG, IgA, IgE, and IgD, each differing in size, arrangement, location
within the body, and function. The five primary functions of antibodies are neutralization, opsonization,
agglutination, complement activation, and antibody-dependent cell-mediated cytotoxicity (ADCC).
18.2 Major Histocompatibility Complexes and Antigen-Presenting Cells
• Major histocompatibility complex (MHC) is a collection of genes coding for glycoprotein molecules
expressed on the surface of all nucleated cells.
• MHC I molecules are expressed on all nucleated cells and are essential for presentation of normal “self”
antigens. Cells that become infected by intracellular pathogens can present foreign antigens on MHC I as well,
marking the infected cell for destruction.
• MHC II molecules are expressed only on the surface of antigen-presenting cells (macrophages, dendritic
cells, and B cells). Antigen presentation with MHC II is essential for the activation of T cells.
• Antigen-presenting cells (APCs) primarily ingest pathogens by phagocytosis, destroy them in the
phagolysosomes, process the protein antigens, and select the most antigenic/immunodominant epitopes with
MHC II for presentation to T cells.
• Cross-presentation is a mechanism of antigen presentation and T-cell activation used by dendritic cells not
directly infected by the pathogen; it involves phagocytosis of the pathogen but presentation on MHC I rather
than MHC II.
18.3 T Lymphocytes and Cellular Immunity
• Immature T lymphocytes are produced in the red bone marrow and travel to the thymus for maturation.
• Thymic selection is a three-step process of negative and positive selection that determines which T cells will
mature and exit the thymus into the peripheral bloodstream.
• Central tolerance involves negative selection of self-reactive T cells in the thymus, and peripheral tolerance
814 Chapter 18 | Adaptive Specific Host Defenses

involves anergy and regulatory T cells that prevent self-reactive immune responses and autoimmunity.
• The TCR is similar in structure to immunoglobulins, but less complex. Millions of unique epitope-binding
TCRs are encoded through a process of genetic rearrangement of V, D, and J gene segments.
• T cells can be divided into three classes—helper T cells, cytotoxic T cells, and regulatory T cells—based
on their expression of CD4 or CD8, the MHC molecules with which they interact for activation, and their
respective functions.
• Activated helper T cells differentiate into TH1, TH2, TH17, or memory T cell subtypes. Differentiation is
directed by the specific cytokines to which they are exposed. TH1, TH2, and TH17 perform different functions
related to stimulation of adaptive and innate immune defenses. Memory T cells are long-lived cells that can
respond quickly to secondary exposures.
• Once activated, cytotoxic T cells target and kill cells infected with intracellular pathogens. Killing requires
recognition of specific pathogen epitopes presented on the cell surface using MHC I molecules. Killing is
mediated by perforin and granzymes that induce apoptosis.
• Superantigens are bacterial or viral proteins that cause a nonspecific activation of helper T cells, leading to
an excessive release of cytokines (cytokine storm) and a systemic, potentially fatal inflammatory response.
18.4 B Lymphocytes and Humoral Immunity
• B lymphocytes or B cells produce antibodies involved in humoral immunity. B cells are produced in the bone
marrow, where the initial stages of maturation occur, and travel to the spleen for final steps of maturation into
naïve mature B cells.
• B-cell receptors (BCRs) are membrane-bound monomeric forms of IgD and IgM that bind specific antigen
epitopes with their Fab antigen-binding regions. Diversity of antigen binding specificity is created by genetic
rearrangement of V, D, and J segments similar to the mechanism used for TCR diversity.
• Protein antigens are called T-dependent antigens because they can only activate B cells with the cooperation
of helper T cells. Other molecule classes do not require T cell cooperation and are called T-independent
antigens.
• T cell-independent activation of B cells involves cross-linkage of BCRs by repetitive nonprotein antigen
epitopes. It is characterized by the production of IgM by plasma cells and does not produce memory B cells.
• T cell-dependent activation of B cells involves processing and presentation of protein antigens to helper T
cells, activation of the B cells by cytokines secreted from activated TH2 cells, and plasma cells that produce
different classes of antibodies as a result of class switching. Memory B cells are also produced.
• Secondary exposures to T-dependent antigens result in a secondary antibody response initiated by memory
B cells. The secondary response develops more quickly and produces higher and more sustained levels of
antibody with higher affinity for the specific antigen.
18.5 Vaccines
• Adaptive immunity can be divided into four distinct classifications: natural active immunity, natural
passive immunity, artificial passive immunity, and artificial active immunity.
• Artificial active immunity is the foundation for vaccination and vaccine development. Vaccination programs
not only confer artificial immunity on individuals, but also foster herd immunity in populations.
• Variolation against smallpox originated in the 10th century in China, but the procedure was risky because
it could cause the disease it was intended to prevent. Modern vaccination was developed by Edward Jenner,
who developed the practice of inoculating patients with infectious materials from cowpox lesions to prevent
smallpox.
• Live attenuated vaccines and inactivated vaccines contain whole pathogens that are weak, killed, or
inactivated. Subunit vaccines, toxoid vaccines, and conjugate vaccines contain acellular components with
antigens that stimulate an immune response.

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Chapter 18 | Adaptive Specific Host Defenses 815

Review Questions
Multiple Choice 8. Which type of antigen-presenting molecule is found
1. Antibodies are produced by ________. only on macrophages, dendritic cells, and B cells?
a. plasma cells a. MHC I
b. T cells b. MHC II
c. bone marrow c. T-cell receptors
d. Macrophages d. B-cell receptors

2. Cellular adaptive immunity is carried out by 9. What is a superantigen?

________. a. a protein that is highly efficient at stimulating
a. B cells a single type of productive and specific T cell
b. T cells response
c. bone marrow b. a protein produced by antigen-presenting cells to
d. neutrophils enhance their presentation capabilities
c. a protein produced by T cells as a way of
3. A single antigen molecule may be composed of increasing the antigen activation they receive
many individual ________. from antigen-presenting cells
a. T-cell receptors d. a protein that activates T cells in a nonspecific
b. B-cell receptors and uncontrolled manner
c. MHC II
d. epitopes 10. To what does the TCR of a helper T cell bind?
a. antigens presented with MHC I molecules
4. Which class of molecules is the most antigenic? b. antigens presented with MHC II molecules
a. polysaccharides c. free antigen in a soluble form
b. lipids d. haptens only
c. proteins
d. carbohydrates 11. Cytotoxic T cells will bind with their TCR to which
of the following?
5. MHC I molecules present a. antigens presented with MHC I molecules
a. processed foreign antigens from proteasomes. b. antigens presented with MHC II molecules
b. processed self-antigens from phagolysosome. c. free antigen in a soluble form
c. antibodies. d. haptens only
d. T cell antigens.
12. A ________ molecule is a glycoprotein used to
6. MHC II molecules present identify and distinguish white blood cells.
a. processed self-antigens from proteasomes. a. T-cell receptor
b. processed foreign antigens from b. B-cell receptor
phagolysosomes. c. MHC I
c. antibodies. d. cluster of differentiation
d. T cell receptors.
13. Name the T helper cell subset involved in antibody
7. Which type of antigen-presenting molecule is found production.
on all nucleated cells? a. TH1
a. MHC II b. TH2
b. MHC I c. TH17
c. antibodies d. CTL
d. B-cell receptors
816 Chapter 18 | Adaptive Specific Host Defenses

14. Which of the following would be a T-dependent

antigen?
a. lipopolysaccharide
b. glycolipid
c. protein
d. carbohydrate

15. Which of the following would be a BCR?

a. CD4
b. MHC II
c. MHC I
d. IgD

16. Which of the following does not occur during the

lag period of the primary antibody response?
a. activation of helper T cells
b. class switching to IgG
c. presentation of antigen with MHC II
d. binding of antigen to BCRs

17. A patient is bitten by a dog with confirmed rabies

infection. After treating the bite wound, the physician
injects the patient with antibodies that are specific for
the rabies virus to prevent the development of an active
infection. This is an example of:
a. Natural active immunity
b. Artificial active immunity
c. Natural passive immunity
d. Artificial passive immunity

18. A patient gets a cold, and recovers a few days later.

The patient's classmates come down with the same cold
roughly a week later, but the original patient does not get
the same cold again. This is an example of:
a. Natural active immunity
b. Artificial active immunity
c. Natural passive immunity
d. Artificial passive immunity

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Chapter 18 | Adaptive Specific Host Defenses 817

Matching
19. Match the antibody class with its description.
___IgA A. This class of antibody is the only one that can cross the placenta.

___IgD B. This class of antibody is the first to appear after activation of B cells.

___IgE C. This class of antibody is involved in the defense against parasitic infections and involved in allergic
responses.

___IgG D. This class of antibody is found in very large amounts in mucus secretions.

___IgM E. This class of antibody is not secreted by B cells but is expressed on the surface of naïve B cells.

20. Match each type of vaccine with the corresponding example.

___inactivated vaccine A. Weakened influenza virions that can only replicate in the slightly lower
temperatures of the nasal passages are sprayed into the nose. They do not cause
serious flu symptoms, but still produce an active infection that induces a protective
adaptive immune response.

___live attenuated vaccine B. Tetanus toxin molecules are harvested and chemically treated to render them
harmless. They are then injected into a patient’s arm.

___toxoid vaccine C. Influenza virus particles grown in chicken eggs are harvested and chemically
treated to render them noninfectious. These immunogenic particles are then
purified and packaged and administered as an injection.

___subunit vaccine D. The gene for hepatitis B virus surface antigen is inserted into a yeast genome.
The modified yeast is grown and the virus protein is produced, harvested, purified,
and used in a vaccine.

Fill in the Blank

21. There are two critically important aspects of adaptive immunity. The first is specificity, while the second is
________.

22. ________ immunity involves the production of antibody molecules that bind to specific antigens.

23. The heavy chains of an antibody molecule contain ________ region segments, which help to determine its class
or isotype.

24. The variable regions of the heavy and light chains form the ________ sites of an antibody.

25. MHC molecules are used for antigen ________ to T cells.

26. MHC II molecules are made up of two subunits (α and β) of approximately equal size, whereas MHC I molecules
consist of a larger α subunit and a smaller subunit called ________.

27. A ________ T cell will become activated by presentation of foreign antigen associated with an MHC I molecule.

28. A ________ T cell will become activated by presentation of foreign antigen in association with an MHC II
molecule.

29. A TCR is a protein dimer embedded in the plasma membrane of a T cell. The ________ region of each of the
two protein chains is what gives it the capability to bind to a presented antigen.

30. Peripheral tolerance mechanisms function on T cells after they mature and exit the ________.

31. Both ________ and effector T cells are produced during differentiation of activated T cells.
818 Chapter 18 | Adaptive Specific Host Defenses

32. ________ antigens can stimulate B cells to become activated but require cytokine assistance delivered by helper
T cells.

33. T-independent antigens can stimulate B cells to become activated and secrete antibodies without assistance from
helper T cells. These antigens possess ________ antigenic epitopes that cross-link BCRs.

34. A(n) ________ pathogen is in a weakened state; it is still capable of stimulating an immune response but does
not cause a disease.

35. ________ immunity occurs when antibodies from one individual are harvested and given to another to protect
against disease or treat active disease.

36. In the practice of ________, scabs from smallpox victims were used to immunize susceptible individuals against
smallpox.

Short Answer
37. What is the difference between humoral and cellular adaptive immunity?

38. What is the difference between an antigen and a hapten?

39. Describe the mechanism of antibody-dependent cell-mediated cytotoxicity.

40. What is the basic difference in effector function between helper and cytotoxic T cells?

41. What necessary interactions are required for activation of helper T cells and activation/effector function of
cytotoxic T cells?

42. Briefly compare the pros and cons of inactivated versus live attenuated vaccines.

Critical Thinking
43. Which mechanism of antigen presentation would be used to present antigens from a cell infected with a virus?

44. Which pathway of antigen presentation would be used to present antigens from an extracellular bacterial
infection?

45. A patient lacks the ability to make functioning T cells because of a genetic disorder. Would this patient’s B cells
be able to produce antibodies in response to an infection? Explain your answer.

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Chapter 19 | Diseases of the Immune System 819

Chapter 19

Diseases of the Immune System

Figure 19.1 Bee stings and other allergens can cause life-threatening, systemic allergic reactions. Sensitive
individuals may need to carry an epinephrine auto-injector (e.g., EpiPen) in case of a sting. A bee-sting allergy is an
example of an immune response that is harmful to the host rather than protective; epinephrine counteracts the severe
drop in blood pressure that can result from the immune response. (credit right: modification of work by Carol
Bleistine)

Chapter Outline
19.1 Hypersensitivities
19.2 Autoimmune Disorders
19.3 Organ Transplantation and Rejection
19.4 Immunodeficiency
19.5 Cancer Immunobiology and Immunotherapy

Introduction
An allergic reaction is an immune response to a type of antigen called an allergen. Allergens can be found in many
different items, from peanuts and insect stings to latex and some drugs. Unlike other kinds of antigens, allergens are
not necessarily associated with pathogenic microbes, and many allergens provoke no immune response at all in most
people.
Allergic responses vary in severity. Some are mild and localized, like hay fever or hives, but others can result in
systemic, life-threatening reactions. Anaphylaxis, for example, is a rapidly developing allergic reaction that can cause
a dangerous drop in blood pressure and severe swelling of the throat that may close off the airway.
Allergies are just one example of how the immune system—the system normally responsible for preventing
disease—can actually cause or mediate disease symptoms. In this chapter, we will further explore allergies and other
disorders of the immune system, including hypersensitivity reactions, autoimmune diseases, transplant rejection, and
diseases associated with immunodeficiency.
820 Chapter 19 | Diseases of the Immune System

19.1 Hypersensitivities
Learning Objectives
• Identify and compare the distinguishing characteristics, mechanisms, and major examples of type I, II, III, and
IV hypersensitivities
In Adaptive Specific Host Defenses, we discussed the mechanisms by which adaptive immune defenses, both
humoral and cellular, protect us from infectious diseases. However, these same protective immune defenses can also
be responsible for undesirable reactions called hypersensitivity reactions. Hypersensitivity reactions are classified by
their immune mechanism.
• Type I hypersensitivity reactions involve immunoglobulin E (IgE) antibody against soluble antigen, triggering
mast cell degranulation.
• Type II hypersensitivity reactions involve IgG and IgM antibodies directed against cellular antigens, leading
to cell damage mediated by other immune system effectors.
• Type III hypersensitivity reactions involve the interactions of IgG, IgM, and, occasionally, IgA[1] antibodies
with antigen to form immune complexes. Accumulation of immune complexes in tissue leads to tissue damage
mediated by other immune system effectors.
• Type IV hypersensitivity reactions are T-cell–mediated reactions that can involve tissue damage mediated by
activated macrophages and cytotoxic T cells.

Type I Hypersensitivities
When a presensitized individual is exposed to an allergen, it can lead to a rapid immune response that occurs
almost immediately. Such a response is called an allergy and is classified as a type I hypersensitivity. Allergens
may be seemingly harmless substances such as animal dander, molds, or pollen. Allergens may also be substances
considered innately more hazardous, such as insect venom or therapeutic drugs. Food intolerances can also yield
allergic reactions as individuals become sensitized to foods such as peanuts or shellfish (Figure 19.2). Regardless
of the allergen, the first exposure activates a primary IgE antibody response that sensitizes an individual to type I
hypersensitivity reaction upon subsequent exposure.

Clinical Focus

Part 1
Kerry, a 40-year-old airline pilot, has made an appointment with her primary care physician to discuss a rash
that develops whenever she spends time in the sun. As she explains to her physician, it does not seem
like sunburn. She is careful not to spend too much time in the sun and she uses sunscreen. Despite these
precautions, the rash still appears, manifesting as red, raised patches that get slightly scaly. The rash persists
for 7 to 10 days each time, and it seems to largely go away on its own. Lately, the rashes have also begun to
appear on her cheeks and above her eyes on either side of her forehead.
• Is Kerry right to be concerned, or should she simply be more careful about sun exposure?
• Are there conditions that might be brought on by sun exposure that Kerry’s physician should be
considering?
Jump to the next Clinical Focus box.

1. D.S. Strayer et al (eds). Rubin’s Pathology: Clinicopathologic Foundations of Medicine. 7th ed. 2Philadelphia, PA: Lippincott, Williams
& Wilkins, 2014.

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Chapter 19 | Diseases of the Immune System 821

Figure 19.2 (a) Allergens in plant pollen, shown here in a colorized electron micrograph, may trigger allergic rhinitis
or hay fever in sensitive individuals. (b) Skin rashes are often associated with allergic reactions. (c) Peanuts can be
eaten safely by most people but can provoke severe allergic reactions in sensitive individuals.

For susceptible individuals, a first exposure to an allergen activates a strong TH2 cell response (Figure 19.3).
Cytokines interleukin (IL)-4 and IL-13 from the TH2 cells activate B cells specific to the same allergen, resulting in
clonal proliferation, differentiation into plasma cells, and antibody-class switch from production of IgM to production
of IgE. The fragment crystallizable (Fc) regions of the IgE antibodies bind to specific receptors on the surface of
mast cells throughout the body. It is estimated that each mast cell can bind up to 500,000 IgE molecules, with each
IgE molecule having two allergen-specific fragment antigen-binding (Fab) sites available for binding allergen on
subsequent exposures. By the time this occurs, the allergen is often no longer present and there is no allergic reaction,
but the mast cells are primed for a subsequent exposure and the individual is sensitized to the allergen.
On subsequent exposure, allergens bind to multiple IgE molecules on mast cells, cross-linking the IgE molecules.
Within minutes, this cross-linking of IgE activates the mast cells and triggers degranulation, a reaction in which the
contents of the granules in the mast cell are released into the extracellular environment. Preformed components that
are released from granules include histamine, serotonin, and bradykinin (Table 19.1). The activated mast cells also
release newly formed lipid mediators (leukotrienes and prostaglandins from membrane arachadonic acid metabolism)
and cytokines such as tumor necrosis factor (Table 19.2).
The chemical mediators released by mast cells collectively cause the inflammation and signs and symptoms
associated with type I hypersensitivity reactions. Histamine stimulates mucus secretion in nasal passages and tear
formation from lacrimal glands, promoting the runny nose and watery eyes of allergies. Interaction of histamine
with nerve endings causes itching and sneezing. The vasodilation caused by several of the mediators can result in
hives, headaches, angioedema (swelling that often affects the lips, throat, and tongue), and hypotension (low blood
pressure). Bronchiole constriction caused by some of the chemical mediators leads to wheezing, dyspnea (difficulty
breathing), coughing, and, in more severe cases, cyanosis (bluish color to the skin or mucous membranes). Vomiting
can result from stimulation of the vomiting center in the cerebellum by histamine and serotonin. Histamine can also
cause relaxation of intestinal smooth muscles and diarrhea.

Selected Preformed Components of Mast Cell Granules

Granule Activity
Component

Heparin Stimulates the generation of bradykinin, which causes increased vascular permeability,
vasodilation, bronchiole constriction, and increased mucus secretion

Histamine Causes smooth-muscle contraction, increases vascular permeability, increases mucus and tear
formation

Serotonin Increases vascular permeability, causes vasodilation and smooth-muscle contraction

Table 19.1
822 Chapter 19 | Diseases of the Immune System

Selected Newly Formed Chemical Mediators of Inflammation and Allergic Response

Chemical Activity
Mediator

Leukotriene Causes smooth-muscle contraction and mucus secretion, increases vascular

permeability

Prostaglandin Causes smooth-muscle contraction and vasodilation

TNF-α (cytokine) Causes inflammation and stimulates cytokine production by other cell types

Table 19.2

Figure 19.3 On first exposure to an allergen in a susceptible individual, antigen-presenting cells process and
present allergen epitopes with major histocompatibility complex (MHC) II to T helper cells. B cells also process and
present the same allergen epitope to TH2 cells, which release cytokines IL-4 and IL-13 to stimulate proliferation and
differentiation into IgE-secreting plasma cells. The IgE molecules bind to mast cells with their Fc region, sensitizing
the mast cells for activation with subsequent exposure to the allergen. With each subsequent exposure, the allergen
cross-links IgE molecules on the mast cells, activating the mast cells and causing the release of preformed chemical
mediators from granules (degranulation), as well as newly formed chemical mediators that collectively cause the
signs and symptoms of type I hypersensitivity reactions.

Type I hypersensitivity reactions can be either localized or systemic. Localized type I hypersensitivity reactions
include hay fever rhinitis, hives, and asthma (Table 19.3). Systemic type I hypersensitivity reactions are referred to
as anaphylaxis or anaphylactic shock. Although anaphylaxis shares many symptoms common with the localized
type I hypersensitivity reactions, the swelling of the tongue and trachea, blockage of airways, dangerous drop in blood
pressure, and development of shock can make anaphylaxis especially severe and life-threatening. In fact, death can

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Chapter 19 | Diseases of the Immune System 823

occur within minutes of onset of signs and symptoms.

Late-phase reactions in type I hypersensitivities may develop 4–12 hours after the early phase and are mediated by
eosinophils, neutrophils, and lymphocytes that have been recruited by chemotactic factors released from mast cells.
Activation of these recruited cells leads to the release of more chemical mediators that cause tissue damage and late-
phase symptoms of swelling and redness of the skin, coughing, wheezing, and nasal discharge.
Individuals who possess genes for maladaptive traits, such as intense type I hypersensitivity reactions to otherwise
harmless components of the environment, would be expected to suffer reduced reproductive success. With this kind
of evolutionary selective pressure, such traits would not be expected to persist in a population. This suggests that
type I hypersensitivities may have an adaptive function. There is evidence that the IgE produced during type I
hypersensitivity reactions is actually meant to counter helminth infections[2]. Helminths are one of few organisms
that possess proteins that are targeted by IgE. In addition, there is evidence that helminth infections at a young age
reduce the likelihood of type I hypersensitivities to innocuous substances later in life. Thus it may be that allergies
are an unfortunate consequence of strong selection in the mammalian lineage or earlier for a defense against parasitic
worms.

Type I Hypersensitivities
Common Cause Signs and Symptoms
Name

Allergy-induced Inhalation of allergens Constriction of bronchi, labored breathing, coughing, chills,

asthma body aches

Anaphylaxis Systemic reaction to Hives, itching, swelling of tongue and throat, nausea, vomiting,
allergens low blood pressure, shock

Hay fever Inhalation of mold or Runny nose, watery eyes, sneezing

pollen

Hives (urticaria) Food or drug allergens, Raised, bumpy skin rash with itching; bumps may converge into
insect stings large raised areas

Table 19.3

• What are the cells that cause a type I hypersensitivity reaction?

• Describe the differences between immediate and late-phase type I hypersensitivity reactions.
• List the signs and symptoms of anaphylaxis.

Micro Connections

The Hygiene Hypothesis

In most modern societies, good hygiene is associated with regular bathing, and good health with cleanliness.
But some recent studies suggest that the association between health and clean living may be a faulty one.
Some go so far as to suggest that children should be encouraged to play in the dirt—or even eat dirt[3]—for

2. C.M. Fitzsimmons et al. “Helminth Allergens, Parasite-Specific IgE, and Its Protective Role in Human Immunity.” Frontier in
Immunology 5 (2015):47.
824 Chapter 19 | Diseases of the Immune System

the benefit of their health. This recommendation is based on the so-called hygiene hypothesis, which proposes
that childhood exposure to antigens from a diverse range of microbes leads to a better-functioning immune
system later in life.
The hygiene hypothesis was first suggested in 1989 by David Strachan[4], who observed an inverse
relationship between the number of older children in a family and the incidence of hay fever. Although hay fever
in children had increased dramatically during the mid-20th century, incidence was significantly lower in families
with more children. Strachan proposed that the lower incidence of allergies in large families could be linked
to infections acquired from older siblings, suggesting that these infections made children less susceptible to
allergies. Strachan also argued that trends toward smaller families and a greater emphasis on cleanliness
in the 20th century had decreased exposure to pathogens and thus led to higher overall rates of allergies,
asthma, and other immune disorders.
Other researchers have observed an inverse relationship between the incidence of immune disorders and
infectious diseases that are now rare in industrialized countries but still common in less industrialized
countries.[5] In developed nations, children under the age of 5 years are not exposed to many of the microbes,
molecules, and antigens they almost certainly would have encountered a century ago. The lack of early
challenges to the immune system by organisms with which humans and their ancestors evolved may result in
failures in immune system functioning later in life.

Type II (Cytotoxic) Hypersensitivities

Immune reactions categorized as type II hypersensitivities, or cytotoxic hypersensitivities, are mediated by IgG
and IgM antibodies binding to cell-surface antigens or matrix-associated antigens on basement membranes. These
antibodies can either activate complement, resulting in an inflammatory response and lysis of the targeted cells, or
they can be involved in antibody-dependent cell-mediated cytotoxicity (ADCC) with cytotoxic T cells.
In some cases, the antigen may be a self-antigen, in which case the reaction would also be described as an autoimmune
disease. (Autoimmune diseases are described in Autoimmune Disorders). In other cases, antibodies may bind to
naturally occurring, but exogenous, cell-surface molecules such as antigens associated with blood typing found on
red blood cells (RBCs). This leads to the coating of the RBCs by antibodies, activation of the complement cascade,
and complement-mediated lysis of RBCs, as well as opsonization of RBCs for phagocytosis. Two examples of type
II hypersensitivity reactions involving RBCs are hemolytic transfusion reaction (HTR) and hemolytic disease of the
newborn (HDN). These type II hypersensitivity reactions, which will be discussed in greater detail, are summarized
in Table 19.4.
Immunohematology is the study of blood and blood-forming tissue in relation to the immune response. Antibody-
initiated responses against blood cells are type II hypersensitivities, thus falling into the field of immunohematology.
For students first learning about immunohematology, understanding the immunological mechanisms involved is made
even more challenging by the complex nomenclature system used to identify different blood-group antigens, often
called blood types. The first blood-group antigens either used alphabetical names or were named for the first person
known to produce antibodies to the red blood cell antigen (e.g., Kell, Duffy, or Diego). However, in 1980, the
International Society of Blood Transfusion (ISBT) Working Party on Terminology created a standard for blood-group
terminology in an attempt to more consistently identify newly discovered blood group antigens. New antigens are
now given a number and assigned to a blood-group system, collection, or series. However, even with this effort,
blood-group nomenclature is still inconsistent.

3. S.T. Weiss. “Eat Dirt—The Hygiene Hypothesis and Allergic Diseases.” New England Journal of Medicine 347 no. 12 (2002):930–931.
4. D.P. Strachan “Hay Fever, Hygiene, and Household Size.” British Medical Journal 299 no. 6710 (1989):1259.
5. H. Okada et al. “The ‘Hygiene Hypothesis’ for Autoimmune and Allergic Diseases: An Update.” Clinical & Experimental Immunology
160 no. 1 (2010):1–9.

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Chapter 19 | Diseases of the Immune System 825

Common Type II Hypersensitivities

Common Name Cause Signs and Symptoms

Hemolytic IgG from mother crosses the Anemia, edema, enlarged liver or spleen, hydrops
disease of the placenta, targeting the fetus’ RBCs (fluid in body cavity), leading to death of newborn
newborn (HDN) for destruction in severe cases

Hemolytic IgG and IgM bind to antigens on Fever, jaundice, hypotension, disseminated
transfusion transfused RBCs, targeting donor intravascular coagulation, possibly leading to
reactions (HTR) RBCs for destruction kidney failure and death

Table 19.4

ABO Blood Group Incompatibility

The recognition that individuals have different blood types was first described by Karl Landsteiner (1868–1943) in
the early 1900s, based on his observation that serum from one person could cause a clumping of RBCs from another.
These studies led Landsteiner to the identification of four distinct blood types. Subsequent research by other scientists
determined that the four blood types were based on the presence or absence of surface carbohydrates “A” and “B,”
and this provided the foundation for the ABO blood group system that is still in use today (Figure 19.4). The
functions of these antigens are unknown, but some have been associated with normal biochemical functions of the
cell. Furthermore, ABO blood types are inherited as alleles (one from each parent), and they display patterns of
dominant and codominant inheritance. The alleles for A and B blood types are codominant to each other, and both
are dominant over blood type O. Therefore, individuals with genotypes of AA or AO have type A blood and express
the A carbohydrate antigen on the surface of their RBCs. People with genotypes of BB or BO have type B blood and
express the B carbohydrate antigen on the surface of their RBCs. Those with a genotype of AB have type AB blood
and express both A and B carbohydrate antigens on the surface of their RBCs. Finally, individuals with a genotype of
OO have type O blood and lack A and B carbohydrate on the surface of their RBCs.
It is important to note that the RBCs of all four ABO blood types share a common protein receptor molecule, and
it is the addition of specific carbohydrates to the protein receptors that determines A, B, and AB blood types. The
genes that are inherited for the A, B, and AB blood types encode enzymes that add the carbohydrate component to
the protein receptor. Individuals with O blood type still have the protein receptor but lack the enzymes that would add
carbohydrates that would make their red blood cell type A, B, or AB.
IgM antibodies in plasma that cross-react with blood group antigens not present on an individual’s own RBCs are
called isohemagglutinins (Figure 19.4). Isohemagglutinins are produced within the first few weeks after birth and
persist throughout life. These antibodies are produced in response to exposure to environmental antigens from food
and microorganisms. A person with type A blood has A antigens on the surface of their RBCs and will produce anti-B
antibodies to environmental antigens that resemble the carbohydrate component of B antigens. A person with type B
blood has B antigens on the surface of their RBCs and will produce anti-A antibodies to environmental antigens that
are similar to the carbohydrate component of A antigens. People with blood type O lack both A and B antigens on
their RBCs and, therefore, produce both anti-A and anti-B antibodies. Conversely, people with AB blood type have
both A and B antigens on their RBCs and, therefore, lack anti-A and anti-B antibodies.
826 Chapter 19 | Diseases of the Immune System

Figure 19.4

A patient may require a blood transfusion because they lack sufficient RBCs (anemia) or because they have
experienced significant loss of blood volume through trauma or disease. Although the blood transfusion is given to
help the patient, it is essential that the patient receive a transfusion with matching ABO blood type. A transfusion with
an incompatible ABO blood type may lead to a strong, potentially lethal type II hypersensitivity cytotoxic response
called hemolytic transfusion reaction (HTR) (Figure 19.5).
For instance, if a person with type B blood receives a transfusion of type A blood, their anti-A antibodies will bind to
and agglutinate the transfused RBCs. In addition, activation of the classical complement cascade will lead to a strong
inflammatory response, and the complement membrane attack complex (MAC) will mediate massive hemolysis of
the transfused RBCs. The debris from damaged and destroyed RBCs can occlude blood vessels in the alveoli of the
lungs and the glomeruli of the kidneys. Within 1 to 24 hours of an incompatible transfusion, the patient experiences
fever, chills, pruritus (itching), urticaria (hives), dyspnea, hemoglobinuria (hemoglobin in the urine), and hypotension
(low blood pressure). In the most serious reactions, dangerously low blood pressure can lead to shock, multi-organ
failure, and death of the patient.
Hospitals, medical centers, and associated clinical laboratories typically use hemovigilance systems to minimize the
risk of HTRs due to clerical error. Hemovigilance systems are procedures that track transfusion information from the
donor source and blood products obtained to the follow-up of recipient patients. Hemovigilance systems used in many
countries identify HTRs and their outcomes through mandatory reporting (e.g., to the Food and Drug Administration
in the United States), and this information is valuable to help prevent such occurrences in the future. For example,
if an HTR is found to be the result of laboratory or clerical error, additional blood products collected from the donor
at that time can be located and labeled correctly to avoid additional HTRs. As a result of these measures, HTR-
associated deaths in the United States occur in about one per 2 million transfused units. [6]

6. E.C. Vamvakas, M.A. Blajchman. “Transfusion-Related Mortality: The Ongoing Risks of Allogeneic Blood Transfusion and the
Available Strategies for Their Prevention.” Blood 113 no. 15 (2009):3406–3417.

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Chapter 19 | Diseases of the Immune System 827

Figure 19.5 A type II hypersensitivity hemolytic transfusion reaction (HTR) leading to hemolytic anemia. Blood from
a type A donor is administered to a patient with type B blood. The anti-A isohemagglutinin IgM antibodies in the
recipient bind to and agglutinate the incoming donor type A red blood cells. The bound anti-A antibodies activate the
classical complement cascade, resulting in destruction of the donor red blood cells.

Rh Factors
Many different types of erythrocyte antigens have been discovered since the description of the ABO red cell antigens.
The second most frequently described RBC antigens are Rh factors, named after the rhesus macaque (Macaca
mulatta) factors identified by Karl Landsteiner and Alexander Weiner in 1940. The Rh system of RBC antigens is the
most complex and immunogenic blood group system, with more than 50 specificities identified to date. Of all the Rh
antigens, the one designated Rho (Weiner) or D (Fisher-Race) is the most immunogenic. Cells are classified as Rh
positive (Rh+) if the Rho/D antigen is present or as Rh negative (Rh−) if the Rho/D antigen is absent. In contrast to the
carbohydrate molecules that distinguish the ABO blood groups and are the targets of IgM isohemagglutinins in HTRs,
the Rh factor antigens are proteins. As discussed in B Lymphocytes and Humoral Immunity, protein antigens
activate B cells and antibody production through a T-cell–dependent mechanism, and the TH2 cells stimulate class
switching from IgM to other antibody classes. In the case of Rh factor antigens, TH2 cells stimulate class switching
to IgG, and this has important implications for the mechanism of HDN.
Like ABO incompatibilities, blood transfusions from a donor with the wrong Rh factor antigens can cause a type II
hypersensitivity HTR. However, in contrast to the IgM isohemagglutinins produced early in life through exposure
to environmental antigens, production of anti-Rh factor antibodies requires the exposure of an individual with Rh−
blood to Rh+ positive RBCs and activation of a primary antibody response. Although this primary antibody response
can cause an HTR in the transfusion patient, the hemolytic reaction would be delayed up to 2 weeks during the
extended lag period of a primary antibody response (B Lymphocytes and Humoral Immunity). However, if
the patient receives a subsequent transfusion with Rh+ RBCs, a more rapid HTR would occur with anti-Rh factor
antibody already present in the blood. Furthermore, the rapid secondary antibody response would provide even more
anti-Rh factor antibodies for the HTR.
Rh factor incompatibility between mother and fetus can also cause a type II hypersensitivity hemolytic reaction,
referred to as hemolytic disease of the newborn (HDN) (Figure 19.6). If an Rh− woman carries an Rh+ baby to
term, the mother’s immune system can be exposed to Rh+ fetal red blood cells. This exposure will usually occur
during the last trimester of pregnancy and during the delivery process. If this exposure occurs, the Rh+ fetal RBCs
will activate a primary adaptive immune response in the mother, and anti-Rh factor IgG antibodies will be produced.
IgG antibodies are the only class of antibody that can cross the placenta from mother to fetus; however, in most cases,
the first Rh+ baby is unaffected by these antibodies because the first exposure typically occurs late enough in the
828 Chapter 19 | Diseases of the Immune System

pregnancy that the mother does not have time to mount a sufficient primary antibody response before the baby is
born.
If a subsequent pregnancy with an Rh+ fetus occurs, however, the mother’s second exposure to the Rh factor antigens
causes a strong secondary antibody response that produces larger quantities of anti-Rh factor IgG. These antibodies
can cross the placenta from mother to fetus and cause HDN, a potentially lethal condition for the baby (Figure 19.6).
Prior to the development of techniques for diagnosis and prevention, Rh factor incompatibility was the most common
cause of HDN, resulting in thousands of infant deaths each year worldwide.[7] For this reason, the Rh factors of
prospective parents are regularly screened, and treatments have been developed to prevent HDN caused by Rh
incompatibility. To prevent Rh factor-mediated HDN, human Rho(D) immune globulin (e.g., RhoGAM) is injected
intravenously or intramuscularly into the mother during the 28th week of pregnancy and within 72 hours after
delivery. Additional doses may be administered after events that may result in transplacental hemorrhage (e.g.,
umbilical blood sampling, chorionic villus sampling, abdominal trauma, amniocentesis). This treatment is initiated
during the first pregnancy with an Rh+ fetus. The anti-Rh antibodies in Rho(D) immune globulin will bind to the Rh
factor of any fetal RBCs that gain access to the mother’s bloodstream, preventing these Rh+ cells from activating the
mother’s primary antibody response. Without a primary anti-Rh factor antibody response, the next pregnancy with an
Rh+ will have minimal risk of HDN. However, the mother will need to be retreated with Rho(D) immune globulin
during that pregnancy to prevent a primary anti-Rh antibody response that could threaten subsequent pregnancies.

Figure 19.6 (a) When an Rh− mother has an Rh+ fetus, fetal erythrocytes are introduced into the mother’s
circulatory system before or during birth, leading to production of anti-Rh IgG antibodies. These antibodies remain in
the mother and, if she becomes pregnant with a second Rh+ baby, they can cross the placenta and attach to fetal
Rh+ erythrocytes. Complement-mediated hemolysis of fetal erythrocytes results in a lack of sufficient cells for proper
oxygenation of the fetus. (b) HDN can be prevented by administering Rho(D) immune globulin during and after each
pregnancy with an Rh+ fetus. The immune globulin binds fetal Rh+ RBCs that gain access to the mother’s
bloodstream, preventing activation of her primary immune response.

7. G. Reali. “Forty Years of Anti-D Immunoprophylaxis.” Blood Transfusion 5 no. 1 (2007):3–6.

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Chapter 19 | Diseases of the Immune System 829

Link to Learning

Use this interactive Blood Typing Game (https://openstax.org/l/

22actbloodtyping) to reinforce your knowledge of blood typing.

• What happens to cells that possess incompatible antigens in a type II hypersensitivity reaction?
• Describe hemolytic disease of the newborn and explain how it can be prevented.

Clinical Focus

Part 2
Kerry’s primary care physician is not sure why Kerry seems to develop rashes after spending time in the sun,
so she orders a urinalysis and basic blood tests. The results reveal that Kerry has proteinuria (abnormal protein
levels in the urine), hemoglobinuria (excess hemoglobin in the urine), and a low hematocrit (RBC count). These
tests suggest that Kerry is suffering from a mild bout of hemolytic anemia. The physician suspects that the
problem might be autoimmune, so she refers Kerry to a rheumatologist for additional testing and diagnosis.
• Rheumatologists specialize in musculoskeletal diseases such as arthritis, osteoporosis, and joint pain.
Why might Kerry’s physician refer her to this particular type of specialist even though she is exhibiting
none of these symptoms?
Jump to the next Clinical Focus box. Go back to the previous Clinical Focus box.

Type III Hypersensitivities

Type III hypersensitivities are immune-complex reactions that were first characterized by Nicolas Maurice Arthus
(1862–1945) in 1903. To produce antibodies for experimental procedures, Arthus immunized rabbits by injecting
them with serum from horses. However, while immunizing rabbits repeatedly with horse serum, Arthus noticed a
previously unreported and unexpected localized subcutaneous hemorrhage with edema at the site of injection. This
reaction developed within 3 to10 hours after injection. This localized reaction to non-self serum proteins was called
an Arthus reaction. An Arthus reaction occurs when soluble antigens bind with IgG in a ratio that results in the
accumulation of antigen-antibody aggregates called immune complexes.
A unique characteristic of type III hypersensitivity is antibody excess (primarily IgG), coupled with a relatively low
concentration of antigen, resulting in the formation of small immune complexes that deposit on the surface of the
epithelial cells lining the inner lumen of small blood vessels or on the surfaces of tissues (Figure 19.7). This immune
complex accumulation leads to a cascade of inflammatory events that include the following:
1. IgG binding to antibody receptors on localized mast cells, resulting in mast-cell degranulation
2. Complement activation with production of pro-inflammatory C3a and C5a (see Chemical Defenses)
3. Increased blood-vessel permeability with chemotactic recruitment of neutrophils and macrophages
Because these immune complexes are not an optimal size and are deposited on cell surfaces, they cannot be
830 Chapter 19 | Diseases of the Immune System

phagocytosed in the usual way by neutrophils and macrophages, which, in turn, are often described as “frustrated.”
Although phagocytosis does not occur, neutrophil degranulation results in the release of lysosomal enzymes that cause
extracellular destruction of the immune complex, damaging localized cells in the process. Activation of coagulation
pathways also occurs, resulting in thrombi (blood clots) that occlude blood vessels and cause ischemia that can lead
to vascular necrosis and localized hemorrhage.
Systemic type III hypersensitivity (serum sickness) occurs when immune complexes deposit in various body sites,
resulting in a more generalized systemic inflammatory response. These immune complexes involve non-self proteins
such as antibodies produced in animals for artificial passive immunity (see Vaccines), certain drugs, or microbial
antigens that are continuously released over time during chronic infections (e.g., subacute bacterial endocarditis,
chronic viral hepatitis). The mechanisms of serum sickness are similar to those described in localized type III
hypersensitivity but involve widespread activation of mast cells, complement, neutrophils, and macrophages, which
causes tissue destruction in areas such as the kidneys, joints, and blood vessels. As a result of tissue destruction,
symptoms of serum sickness include chills, fever, rash, vasculitis, and arthritis. Development of glomerulonephritis
or hepatitis is also possible.
Autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis can also involve
damaging type III hypersensitivity reactions when auto-antibodies form immune complexes with self antigens. These
conditions are discussed in Autoimmune Disorders.

Figure 19.7 Type III hypersensitivities and the systems they affect. (a) Immune complexes form and deposit in
tissue. Complement activation, stimulation of an inflammatory response, and recruitment and activation of neutrophils
result in damage to blood vessels, heart tissue, joints, skin, and/or kidneys. (b) If the kidneys are damaged by a type
III hypersensitivity reaction, dialysis may be required.

• Why is antibody excess important in type III hypersensitivity?

• Describe the differences between the Arthus reaction and serum sickness.

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Chapter 19 | Diseases of the Immune System 831

Micro Connections

Diphtheria Antitoxin
Antibacterial sera are much less commonly used now than in the past, having been replaced by toxoid
vaccines. However, a diphtheria antitoxin produced in horses is one example of such a treatment that is still
used in some parts of the world. Although it is not licensed by the FDA for use in the United States, diphtheria
antitoxin can be used to treat cases of diphtheria, which are caused by the bacterium Corynebacterium
diphtheriae.[8] The treatment is not without risks, however. Serum sickness can occur when the patient
develops an immune response to non-self horse proteins. Immune complexes are formed between the horse
proteins and circulating antibodies when the two exist in certain proportions. These immune complexes can
deposit in organs, causing damage such as arthritis, nephritis, rash, and fever. Serum sickness is usually
transient with no permanent damage unless the patient is chronically exposed to the antigen, which can
then result in irreversible damage to body sites such as joints and kidneys. Over time, phagocytic cells such
as macrophages are able to clear the horse serum antigens, which results in improvement of the patient’s
condition and a decrease in symptoms as the immune response dissipates.

Clinical Focus

Part 3
Kerry does not make it to the rheumatologist. She has a seizure as she is leaving her primary care physician’s
office. She is quickly rushed to the emergency department, where her primary care physician relates her
medical history and recent test results. The emergency department physician calls in the rheumatologist on
staff at the hospital for consultation. Based on the symptoms and test results, the rheumatologist suspects that
Kerry has lupus and orders a pair of blood tests: an antinuclear antibody test (ANA) to look for antibodies that
bind to DNA and another test that looks for antibodies that bind to a self-antigen called the Smith antigen (Sm).
• Based on the blood tests ordered, what type of reaction does the rheumatologist suspect is causing
Kerry’s seizure?
Jump to the next Clinical Focus box. Go back to the previous Clinical Focus box.

Type IV Hypersensitivities
Type IV hypersensitivities are not mediated by antibodies like the other three types of hypersensitivities. Rather,
type IV hypersensitivities are regulated by T cells and involve the action of effector cells. These types of
hypersensitivities can be organized into three subcategories based on T-cell subtype, type of antigen, and the resulting
effector mechanism (Table 19.5).
In the first type IV subcategory, CD4 TH1-mediated reactions are described as delayed-type hypersensitivities (DTH).
The sensitization step involves the introduction of antigen into the skin and phagocytosis by local antigen presenting
cells (APCs). The APCs activate helper T cells, stimulating clonal proliferation and differentiation into memory
TH1 cells. Upon subsequent exposure to the antigen, these sensitized memory TH1 cells release cytokines that
activate macrophages, and activated macrophages are responsible for much of the tissue damage. Examples of this
TH1-mediated hypersensitivity are observed in tuberculin the Mantoux skin test and contact dermatitis, such as
occurs in latex allergy reactions.
In the second type IV subcategory, CD4 TH2-mediated reactions result in chronic asthma or chronic allergic rhinitis.
In these cases, the soluble antigen is first inhaled, resulting in eosinophil recruitment and activation with the release

8. Centers for Disease Control and Prevention. “Diphtheria Antitoxin.” http://www.cdc.gov/diphtheria/dat.html. Accessed March 25, 2016.
832 Chapter 19 | Diseases of the Immune System

of cytokines and inflammatory mediators.

In the third type IV subcategory, CD8 cytotoxic T lymphocyte (CTL)-mediated reactions are associated with tissue
transplant rejection and contact dermatitis (Figure 19.8). For this form of cell-mediated hypersensitivity, APCs
process and present the antigen with MHC I to naïve CD8 T cells. When these naïve CD8 T cells are activated, they
proliferate and differentiate into CTLs. Activated TH1 cells can also enhance the activation of the CTLs. The activated
CTLs then target and induce granzyme-mediated apoptosis in cells presenting the same antigen with MHC I. These
target cells could be “self” cells that have absorbed the foreign antigen (such as with contact dermatitis due to poison
ivy), or they could be transplanted tissue cells displaying foreign antigen from the donor.

Figure 19.8 Exposure to hapten antigens in poison ivy can cause contact dermatitis, a type IV hypersensitivity. (a)
The first exposure to poison ivy does not result in a reaction. However, sensitization stimulates helper T cells, leading
to production of memory helper T cells that can become reactivated on future exposures. (b) Upon secondary
exposure, the memory helper T cells become reactivated, producing inflammatory cytokines that stimulate
macrophages and cytotoxic T cells to induce an inflammatory lesion at the exposed site. This lesion, which will persist
until the allergen is removed, can inflict significant tissue damage if it continues long enough.

Type IV Hypersensitivities
Subcategory Antigen Effector Mechanism Examples

1 Soluble Activated macrophages damage Contact dermatitis (e.g., exposure to

antigen tissue and promote inflammatory latex) and delayed-type hypersensitivity
response (e.g., tuberculin reaction)

2 Soluble Eosinophil recruitment and Chronic asthma and chronic allergic

antigen activation release cytokines and rhinitis
pro-inflammatory chemicals

Table 19.5

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Chapter 19 | Diseases of the Immune System 833

Type IV Hypersensitivities
Subcategory Antigen Effector Mechanism Examples

3 Cell- CTL-mediated cytotoxicity Contact dermatitis (e.g., contact with

associated poison ivy) and tissue-transplant rejection
antigen

Table 19.5

• Describe the three subtypes of type IV hypersensitivity.

• Explain how T cells contribute to tissue damage in type IV hypersensitivity.

Micro Connections

Using Delayed Hypersensitivity to Test for TB

Austrian pediatrician Clemans von Pirquet (1874–1929) first described allergy mechanisms, including type
III serum sickness.[9] His interest led to the development of a test for tuberculosis (TB), using the tuberculin
antigen, based on earlier work identifying the TB pathogen performed by Robert Koch. Pirquet’s method
involved scarification, which results in simultaneous multiple punctures, using a device with an array of needles
to break the skin numerous times in a small area. The device Pirquet used was similar to the tine test device
with four needles seen in Figure 19.9.
The tips of all the needles in the array are coated with tuberculin, a protein extract of TB bacteria, effectively
introducing the tuberculin into the skin. One to 3 days later, the area can be examined for a delayed
hypersensitivity reaction, signs of which include swelling and redness.
As you can imagine, scarification was not a pleasant experience,[10] and the numerous skin punctures put
the patient at risk of developing bacterial infection of the skin. Mantoux modified Pirquet’s test to use a single
subcutaneous injection of purified tuberculin material. A positive test, which is indicated by a delayed localized
swelling at the injection site, does not necessarily mean that the patient is currently infected with active TB.
Because type IV (delayed-type) hypersensitivity is mediated by reactivation of memory T cells, such cells may
have been created recently (due to an active current infection) or years prior (if a patient had TB and had
spontaneously cleared it, or if it had gone into latency). However, the test can be used to confirm infection in
cases in which symptoms in the patient or findings on a radiograph suggest its presence.

9. B. Huber “100 Jahre Allergie: Clemens von Pirquet–sein Allergiebegriff und das ihm zugrunde liegende Krankheitsverständnis.” Wiener
Klinische Wochenschrift 118 no. 19–20 (2006):573–579.
10. C.A. Stewart. “The Pirquet Test: Comparison of the Scarification and the Puncture Methods of Application.” Archives of Pediatrics &
Adolescent Medicine 35 no. 3 (1928):388–391.
834 Chapter 19 | Diseases of the Immune System

Figure 19.9 The modern version of Pirquet’s scarification is the tine test, which uses devices like this to
administer tuberculin antigen into the skin, usually on the inside of the forearm. The tine test is considered
less reliable than the Mantoux test. (credit: modification of work by the Centers for Disease Control and
Prevention)

Hypersensitivity Pneumonitis
Some disease caused by hypersensitivities are not caused exclusively by one type. For example, hypersensitivity
pneumonitis (HP), which is often an occupational or environmental disease, occurs when the lungs become inflamed
due to an allergic reaction to inhaled dust, endospores, bird feathers, bird droppings, molds, or chemicals. HP goes by
many different names associated with various forms of exposure (Figure 19.10). HP associated with bird droppings
is sometimes called pigeon fancier’s lung or poultry worker’s lung—both common in bird breeders and handlers.
Cheese handler’s disease, farmer’s lung, sauna takers' disease, and hot-tub lung are other names for HP associated
with exposure to molds in various environments.
Pathology associated with HP can be due to both type III (mediated by immune complexes) and type IV (mediated
by TH1 cells and macrophages) hypersensitivities. Repeated exposure to allergens can cause alveolitis due to the
formation of immune complexes in the alveolar wall of the lung accompanied by fluid accumulation, and the
formation of granulomas and other lesions in the lung as a result of TH1-mediated macrophage activation. Alveolitis
with fluid and granuloma formation results in poor oxygen perfusion in the alveoli, which, in turn, can cause
symptoms such as coughing, dyspnea, chills, fever, sweating, myalgias, headache, and nausea. Symptoms may occur
as quickly as 2 hours after exposure and can persist for weeks if left untreated.

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Chapter 19 | Diseases of the Immune System 835

Figure 19.10 Occupational exposure to dust, mold, and other allergens can result in hypersensitivity pneumonitis.
(a) People exposed daily to large numbers of birds may be susceptible to poultry worker’s lung. (b) Workers in a
cheese factory may become sensitized to different types of molds and develop cheese handler’s disease. (credit a:
modification of work by The Global Orphan Project)

• Explain why hypersensitivity pneumonitis is considered an occupational disease.

Figure 19.11 summarizes the mechanisms and effects of each type of hypersensitivity discussed in this section.
836 Chapter 19 | Diseases of the Immune System

Figure 19.11 Components of the immune system cause four types of hypersensitivities. Notice that types I–III are B-
cell/antibody-mediated hypersensitivities, whereas type IV hypersensitivity is exclusively a T-cell phenomenon.

Diagnosis of Hypersensitivities
Diagnosis of type I hypersensitivities is a complex process requiring several diagnostic tests in addition to a well-
documented patient history. Serum IgE levels can be measured, but elevated IgE alone does not confirm allergic
disease. As part of the process to identify the antigens responsible for a type I reaction allergy, testing through a
prick puncture skin test (PPST) or an intradermal test can be performed. PPST is carried out with the introduction of
allergens in a series of superficial skin pricks on the patient’s back or arms (Figure 19.12). PPSTs are considered to
be the most convenient and least expensive way to diagnose allergies, according to the US Joint Council of Allergy
and the European Academy of Allergy and Immunology. The second type of testing, the intradermal test, requires
injection into the dermis with a small needle. This needle, also known as a tuberculin needle, is attached to a syringe
containing a small amount of allergen. Both the PPST and the intradermal tests are observed for 15–20 minutes for
a wheal-flare reaction to the allergens. Measurement of any wheal (a raised, itchy bump) and flare (redness) within
minutes indicates a type I hypersensitivity, and the larger the wheal-flare reaction, the greater the patient’s sensitivity
to the allergen.
Type III hypersensitivities can often be misdiagnosed because of their nonspecific inflammatory nature. The
symptoms are easily visible, but they may be associated with any of a number of other diseases. A strong,
comprehensive patient history is crucial to proper and accurate diagnosis. Tests used to establish the diagnosis
of hypersensitivity pneumonitis (resulting from type III hypersensitivity) include bronchoalveolar lavage (BAL),
pulmonary function tests, and high-resolution computed tomography (HRCT).

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Chapter 19 | Diseases of the Immune System 837

Figure 19.12 Results of an allergy skin-prick test to test for type I hypersensitivity to a group of potential allergens. A
positive result is indicated by a raised area (wheal) and surrounding redness (flare). (credit: modification of work by
“OakleyOriginals”/Flickr)

• Describe the prick puncture skin test.

• Explain why type III hypersensitivities can be difficult to diagnose.

Treatments of Hypersensitivities
Allergic reactions can be treated in various ways. Prevention of allergic reactions can be achieved by desensitization
(hyposensitization) therapy, which can be used to reduce the hypersensitivity reaction through repeated injections of
allergens. Extremely dilute concentrations of known allergens (determined from the allergen tests) are injected into
the patient at prescribed intervals (e.g., weekly). The quantity of allergen delivered by the shots is slowly increased
over a buildup period until an effective dose is determined and that dose is maintained for the duration of treatment,
which can last years. Patients are usually encouraged to remain in the doctor’s office for 30 minutes after receiving
the injection in case the allergens administered cause a severe systemic reaction. Doctors’ offices that administer
desensitization therapy must be prepared to provide resuscitation and drug treatment in the case of such an event.
Desensitization therapy is used for insect sting allergies and environmental allergies. The allergy shots elicit the
production of different interleukins and IgG antibody responses instead of IgE. When excess allergen-specific IgG
antibodies are produced and bind to the allergen, they can act as blocking antibodies to neutralize the allergen before
it can bind IgE on mast cells. There are early studies using oral therapy for desensitization of food allergies that are
promising.[11][12] These studies involve feeding children who have allergies tiny amounts of the allergen (e.g., peanut

11. C.L. Schneider et al. “A Pilot Study of Omalizumab to Facilitate Rapid Oral Desensitization in High-Risk Peanut-Allergic Patients.”
Journal of Allergy and Clinical Immunology 132 no. 6 (2013):1368–1374.
12. P. Varshney et al. “A Randomized Controlled Study of Peanut Oral Immunotherapy: Clinical Desensitization and Modulation of the
Allergic Response.” Journal of Allergy and Clinical Immunology 127 no. 3 (2011):654–660.
838 Chapter 19 | Diseases of the Immune System

flour) or related proteins over time. Many of the subjects show reduced severity of reaction to the food allergen after
the therapy.
There are also therapies designed to treat severe allergic reactions. Emergency systemic anaphylaxis is treated initially
with an epinephrine injection, which can counteract the drop in blood pressure. Individuals with known severe
allergies often carry a self-administering auto-injector that can be used in case of exposure to the allergen (e.g., an
insect sting or accidental ingestion of a food that causes a severe reaction). By self-administering an epinephrine shot
(or sometimes two), the patient can stem the reaction long enough to seek medical attention. Follow-up treatment
generally involves giving the patient antihistamines and slow-acting corticosteroids for several days after the reaction
to prevent potential late-phase reactions. However, the effects of antihistamine and corticosteroid treatment are not
well studied and are used based on theoretical considerations.
Treatment of milder allergic reactions typically involves antihistamines and other anti-inflammatory drugs. A variety
of antihistamine drugs are available, in both prescription and over-the-counter strengths. There are also
antileukotriene and antiprostaglandin drugs that can be used in tandem with antihistamine drugs in a combined (and
more effective) therapy regime.
Treatments of type III hypersensitivities include preventing further exposure to the antigen and the use of anti-
inflammatory drugs. Some conditions can be resolved when exposure to the antigen is prevented. Anti-inflammatory
corticosteroid inhalers can also be used to diminish inflammation to allow lung lesions to heal. Systemic
corticosteroid treatment, oral or intravenous, is also common for type III hypersensitivities affecting body systems.
Treatment of hypersensitivity pneumonitis includes avoiding the allergen, along with the possible addition of
prescription steroids such as prednisone to reduce inflammation.
Treatment of type IV hypersensitivities includes antihistamines, anti-inflammatory drugs, analgesics, and, if possible,
eliminating further exposure to the antigen.

• Describe desensitization therapy.

• Explain the role of epinephrine in treatment of hypersensitivity reactions.

19.2 Autoimmune Disorders

Learning Objectives
• Explain why autoimmune disorders develop
• Provide a few examples of organ-specific and systemic autoimmune diseases
In 1970, artist Walt Kelly developed a poster promoting Earth Day, featuring a character from Pogo, his daily
newspaper comic strip. In the poster, Pogo looks out across a litter-strewn forest and says wryly, “We have met the
enemy and he is us.” Pogo was not talking about the human immune system, but he very well could have been.
Although the immune system protects the body by attacking invading “enemies” (pathogens), in some cases, the
immune system can mistakenly identify the body’s own cells as the enemy, resulting in autoimmune disease.
Autoimmune diseases are those in which the body is attacked by its own specific adaptive immune response. In
normal, healthy states, the immune system induces tolerance, which is a lack of an anti-self immune response.
However, with autoimmunity, there is a loss of immune tolerance, and the mechanisms responsible for autoimmune
diseases include type II, III, and IV hypersensitivity reactions. Autoimmune diseases can have a variety of mixed
symptoms that flare up and disappear, making diagnosis difficult.
The causes of autoimmune disease are a combination of the individual's genetic makeup and the effect of
environmental influences, such as sunlight, infections, medications, and environmental chemicals. However, the

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Chapter 19 | Diseases of the Immune System 839

vagueness of this list reflects our poor understanding of the etiology of these diseases. Except in a very few specific
diseases, the initiation event(s) of most autoimmune states has not been fully characterized.
There are several possible causes for the origin of autoimmune diseases and autoimmunity is likely due to several
factors. Evidence now suggests that regulatory T and B cells play an essential role in the maintenance of tolerance
and prevention of autoimmune responses. The regulatory T cells are especially important for inhibiting autoreactive
T cells that are not eliminated during thymic selection and escape the thymus (see T Lymphocytes and Cellular
Immunity). In addition, antigen mimicry between pathogen antigens and our own self antigens can lead to cross-
reactivity and autoimmunity. Hidden self-antigens may become exposed because of trauma, drug interactions, or
disease states, and trigger an autoimmune response. All of these factors could contribute to autoimmunity. Ultimately,
damage to tissues and organs in the autoimmune disease state comes as a result of inflammatory responses that are
inappropriate; therefore, treatment often includes immunosuppressive drugs and corticosteroids.

Organ-Specific Autoimmune Diseases

Some autoimmune diseases are considered organ specific, meaning that the immune system targets specific organs
or tissues. Examples of organ-specific autoimmune diseases include celiac disease, Graves disease, Hashimoto
thyroiditis, type I diabetes mellitus, and Addison disease.

Celiac Disease
Celiac disease is largely a disease of the small intestine, although other organs may be affected. People in their 30s and
40s, and children are most commonly affected, but celiac disease can begin at any age. It results from a reaction to
proteins, commonly called gluten, found mainly in wheat, barley, rye, and some other grains. The disease has several
genetic causes (predispositions) and poorly understood environmental influences. On exposure to gluten, the body
produces various autoantibodies and an inflammatory response. The inflammatory response in the small intestine
leads to a reduction in the depth of the microvilli of the mucosa, which hinders absorption and can lead to weight loss
and anemia. The disease is also characterized by diarrhea and abdominal pain, symptoms that are often misdiagnosed
as irritable bowel syndrome.
Diagnosis of celiac disease is accomplished from serological tests for the presence of primarily IgA antibodies
to components of gluten, the transglutinaminase enzyme, and autoantibodies to endomysium, a connective tissue
surrounding muscle fibers. Serological tests are typically followed up with endoscopy and biopsy of the duodenal
mucosa. Serological screening surveys have found about 1% of individuals in the United Kingdom are positive even
though they do not all display symptoms.[13] This early recognition allows for more careful monitoring and prevention
of severe disease.
Celiac disease is treated with complete removal of gluten-containing foods from the diet, which results in improved
symptoms and reduced risk of complications. Other theoretical approaches include breeding grains that do not contain
the immunologically reactive components or developing dietary supplements that contain enzymes that break down
the protein components that cause the immune response.[14]

Disorders of the Thyroid

Graves disease is the most common cause of hyperthyroidism in the United States. Symptoms of Graves disease
result from the production of thyroid-stimulating immunoglobulin (TSI) also called TSH-receptor antibody. TSI
targets and binds to the receptor for thyroid stimulating hormone (TSH), which is naturally produced by the
pituitary gland. TSI may cause conflicting symptoms because it may stimulate the thyroid to make too much thyroid
hormone or block thyroid hormone production entirely, making diagnosis more difficult. Signs and symptoms of
Graves disease include heat intolerance, rapid and irregular heartbeat, weight loss, goiter (a swollen thyroid gland,
protruding under the skin of the throat [Figure 19.13]) and exophthalmia (bulging eyes) often referred to as Graves

13. D.A. Van Heel, J. West. “Recent Advances in Coeliac Disease.” Gut 55 no. 7 (2006):1037—1046.
14. ibid.
840 Chapter 19 | Diseases of the Immune System

ophthalmopathy (Figure 19.14).

The most common cause of hypothyroidism in the United States is Hashimoto thyroiditis, also called chronic
lymphocytic thyroiditis. Patients with Hashimoto thyroiditis often develop a spectrum of different diseases because
they are more likely to develop additional autoimmune diseases such as Addison disease (discussed later in this
section), type 1 diabetes, rheumatoid arthritis, and celiac disease. Hashimoto thyroiditis is a TH1 cell-mediated disease
that occurs when the thyroid gland is attacked by cytotoxic lymphocytes, macrophages, and autoantibodies. This
autoimmune response leads to numerous symptoms that include goiter (Figure 19.13), cold intolerance, muscle
weakness, painful and stiff joints, depression, and memory loss.

Figure 19.13 Goiter, a hypertrophy of the thyroid, is a symptom of Graves disease and Hashimoto thyroiditis.

Figure 19.14 Exophthalmia, or Graves ophthalmopathy, is a sign of Graves disease. (credit: modification of work by
Jonathan Trobe, University of Michigan Kellogg Eye Center)

Type 1 Diabetes
Juvenile diabetes, or type 1 diabetes mellitus, is usually diagnosed in children and young adults. It is a T-cell-
dependent autoimmune disease characterized by the selective destruction of the β cells of the islets of Langerhans
in the pancreas by CD4 TH1-mediated CD8 T cells, anti-β-cell antibodies, and macrophage activity. There is also
evidence that viral infections can have either a potentiating or inhibitory role in the development of type 1 diabetes
(T1D) mellitus. The destruction of the β cells causes a lack of insulin production by the pancreas. In T1D, β-
cell destruction may take place over several years, but symptoms of hyperglycemia, extreme increase in thirst and
urination, weight loss, and extreme fatigue usually have a sudden onset, and diagnosis usually does not occur until
most β cells have already been destroyed.

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Chapter 19 | Diseases of the Immune System 841

Autoimmune Addison Disease

Destruction of the adrenal glands (the glands lying above the kidneys that produce glucocorticoids,
mineralocorticoids, and sex steroids) is the cause of Addison disease, also called primary adrenal insufficiency (PAI).
Today, up to 80% of Addison disease cases are diagnosed as autoimmune Addison disease (AAD), which is caused
by an autoimmune response to adrenal tissues disrupting adrenal function. Disruption of adrenal function causes
impaired metabolic processes that require normal steroid hormone levels, causing signs and symptoms throughout
the body. There is evidence that both humoral and CD4 TH1-driven CD8 T-cell–mediated immune mechanisms
are directed at the adrenal cortex in AAD. There is also evidence that the autoimmune response is associated with
autoimmune destruction of other endocrine glands as well, such as the pancreas and thyroid, conditions collectively
referred to as autoimmune polyendocrine syndromes (APS). In up to 80% of patients with AAD, antibodies are
produced to three enzymes involved in steroid synthesis: 21-hydroxylase (21-OH), 17α-hydroxylase, and cholesterol
side-chain–cleaving enzyme.[15] The most common autoantibody found in AAD is to 21-OH, and antibodies to any of
the key enzymes for steroid production are diagnostic for AAD. The adrenal cortex cells are targeted, destroyed, and
replaced with fibrous tissue by immune-mediated inflammation. In some patients, at least 90% of the adrenal cortex
is destroyed before symptoms become diagnostic.
Symptoms of AAD include weakness, nausea, decreased appetite, weight loss, hyperpigmentation (Figure 19.15),
hyperkalemia (elevated blood potassium levels), hyponatremia (decreased blood sodium levels), hypoglycemia
(decreased levels of blood sugar), hypotension (decreased blood pressure), anemia, lymphocytosis (decreased levels
of white blood cells), and fatigue. Under extreme stress, such as surgery, accidental trauma, or infection, patients
with AAD may experience an adrenal crisis that causes the patient to vomit, experience abdominal pain, back or leg
cramps, and even severe hypotension leading to shock.

Figure 19.15 Hyperpigmentation is a sign of Addison disease. (credit: modification of work by Petros Perros)

• What are the names of autoimmune diseases that interfere with hormone gland function?
• Describe how the mechanisms of Graves disease and Hashimoto thyroiditis differ.
• Name the cells that are destroyed in type 1 diabetes mellitus and describe the result.

Systemic Autoimmune Diseases

Whereas organ-specific autoimmune diseases target specific organs or tissues, systemic autoimmune diseases are

15. P. Martorell et al. “Autoimmunity in Addison’s Disease.” Netherlands Journal of Medicine 60 no. 7 (2002):269—275.
842 Chapter 19 | Diseases of the Immune System

more generalized, targeting multiple organs or tissues throughout the body. Examples of systemic autoimmune
diseases include multiple sclerosis, myasthenia gravis, psoriasis, rheumatoid arthritis, and systemic lupus
erythematosus.

Multiple Sclerosis
Multiple sclerosis (MS) is an autoimmune central nervous system disease that affects the brain and spinal cord.
Lesions in multiple locations within the central nervous system are a hallmark of multiple sclerosis and are caused
by infiltration of immune cells across the blood-brain barrier. The immune cells include T cells that promote
inflammation, demyelination, and neuron degeneration, all of which disrupt neuronal signaling. Symptoms of MS
include visual disturbances; muscle weakness; difficulty with coordination and balance; sensations such as numbness,
prickling, or “pins and needles”; and cognitive and memory problems.

Myasthenia Gravis
Autoantibodies directed against acetylcholine receptors (AChRs) in the synaptic cleft of neuromuscular junctions
lead to myasthenia gravis (Figure 19.16). Anti-AChR antibodies are high-affinity IgGs and their synthesis requires
activated CD4 T cells to interact with and stimulate B cells. Once produced, the anti-AChR antibodies affect
neuromuscular transmission by at least three mechanisms:
• Complement binding and activation at the neuromuscular junction
• Accelerated AChR endocytosis of molecules cross-linked by antibodies
• Functional AChR blocking, which prevents normal acetylcholine attachment to, and activation of, AChR
Regardless of the mechanism, the effect of anti-AChR is extreme muscle weakness and potentially death through
respiratory arrest in severe cases.

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Chapter 19 | Diseases of the Immune System 843

Figure 19.16 Myasthenia gravis and impaired muscle contraction. (a) Normal release of the neurotransmitter
acetylcholine stimulates muscle contraction. (b) In myasthenia gravis, autoantibodies block the receptors for
acetylcholine (AChr) on muscle cells, resulting in paralysis.

Psoriasis
Psoriasis is a skin disease that causes itchy or sore patches of thick, red skin with silvery scales on elbows, knees,
scalp, back, face, palms, feet, and sometimes other areas. Some individuals with psoriasis also get a form of arthritis
called psoriatic arthritis, in which the joints can become inflamed. Psoriasis results from the complex interplay
between keratinocytes, dendritic cells, and T cells, and the cytokines produced by these various cells. In a process
called cell turnover, skin cells that grow deep in the skin rise to the surface. Normally, this process takes a month. In
psoriasis, as a result of cytokine activation, cell turnover happens in just a few days. The thick inflamed patches of
skin that are characteristic of psoriasis develop because the skin cells rise too fast.

Rheumatoid Arthritis
The most common chronic inflammatory joint disease is rheumatoid arthritis (RA) (Figure 19.17) and it is still
a major medical challenge because of unsolved questions related to the environmental and genetic causes of the
disease. RA involves type III hypersensitivity reactions and the activation of CD4 T cells, resulting in chronic release
of the inflammatory cytokines IL-1, IL-6, and tumor necrosis factor-α (TNF-α). The activated CD4 T cells also
stimulate the production of rheumatoid factor (RF) antibodies and anticyclic citrullinated peptide antibodies (anti-
CCP) that form immune complexes. Increased levels of acute-phase proteins, such as C-reactive protein (CRP), are
also produced as part of the inflammatory process and participate in complement fixation with the antibodies on the
immune complexes. The formation of immune complexes and reaction to the immune factors cause an inflammatory
process in joints, particularly in the hands, feet, and legs. Diagnosis of RA is based on elevated levels of RF, anti-
CCP, quantitative CRP, and the erythrocyte sedimentation rate (ESR) (modified Westergren). In addition, radiographs,
ultrasound, or magnetic resonance imaging scans can identify joint damage, such as erosions, a loss of bone within
844 Chapter 19 | Diseases of the Immune System

the joint, and narrowing of joint space.

Figure 19.17 The radiograph (left) and photograph (right) show damage to the hands typical of rheumatoid arthritis.
(credit right: modification of work by “handarmdoc”/Flickr)

Systemic Lupus Erythematosus

The damage and pathology of systemic lupus erythematosus (SLE) is caused by type III hypersensitivity reactions.
Autoantibodies produced in SLE are directed against nuclear and cytoplasmic proteins. Anti-nuclear antibodies
(ANAs) are present in more than 95% of patients with SLE,[16] with additional autoantibodies including anti-
double–stranded DNA (ds-DNA) and anti-Sm antibodies (antibodies to small nuclear ribonucleoprotein). Anti-ds-
DNA and anti-Sm antibodies are unique to patients with SLE; thus, their presence is included in the classification
criteria of SLE. Cellular interaction with autoantibodies leads to nuclear and cellular destruction, with components
released after cell death leading to the formation of immune complexes.
Because autoantibodies in SLE can target a wide variety of cells, symptoms of SLE can occur in many body locations.
However, the most common symptoms include fatigue, fever with no other cause, hair loss, and a sunlight-sensitive
"butterfly" or wolf-mask (lupus) rash that is found in about 50% of people with SLE (Figure 19.18). The rash is most
often seen over the cheeks and bridge of the nose, but can be widespread. Other symptoms may appear depending
on affected areas. The joints may be affected, leading to arthritis of the fingers, hands, wrists, and knees. Effects on
the brain and nervous system can lead to headaches, numbness, tingling, seizures, vision problems, and personality
changes. There may also be abdominal pain, nausea, vomiting, arrhythmias, shortness of breath, and blood in the
sputum. Effects on the skin can lead to additional areas of skin lesions, and vasoconstriction can cause color changes
in the fingers when they are cold (Raynaud phenomenon). Effects on the kidneys can lead to edema in the legs
and weight gain. A diagnosis of SLE depends on identification of four of 11 of the most common symptoms and
confirmed production of an array of autoantibodies unique to SLE. A positive test for ANAs alone is not diagnostic.

16. C.C. Mok, C.S. Lau. “Pathogenesis of Systemic Lupus Erythematosus.” Journal of Clinical Pathology 56 no. 7 (2003):481—490.

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Chapter 19 | Diseases of the Immune System 845

Figure 19.18 (a) Systemic lupus erythematosus is characterized by autoimmunity to the individual’s own DNA and/
or proteins. (b) This patient is presenting with a butterfly rash, one of the characteristic signs of lupus. (credit a:
modification of work by Mikael Häggström; credit b: modification of work by Shrestha D, Dhakal AK, Shiva RK,
Shakya A, Shah SC, Shakya H)

• List the ways antibodies contribute to the pathogenesis of myasthenia gravis.

• Explain why rheumatoid arthritis is considered a type III hypersensitivity.
• Describe the symptoms of systemic lupus erythematosus and explain why they affect so many different parts
of the body.
• What is recognized as an antigen in myasthenia gravis?

Table 19.6 summarizes the causes, signs, and symptoms of select autoimmune diseases.
846 Chapter 19 | Diseases of the Immune System

Select Autoimmune Diseases

Disease Cause Signs and Symptoms

Addison Destruction of adrenal gland cells by cytotoxic Weakness, nausea, hypotension, fatigue;
disease T cells adrenal crisis with severe pain in abdomen,
lower back, and legs; circulatory system
collapse, kidney failure

Celiac disease Antibodies to gluten become autoantibodies Severe diarrhea, abdominal pain, anemia,
that target cells of the small intestine malnutrition

Diabetes Cytotoxic T-cell destruction of the insulin- Hyperglycemia, extreme increase in thirst
mellitus producing β cells of the pancreas and urination, weight loss, extreme fatigue
(type I)

Graves Autoantibodies target thyroid-stimulating Hyperthyroidism with rapid and irregular

disease hormone receptors, resulting in heartbeat, heat intolerance, weight loss,
overstimulation of the thyroid goiter, exophthalmia

Hashimoto Thyroid gland is attacked by cytotoxic T cells, Thyroiditis with goiter, cold intolerance,
thyroiditis lymphocytes, macrophages, and muscle weakness, painful and stiff joints,
autoantibodies depression, memory loss

Multiple Cytotoxic T-cell destruction of the myelin Visual disturbances, muscle weakness,
sclerosis (MS) sheath surrounding nerve axons in the central impaired coordination and balance,
nervous system numbness, prickling or “pins and needles”
sensations, impaired cognitive function and
memory

Myasthenia Autoantibodies directed against acetylcholine Extreme muscle weakness eventually

gravis receptors within the neuromuscular junction leading to fatal respiratory arrest

Psoriasis Cytokine activation of keratinocytes causes Itchy or sore patches of thick, red skin with
rapid and excessive epidermal cell turnover silvery scales; commonly affects elbows,
knees, scalp, back, face, palms, feet

Rheumatoid Autoantibodies, immune complexes, Joint inflammation, pain and disfigurement,

arthritis complement activation, phagocytes, and T chronic systemic inflammation
cells damage membranes and bone in joints

Systemic Autoantibodies directed against nuclear and Fatigue, fever, joint pain and swelling, hair
lupus cytoplasmic molecules form immune loss, anemia, clotting, a sunlight-sensitive
erythematosus complexes that deposit in tissues. Phagocytic "butterfly" rash, skin lesions,
(SLE) cells and complement activation cause tissue photosensitivity, decreased kidney function,
damage and inflammation memory loss, confusion, depression

Table 19.6

19.3 Organ Transplantation and Rejection

Learning Objectives
• Explain why human leukocyte antigens (HLAs) are important in tissue transplantation
• Explain the types of grafts possible and their potential for interaction with the immune system
• Describe what occurs during graft-versus-host disease (GVHD)
A graft is the transplantation of an organ or tissue to a different location, with the goal of replacing a missing or
damaged organ or tissue. Grafts are typically moved without their attachments to the circulatory system and must
reestablish these, in addition to the other connections and interactions with their new surrounding tissues. There

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Chapter 19 | Diseases of the Immune System 847

are different types of grafts depending on the source of the new tissue or organ. Tissues that are transplanted from
one genetically distinct individual to another within the same species are called allografts. An interesting variant
of the allograft is an isograft, in which tissue from one twin is transplanted to another. As long as the twins are
monozygotic (therefore, essentially genetically identical), the transplanted tissue is virtually never rejected. If tissues
are transplanted from one area on an individual to another area on the same individual (e.g., a skin graft on a
burn patient), it is known as an autograft. If tissues from an animal are transplanted into a human, this is called a
xenograft.

Transplant Rejection
The different types of grafts described above have varying risks for rejection (Table 19.7). Rejection occurs when
the recipient’s immune system recognizes the donor tissue as foreign (non-self), triggering an immune response. The
major histocompatibility complex markers MHC I and MHC II, more specifically identified as human leukocyte
antigens (HLAs), play a role in transplant rejection. The HLAs expressed in tissue transplanted from a genetically
different individual or species may be recognized as non-self molecules by the host’s dendritic cells. If this occurs,
the dendritic cells will process and present the foreign HLAs to the host’s helper T cells and cytotoxic T cells, thereby
activating them. Cytotoxic T cells then target and kill the grafted cells through the same mechanism they use to kill
virus-infected cells; helper T cells may also release cytokines that activate macrophages to kill graft cells.

Types of Tissue and Organ Grafts and Their Complications

Graft Procedure Complications

Autograft From self to self No rejection concerns

Isograft From identical twin to twin Little concern of rejection

Allograft From relative or nonrelative to individual Rejection possible

Xenograft From animal to human Rejection possible

Table 19.7

With the three highly polymorphic MHC I genes in humans (HLA-A, HLA-B, and HLA-C) determining compatibility,
each with many alleles segregating in a population, odds are extremely low that a randomly chosen donor will match
a recipient's six-allele genotype (the two alleles at each locus are expressed codominantly). This is why a parent or a
sibling may be the best donor in many situations—a genetic match between the MHC genes is much more likely and
the organ is much less likely to be rejected.
Although matching all of the MHC genes can lower the risk for rejection, there are a number of additional gene
products that also play a role in stimulating responses against grafted tissue. Because of this, no non-self grafted tissue
is likely to completely avoid rejection. However, the more similar the MHC gene match, the more likely the graft is to
be tolerated for a longer time. Most transplant recipients, even those with tissues well matched to their MHC genes,
require treatment with immunosuppressant drugs for the rest of their lives. This can make them more vulnerable than
the general population to complications from infectious diseases. It can also result in transplant-related malignancies
because the body’s normal defenses against cancer cells are being suppressed.

• What part of the immune response is responsible for graft rejection?

• Explain why blood relatives are preferred as organ donors.
• Describe the role of immunosuppression in transplantation.
848 Chapter 19 | Diseases of the Immune System

Graft-versus-Host Disease
A form of rejection called graft-versus-host disease (GVHD) primarily occurs in recipients of bone marrow
transplants and peripheral blood stem cells. GHVD presents a unique situation because the transplanted tissue is
capable of producing immune cells; APCs in the donated bone marrow may recognize the host cells as non-self,
leading to activation of the donor cytotoxic T cells. Once activated, the donor’s T cells attack the recipient cells,
causing acute GVHD.
Acute GVHD typically develops within weeks after a bone marrow transplant, causing tissue damage affecting the
skin, gastrointestinal tract, liver, and eyes. In addition, acute GVHD may also lead to a cytokine storm, an unregulated
secretion of cytokines that may be fatal. In addition to acute GVHD, there is also the risk for chronic GVHD
developing months after the bone marrow transplant. The mechanisms responsible for chronic GVHD are not well
understood.
To minimize the risk of GVHD, it is critically important to match the HLAs of the host and donor as closely as
possible in bone marrow transplants. In addition, the donated bone marrow is processed before grafting to remove as
many donor APCs and T cells as possible, leaving mostly hematopoietic stem cells.

• Why does GVHD occur in specifically in bone marrow transplants?

• What cells are responsible for GVHD?

The Future of Transplantation

Historically speaking, the practice of transplanting tissues—and the complications that can accompany such
procedures—is a relatively recent development. It was not until 1954 that the first successful organ transplantation
between two humans was achieved. Yet the field of organ transplantation has progressed rapidly since that time.
Nonetheless, the practice of transplanting non-self tissues may soon become obsolete. Scientists are now attempting
to develop methods by which new organs may be grown in vitro from an individual’s own harvested cells to replace
damaged or abnormal ones. Because organs produced in this way would contain the individual’s own cells, they could
be transplanted into the individual without risk for rejection.
An alternative approach that is gaining renewed research interest is genetic modification of donor animals, such as
pigs, to provide transplantable organs that do not elicit an immune response in the recipient. The approach involves
excising the genes in the pig (in the embryo) that are most responsible for the rejection reaction after transplantation.
Finding these genes and effectively removing them is a challenge, however. So too is identifying and neutralizing
risks from viral sequences that might be embedded in the pig genome, posing a risk for infection in the human
recipient.

Link to Learning

There are currently more than a dozen different tissues and organs used in
human transplantations. Learn more about them at this (https://openstax.org/l/
22organstransp) website.

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Chapter 19 | Diseases of the Immune System 849

Clinical Focus

Resolution
Kerry's tests come back positive, confirming a diagnosis of lupus, a disease that occurs 10 times more
frequently in women than men. SLE cannot be cured, but there are various therapies available for reducing
and managing its symptoms. Specific therapies are prescribed based on the particular symptoms presenting
in the patient. Kerry's rheumatologist starts her therapy with a low dose of corticosteroids to reduce her
rashes. She also prescribes a low dose of hydroxychloroquine, an anti-inflammatory drug that is used to
treat inflammation in patients with RA, childhood arthritis, SLE, and other autoimmune diseases. Although the
mechanism of action of hydroxychloroquine is not well defined, it appears that this drug interferes with the
processes of antigen processing and activation of autoimmunity. Because of its mechanism, the effects of
hydroxychloroquine are not as immediate as that of other anti-inflammatory drugs, but it is still considered a
good companion therapy for SLE. Kerry’s doctor also advises her to limit her exposure to sunlight, because
photosensitivity to sunlight may precipitate rashes.
Over the next 6 months, Kerry follows her treatment plan and her symptoms do not return. However, future
flare-ups are likely to occur. She will need to continue her treatment for the rest of her life and seek medical
attention whenever new symptoms develop.
Go back to the previous Clinical Focus box.

19.4 Immunodeficiency
Learning Objectives
• Compare the causes of primary and secondary immunodeficiencies
• Describe treatments for primary and secondary immunodeficiencies
Immunodeficiencies are inherited (primary) or acquired (secondary) disorders in which elements of host immune
defenses are either absent or functionally defective. In developed countries, most immunodeficiencies are inherited,
and they are usually first seen in the clinic as recurrent or overwhelming infections in infants. However, on
a global scale, malnutrition is the most common cause of immunodeficiency and would be categorized as an
acquired immunodeficiency. Acquired immunodeficiencies are more likely to develop later in life, and the pathogenic
mechanisms of many remain obscure.

Primary Immunodeficiency
Primary immunodeficiencies, which number more than 250, are caused by inherited defects of either nonspecific
innate or specific adaptive immune defenses. In general, patients born with primary immunodeficiency (PI)
commonly have an increased susceptibility to infection. This susceptibility can become apparent shortly after
birth or in early childhood for some individuals, whereas other patients develop symptoms later in life. Some
primary immunodeficiencies are due to a defect of a single cellular or humoral component of the immune system;
others may result from defects of more than one component. Examples of primary immunodeficiencies include
chronic granulomatous disease, X-linked agammaglobulinemia, selective IgA deficiency, and severe combined
immunodeficiency disease.

Chronic Granulomatous Disease

The causes of chronic granulomatous disease (CGD) are defects in the NADPH oxidase system of phagocytic cells,
including neutrophils and macrophages, that prevent the production of superoxide radicals in phagolysosomes. The
inability to produce superoxide radicals impairs the antibacterial activity of phagocytes. As a result, infections in
850 Chapter 19 | Diseases of the Immune System

patients with CGD persist longer, leading to a chronic local inflammation called a granuloma. Microorganisms that
are the most common causes of infections in patients with CGD include Aspergillus spp., Staphylococcus aureus,
Chromobacterium violaceum, Serratia marcescens, and Salmonella typhimurium.

X-Linked Agammaglobulinemia
Deficiencies in B cells due to defective differentiation lead to a lack of specific antibody production known as
X-linked agammaglobulinemia. In 1952, Ogden C. Bruton (1908–2003) described the first immunodeficiency in
a boy whose immune system failed to produce antibodies. This defect is inherited on the X chromosome and is
characterized by the absence of immunoglobulin in the serum; it is called Bruton X-linked agammaglobulinemia
(XLA). The defective gene, BTK, in XLA is now known to encode a tyrosine kinase called Bruton tyrosine
kinase (Btk). In patients whose B cells are unable to produce sufficient amounts of Btk, the B-cell maturation
and differentiation halts at the pre-B-cell stage of growth. B-cell maturation and differentiation beyond the pre-B-
cell stage of growth is required for immunoglobulin production. Patients who lack antibody production suffer from
recurrent infections almost exclusively due to extracellular pathogens that cause pyogenic infections: Haemophilus
influenzae, Streptococcus pneumoniae, S. pyogenes, and S. aureus. Because cell-mediated immunity is not impaired,
these patients are not particularly vulnerable to infections caused by viruses or intracellular pathogens.

Selective IgA Deficiency

The most common inherited form of immunoglobulin deficiency is selective IgA deficiency, affecting about one in
800 people. Individuals with selective IgA deficiency produce normal levels of IgG and IgM, but are not able to
produce secretory IgA. IgA deficiency predisposes these individuals to lung and gastrointestinal infections for which
secretory IgA is normally an important defense mechanism. Infections in the lungs and gastrointestinal tract can
involve a variety of pathogens, including H. influenzae, S. pneumoniae, Moraxella catarrhalis, S. aureus, Giardia
lamblia, or pathogenic strains of Escherichia coli.

Severe Combined Immunodeficiency

Patients who suffer from severe combined immunodeficiency (SCID) have B-cell and T-cell defects that impair
T-cell dependent antibody responses as well as cell-mediated immune responses. Patients with SCID also cannot
develop immunological memory, so vaccines provide them no protection, and live attenuated vaccines (e.g., for
varicella-zoster, measles virus, rotavirus, poliovirus) can actually cause the infection they are intended to prevent.
The most common form is X-linked SCID, which accounts for nearly 50% of all cases and occurs primarily in males.
Patients with SCID are typically diagnosed within the first few months of life after developing severe, often life-
threatening, opportunistic infection by Candida spp., Pneumocystis jirovecii, or pathogenic strains of E. coli.
Without treatment, babies with SCID do not typically survive infancy. In some cases, a bone marrow transplant
may successfully correct the defects in lymphocyte development that lead to the SCID phenotype, by replacing the
defective component. However, this treatment approach is not without risks, as demonstrated by the famous case of
David Vetter (1971–1984), better known as “Bubble Boy” (Figure 19.19). Vetter, a patient with SCID who lived in
a protective plastic bubble to prevent exposure to opportunistic microbes, received a bone marrow transplant from
his sister. Because of a latent Epstein-Barr virus infection in her bone marrow, however, he developed mononucleosis
and died of Burkitt lymphoma at the age of 12 years.

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Chapter 19 | Diseases of the Immune System 851

Figure 19.19 David Vetter, popularly known as “The Bubble Boy,” was born with SCID and lived most of his life
isolated inside a plastic bubble. Here he is shown outside the bubble in a suit specially built for him by NASA. (credit:
NASA Johnson Space Center)

• What is the fundamental cause of a primary immunodeficiency?

• Explain why patients with chronic granulomatous disease are especially susceptible to bacterial infections.
• Explain why individuals with selective IgA deficiency are susceptible to respiratory and gastrointestinal
infections.

Secondary Immunodeficiency
A secondary immunodeficiency occurs as a result an acquired impairment of function of B cells, T cells, or both.
Secondary immunodeficiencies can be caused by:
• Systemic disorders such as diabetes mellitus, malnutrition, hepatitis, or HIV infection
• Immunosuppressive treatments such as cytotoxic chemotherapy, bone marrow ablation before transplantation,
or radiation therapy
• Prolonged critical illness due to infection, surgery, or trauma in the very young, elderly, or hospitalized
patients
Unlike primary immunodeficiencies, which have a genetic basis, secondary immunodeficiencies are often reversible
if the underlying cause is resolved. Patients with secondary immunodeficiencies develop an increased susceptibility
to an otherwise benign infection by opportunistic pathogens such as Candida spp., P. jirovecii, and Cryptosporidium.
HIV infection and the associated acquired immunodeficiency syndrome (AIDS) are the best-known secondary
immunodeficiencies. AIDS is characterized by profound CD4 T-cell lymphopenia (decrease in lymphocytes). The
decrease in CD4 T cells is the result of various mechanisms, including HIV-induced pyroptosis (a type of apoptosis
that stimulates an inflammatory response), viral cytopathic effect, and cytotoxicity to HIV-infected cells.
The most common cause of secondary immunodeficiency worldwide is severe malnutrition, which affects both
innate and adaptive immunity. More research and information are needed for the more common causes of secondary
immunodeficiency; however, the number of new discoveries in AIDS research far exceeds that of any other single
852 Chapter 19 | Diseases of the Immune System

cause of secondary immunodeficiency. AIDS research has paid off extremely well in terms of discoveries and
treatments; increased research into the most common cause of immunodeficiency, malnutrition, would likely be as
beneficial.

• What is the most common cause of secondary immunodeficiencies?

• Explain why secondary immunodeficiencies can sometimes be reversed.

Case in Point

An Immunocompromised Host
Benjamin, a 50-year-old male patient who has been receiving chemotherapy to treat his chronic myelogenous
leukemia (CML), a disease characterized by massive overproduction of nonfunctional, malignant myelocytic
leukocytes that crowd out other, healthy leukocytes, is seen in the emergency department. He is complaining
of a productive, wet cough, dyspnea, and fatigue. On examination, his pulse is 120 beats per minute (bpm)
(normal range is 60–100 bpm) and weak, and his blood pressure is 90/60 mm Hg (normal is 120/80 mm Hg).
During auscultation, a distinct crackling can be heard in his lungs as he breathes, and his pulse-oximeter level
(a measurement of blood-oxygen saturation) is 80% (normal is 95%–100%). He has a fever; his temperature
is 38.9 °C (102 °F). Sputum cultures and blood samples are obtained and sent to the lab, but Benjamin goes
into respiratory distress and dies before the results can be obtained.
Benjamin’s death was a result of a combination of his immune system being compromised by his leukemia and
his chemotherapy treatment further weakening his ability to mount an immune response. CML (and leukemia
in general) and corresponding chemotherapy cause a decrease in the number of leukocytes capable of normal
function, leading to secondary immunodeficiency. This increases the risk for opportunistic bacterial, viral,
protozoal, and fungal infections that could include Staphylococcus, enteroviruses, Pneumocystis, Giardia, or
Candida. Benjamin’s symptoms were suggestive of bacterial pneumonia, but his leukemia and chemotherapy
likely complicated and contributed to the severity of the pneumonia, resulting in his death. Because his
leukemia was overproducing certain white blood cells, and those overproduced white blood cells were largely
nonfunctional or abnormal in their function, he did not have the proper immune system blood cells to help him
fight off the infection.

Table 19.8 summarizes primary and secondary immunodeficiencies, their effects on immune function, and typical
outcomes.

Primary and Secondary Immunodeficiencies

Disease Effect on Immune Function Outcomes

Primary Chronic Impaired killing of bacteria Chronic infections and

immunodeficiencies granulomatous within the phagolysosome of granulomas
disease neutrophils and
macrophages

Selective IgA Inability to produce secretory Predisposition to lung and

deficiency IgA gastrointestinal infections

Table 19.8

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Chapter 19 | Diseases of the Immune System 853

Primary and Secondary Immunodeficiencies

Disease Effect on Immune Function Outcomes

Severe combined Deficient humoral and cell- Early development of severe

immunodeficiency mediated immune responses and life-threatening
disease (SCID) opportunistic infections

X-linked Flawed differentiation of B Recurrent infections almost

agammaglobulinemia cells and absence of specific exclusively due to pathogens
antibodies that cause pyogenic infections

Secondary Immunosuppressive Impaired humoral and/or cell- Opportunistic infections, rare

immunodeficiencies therapies (e.g., mediated immune responses cancers
chemotherapy,
radiotherapy)

Malnutrition Impaired humoral and/or cell- Opportunistic infections, rare

mediated immune responses cancers

Viral infection (e.g., Impaired cell-mediated Opportunistic infections, rare

HIV) immune responses due to cancers
CD4 T-cell lymphopenia

Table 19.8

19.5 Cancer Immunobiology and Immunotherapy

Learning Objectives
• Explain how the adaptive specific immune response responds to tumors
• Discuss the risks and benefits of tumor vaccines
Cancer involves a loss of the ability of cells to control their cell cycle, the stages each eukaryotic cell goes through
as it grows and then divides. When this control is lost, the affected cells rapidly divide and often lose the ability to
differentiate into the cell type appropriate for their location in the body. In addition, they lose contact inhibition and
can start to grow on top of each other. This can result in formation of a tumor. It is important to make a distinction
here: The term “cancer” is used to describe the diseases resulting from loss of cell-cycle regulation and subsequent
cell proliferation. But the term “tumor” is more general. A “tumor” is an abnormal mass of cells, and a tumor can be
benign (not cancerous) or malignant (cancerous).
Traditional cancer treatment uses radiation and/or chemotherapy to destroy cancer cells; however, these treatments
can have unwanted side effects because they harm normal cells as well as cancer cells. Newer, promising therapies
attempt to enlist the patient’s immune system to target cancer cells specifically. It is known that the immune system
can recognize and destroy cancerous cells, and some researchers and immunologists also believe, based on the
results of their experiments, that many cancers are eliminated by the body’s own defenses before they can become
a health problem. This idea is not universally accepted by researchers, however, and needs further investigation for
verification.

Cell-Mediated Response to Tumors

Cell-mediated immune responses can be directed against cancer cells, many of which do not have the normal
complement of self-proteins, making them a target for elimination. Abnormal cancer cells may also present tumor
antigens. These tumor antigens are not a part of the screening process used to eliminate lymphocytes during
development; thus, even though they are self-antigens, they can stimulate and drive adaptive immune responses
against abnormal cells.
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Presentation of tumor antigens can stimulate naïve helper T cells to become activated by cytokines such as IL-12 and
differentiate into TH1 cells. TH1 cells release cytokines that can activate natural killer (NK) cells and enhance the
killing of activated cytotoxic T cells. Both NK cells and cytotoxic T cells can recognize and target cancer cells, and
induce apoptosis through the action of perforins and granzymes. In addition, activated cytotoxic T cells can bind to
cell-surface proteins on abnormal cells and induce apoptosis by a second killing mechanism called the CD95 (Fas)
cytotoxic pathway.
Despite these mechanisms for removing cancerous cells from the body, cancer remains a common cause of death.
Unfortunately, malignant tumors tend to actively suppress the immune response in various ways. In some cancers,
the immune cells themselves are cancerous. In leukemia, lymphocytes that would normally facilitate the immune
response become abnormal. In other cancers, the cancerous cells can become resistant to induction of apoptosis. This
may occur through the expression of membrane proteins that shut off cytotoxic T cells or that induce regulatory T
cells that can shut down immune responses.
The mechanisms by which cancer cells alter immune responses are still not yet fully understood, and this is a very
active area of research. As scientists’ understanding of adaptive immunity improves, cancer therapies that harness the
body’s immune defenses may someday be more successful in treating and eliminating cancer.

• How do cancer cells suppress the immune system?

• Describe how the immune system recognizes and destroys cancer cells.

Cancer Vaccines
There are two types of cancer vaccines: preventive and therapeutic. Preventive vaccines are used to prevent cancer
from occurring, whereas therapeutic vaccines are used to treat patients with cancer. Most preventive cancer vaccines
target viral infections that are known to lead to cancer. These include vaccines against human papillomavirus (HPV)
and hepatitis B, which help prevent cervical and liver cancer, respectively.
Most therapeutic cancer vaccines are in the experimental stage. They exploit tumor-specific antigens to stimulate the
immune system to selectively attack cancer cells. Specifically, they aim to enhance TH1 function and interaction with
cytotoxic T cells, which, in turn, results in more effective attack on abnormal tumor cells. In some cases, researchers
have used genetic engineering to develop antitumor vaccines in an approach similar to that used for DNA vaccines
(see Micro Connections: DNA vaccines). The vaccine contains a recombinant plasmid with genes for tumor
antigens; theoretically, the tumor gene would not induce new cancer because it is not functional, but it could trick the
immune system into targeting the tumor gene product as a foreign invader.
The first FDA-approved therapeutic cancer vaccine was sipuleucel-T (Provenge), approved in 2010 to treat certain
cases of prostate cancer.[17] This unconventional vaccine is custom designed using the patient’s own cells. APCs are
removed from the patient and cultured with a tumor-specific molecule; the cells are then returned to the patient.
This approach appears to enhance the patient’s immune response against the cancer cells. Another therapeutic cancer
vaccine (talimogene laherparepvec, also called T-VEC or Imlygic) was approved by the FDA in 2015 for treatment of
melanoma, a form of skin cancer. This vaccine contains a virus that is injected into tumors, where it infects and lyses
the tumor cells. The virus also induces a response in lesions or tumors besides those into which the vaccine is injected,
indicating that it is stimulating a more general (as opposed to local) antitumor immune response in the patient.

17. National Institutes of Health, National Cancer Institute. "Cancer Vaccines." http://www.cancer.gov/about-cancer/causes-prevention/
vaccines-fact-sheet#q8. Accessed on May 20, 2016.

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Chapter 19 | Diseases of the Immune System 855

• Explain the difference between preventative and therapeutic cancer vaccines.

• Describe at least two different approaches to developing therapeutic anti-cancer vaccines.

Micro Connections

Using Viruses to Cure Cancer

Viruses typically destroy the cells they infect—a fact responsible for any number of human diseases. But
the cell-killing powers of viruses may yet prove to be the cure for some types of cancer, which is generally
treated by attempting to rid the body of cancerous cells. Several clinical trials are studying the effects of
viruses targeted at cancer cells. Reolysin, a drug currently in testing phases, uses reoviruses (respiratory
enteric orphan viruses) that can infect and kill cells that have an activated Ras-signaling pathway, a common
mutation in cancerous cells. Viruses such as rubeola (the measles virus) can also be genetically engineered
to aggressively attack tumor cells. These modified viruses not only bind more specifically to receptors
overexpressed on cancer cells, they also carry genes driven by promoters that are only turned on within cancer
cells. Herpesvirus and others have also been modified in this way.

Summary
19.1 Hypersensitivities
• An allergy is an adaptive immune response, sometimes life-threatening, to an allergen.
• Type I hypersensitivity requires sensitization of mast cells with IgE, involving an initial IgE antibody
response and IgE attachment to mast cells. On second exposure to an allergen, cross-linking of IgE molecules
on mast cells triggers degranulation and release of preformed and newly formed chemical mediators of
inflammation. Type I hypersensitivity may be localized and relatively minor (hives and hay fever) or system-
wide and dangerous (systemic anaphylaxis).
• Type II hypersensitivities result from antibodies binding to antigens on cells and initiating cytotoxic
responses. Examples include hemolytic transfusion reaction and hemolytic disease of the newborn.
• Type III hypersensitivities result from formation and accumulation of immune complexes in tissues,
stimulating damaging inflammatory responses.
• Type IV hypersensitivities are not mediated by antibodies, but by helper T-cell activation of macrophages,
eosinophils, and cytotoxic T cells.
19.2 Autoimmune Disorders
• Autoimmune diseases result from a breakdown in immunological tolerance. The actual induction event(s) for
autoimmune states are largely unknown.
• Some autoimmune diseases attack specific organs, whereas others are more systemic.
• Organ-specific autoimmune diseases include celiac disease, Graves disease, Hashimoto thyroiditis, type I
diabetes mellitus, and Addison disease.
• Systemic autoimmune diseases include multiple sclerosis, myasthenia gravis, psoriasis, rheumatoid
arthritis, and systemic lupus erythematosus.
• Treatments for autoimmune diseases generally involve anti-inflammatory and immunosuppressive drugs.
19.3 Organ Transplantation and Rejection
• Grafts and transplants can be classified as autografts, isografts, allografts, or xenografts based on the
856 Chapter 19 | Diseases of the Immune System

genetic differences between the donor’s and recipient’s tissues.

• Genetic differences, especially among the MHC (HLA) genes, will dictate the likelihood that rejection of the
transplanted tissue will occur.
• Transplant recipients usually require immunosuppressive therapy to avoid rejection, even with good genetic
matching. This can create additional problems when immune responses are needed to fight off infectious
agents and prevent cancer.
• Graft-versus-host disease can occur in bone marrow transplants, as the mature T cells in the transplant itself
recognize the recipient’s tissues as foreign.
• Transplantation methods and technology have improved greatly in recent decades and may move into new
areas with the use of stem cell technology to avoid the need for genetic matching of MHC molecules.
19.4 Immunodeficiency
• Primary immunodeficiencies are caused by genetic abnormalities; secondary immunodeficiencies are
acquired through disease, diet, or environmental exposures
• Primary immunodeficiencies may result from flaws in phagocyte killing of innate immunity, or impairment of
T cells and B cells.
• Primary immunodeficiencies include chronic granulomatous disease, X-linked agammaglobulinemia,
selective IgA deficiency, and severe combined immunodeficiency disease.
• Secondary immunodeficiencies result from environmentally induced defects in B cells and/or T cells.
• Causes for secondary immunodeficiencies include malnutrition, viral infection, diabetes, prolonged infections,
and chemical or radiation exposure.
19.5 Cancer Immunobiology and Immunotherapy
• Cancer results from a loss of control of the cell cycle, resulting in uncontrolled cell proliferation and a loss of
the ability to differentiate.
• Adaptive and innate immune responses are engaged by tumor antigens, self-molecules only found on
abnormal cells. These adaptive responses stimulate helper T cells to activate cytotoxic T cells and NK cells of
innate immunity that will seek and destroy cancer cells.
• New anticancer therapies are in development that will exploit natural adaptive immunity anticancer responses.
These include external stimulation of cytotoxic T cells and therapeutic vaccines that assist or enhance the
immune response.

Review Questions
Multiple Choice 3. Which of the following are the main mediators/
1. Which of the following is the type of cell largely initiators of type II hypersensitivity reactions?
responsible for type I hypersensitivity responses? a. antibodies
a. erythrocyte b. mast cells
b. mast cell c. erythrocytes
c. T lymphocyte d. histamines
d. antibody 4. Inflammatory molecules are released by mast cells
2. Type I hypersensitivities require which of the in type I hypersensitivities; type II hypersensitivities,
following initial priming events to occur? however, are characterized by which of the following?
a. sensitization a. cell lysis (cytotoxicity)
b. secondary immune response b. strong antibody reactions against antigens
c. cellular trauma c. leukotriene release upon stimulation
d. degranulation d. localized tissue reactions, such as hives

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Chapter 19 | Diseases of the Immune System 857

5. An immune complex is an aggregate of which of the 12. Which of the following is a genetic disease that
following? results in almost no adaptive immunity due to lack of B
a. antibody molecules and/ or T cells?
b. antigen molecules a. agammaglobulinemia
c. antibody and antigen molecules b. severe combined immunodeficiency
d. histamine molecules c. HIV/AIDS
d. chronic granulomatous disease
6. Which of the following is a common treatment for
type III hypersensitivity reactions? 13. All but which one of the following are examples of
a. anti-inflammatory steroid treatments secondary immunodeficiencies?
b. antihistamine treatments a. HIV/AIDS
c. hyposensitization injections of allergens b. malnutrition
d. RhoGAM injections c. chronic granulomatous disease
d. immunosuppression due to measles infection
7. Which of the following induces a type III
hypersensitivity? 14. Cancer results when a mutation leads to which of
a. release of inflammatory molecules from mast the following?
cells a. cell death
b. accumulation of immune complexes in tissues b. apoptosis
and small blood vessels c. loss of cell-cycle control
c. destruction of cells bound by antigens d. shutdown of the cell cycle
d. destruction of cells bound by antibodies
15. Tumor antigens are ________ that are
8. Which one of the following is not an example of a inappropriately expressed and found on abnormal cells.
type IV hypersensitivity? a. self antigens
a. latex allergy b. foreign antigens
b. Contact dermatitis (e.g., contact with poison ivy) c. antibodies
c. a positive tuberculin skin test d. T-cell receptors
d. hemolytic disease of the newborn

9. Which of the following is an example of an organ-

specific autoimmune disease?
a. rheumatoid arthritis
b. psoriasis
c. Addison disease
d. myasthenia gravis

10. Which of the following is an example of a systemic

autoimmune disease?
a. Hashimoto thyroiditis
b. type I diabetes mellitus
c. Graves disease
d. myasthenia gravis

11. Which of the following is a genetic disease that

results in lack of production of antibodies?
a. agammaglobulinemia
b. myasthenia gravis
c. HIV/AIDS
d. chronic granulomatous disease
858 Chapter 19 | Diseases of the Immune System

Matching
16. Match the graft with its description.
___autograft A. donor is a different species than the recipient

___allograft B. donor and recipient are the same individual

___xenograft C. donor is an identical twin of the recipient

___isograft D. donor is the same species as the recipient, but genetically different

Fill in the Blank

17. Antibodies involved in type I hypersensitivities are of the ________ class.

18. Allergy shots work by shifting antibody responses to produce ________ antibodies.

19. A person who is blood type A would have IgM hemagglutinin antibodies against type ________ red blood cells
in their plasma.

20. The itchy and blistering rash that develops with contact to poison ivy is caused by a type ________
hypersensitivity reaction.

21. The thyroid-stimulating immunoglobulin that acts like thyroid-stimulating hormone and causes Graves disease
is an antibody to the ________.

22. For a transplant to have the best chances of avoiding rejection, the genes coding for the ________ molecules
should be closely matched between donor and recipient.

23. Because it is a “transplant” that can include APCs and T cells from the donor, a bone marrow transplant may
induce a very specific type of rejection known as ________ disease.

24. Diseases due to ________ abnormalities are termed primary immunodeficiencies.

25. A secondary immunodeficiency is ________, rather than genetic.

26. A ________ cancer vaccine is one that stops the disease from occurring in the first place.

27. A ________ cancer vaccine is one that will help to treat the disease after it has occurred.

Short Answer
28. Although both type I and type II hypersensitivities involve antibodies as immune effectors, different mechanisms
are involved with these different hypersensitivities. Differentiate the two.

29. What types of antibodies are most common in type III hypersensitivities, and why?

30. Why is a parent usually a better match for transplanted tissue to a donor than a random individual of the same
species?

31. Compare the treatments for primary and secondary immunodeficiencies.

32. How can tumor antigens be effectively targeted without inducing an autoimmune (anti-self) response?

Critical Thinking
33. Patients are frequently given instructions to avoid allergy medications for a period of time prior to allergy testing.
Why would this be important?

34. In some areas of the world, a tuberculosis vaccine known as bacillus Calmette-Guérin (BCG) is used. It is not
used in the United States. Every person who has received this vaccine and mounted a protective response will have
a positive reaction in a tuberculin skin test. Why? What does this mean for the usefulness of this skin test in those
countries where this vaccine is used?

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