Innate defense system

MPM 260
Objectives

▪ Understand the Importance of immunology

▪ Know the types of Immunity
▪ Know the components of the innate immunity
▪ Explain the innate defense mechanisms
▪ Explain the mechanism of phagocytosis and
intracellular killing
▪ Explain the complement system
▪ Explain the innate response to viral and parasitic
infections
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 What is immunology?
▪ Immune (Latin- “immunus”)
▪ To be free
▪ People survived calamity of epidemic diseases when
faced with the same disease again

▪ The study of physiological mechanisms that humans and

other animals use to defend their bodies from invading
organisms
▪ Bacteria, Viruses, Fungi, Parasites, Toxins
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Immunology

▪ a study of the structure of immune system

and its functions

▪ aims to introduce immune system as a system

of defense against infections and to identify
its strengths and weaknesses in understanding
the pathogenesis and prevention of disease

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 Immune system

▪ is a collection of cells and proteins that function to

protect the skin, respiratory passages, intestinal
tract and other areas from foreign antigens, such
as microbes (organisms such as bacteria, fungi, and
parasites), viruses, cancer cells, and toxins

Warrington et al. Allergy, Asthma &

Clinical Immunology, 2011

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 ▪ Immunity

▪ an acquired resistance to infectious disease that is specific, i.e.,

resistance against a particular disease-causing pathogen.

▪ “Protection” from infection, tumors, etc.

▪ Innate immunity is always available

▪ Adaptive immunity distinguishes “self” from “non-self” and involves

immune system “education”

▪ Responses that may result in host tissue damage

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Immunology
Antigen

▪ A substance (antigen) that is capable of reacting

with the products of a specific immune response,
e.g., antibody or specific sensitized T-lymphocytes.

▪ A “self” component may be considered an antigen

even though one does not generally make immune
responses against those components.
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Immunology

▪ Antigen
▪ Any molecule that binds to immunoglobulin
or Tcell receptor

▪ Pathogen
▪ Microorganism that can cause disease

▪ Antibody (Ab)
▪ Secreted immunoglobulin

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 ▪ Immunoglobulin (Ig)
▪ Antigen binding molecules of B cells

▪ Vaccination
▪ Deliberate induction of protective immunity
to a pathogen

▪ Immunization
▪ The ability to resist infection

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 Types of Immunity

▪ Innate (non-specific) Immunity

▪ Host defense mechanisms that act from the start of an
infection but do not adapt to a particular pathogen

▪ Natural (inborn) resistance, it includes

▪ Physical barrier (e.g. Skin & mucus membranes).
▪ Cellular system (e.g. phagocytic cells).
▪ Chemical system (circulating glycoproteins such as complement)
▪ Inflammation

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The Concept of Immunity
▪ Susceptibility: Lack of resistance to a disease.
▪ Immunity: Ability to ward off disease.
▪ Innate immunity: Defenses against any pathogen.
▪ Adaptive immunity: Immunity, resistance to a specific
pathogen. Ref.: Microbiology an introduction- [Gerard_J._Tortora,_Berdell_R._Funke,_Christine_L.]

Fig 16.1
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 First Line of Defense:
Skin and Mucous Membranes
Physical Factors Fig 16.1
▪ Epidermis: consists of tightly
packed cells with keratin, a
protective protein
▪ Two other protective physical
factors of skin?
▪ Mucus of mucous Fig 16.2
membranes
▪ Lacrimal apparatus
▪ Saliva
▪ Nose hairs
▪ (Muco)-ciliary escalator
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Chemical Factors

▪ Fungistatic fatty acids in sebum

▪ Low pH (3-5) of skin
▪ Lysozyme in _______________________
▪ Low pH (?) of gastric juice
▪ Transferrins in blood

Also important: Antagonism and

competitive exclusion of normal microbiota
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 Microbial Antagonism
Microbial Antagonism:
When one microorganism kill, injure, or inhibit the growth of
another microorganism.

▪ Resident Normal microbiota prevent colonization of

pathogens in a body site by:
1. Competition for colonization sites.
2. Competition for nutrition.
3. Production of substances that kill pathogens.

▪ Antagonism decreases after prolonged use of broad-spectrum

antibiotics.
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 1st Line
Defense in
Human
Second Line of Defense: Formed Elements
in Blood Compare to Table 16.1

60-70%
2-4%

0.5-1%%

3-8%

20-25%
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Determinants recognized by the
innate immune response
▪ PAMPs- pathogen associated
molecular patterns

▪ PRRs- pattern recognition

receptors
▪ Toll-like receptors on
macrophages bind pathogen
and cause activation
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Determinants recognized by the
innate immune system
Macrophage
Opsonization: Production of IFN activation; secretion
Phagocytosis
complement activation (antiviral) of inflammatory
cytokines

PAMP= microbial PAMP= polyanions

PAMP= dsRNA PAMP= LPS
cell wall PRR= scavenger
PRR= TLR3 PRR= TLR4
PRR= complement receptors

PAMP= mannose-
PAMP= U-rich
containing carbs PAMP= flagellin
ssRNA (viral)
PRR= mannose- PRR= TLR5
PRR= TLR7
binding protein

PAMP= CpG
containing DNA
PRR= TLR9

U – uracil
CpG or CG – cytosine & guanine
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 Cytokines!
TLRs on Ms,
dendritic cells,
epithelial cells PAMPs recognition

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Horseshoe structure of TLR3, showing attached sugars
(spheres) and internal structures

Fig. 16.7

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 Process of Phagocytosis

Phagocytes engulf and kill microorganisms

Steps of phagocytosis:
• Chemotaxis
• Recognition and attachment
• Engulfment and creation of phagosome
• Fusion of phagosome with lysosome
• Destruction and digestion
• Residual body → Exocytosis
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Copyright © 2006 Pearson Education, Inc., publishing as Benjamin Cummings
Phagocytosis
Microbial Evasion of Phagocytosis
Inhibit adherence: M Streptococcus pyogenes, S.
protein, capsules pneumoniae
Kill phagocytes:
Staphylococcus aureus
Leukocidins
Lyse phagocytes:
Membrane attack Listeria monocytogenes
complex
Escape phagosome Shigella
Prevent phagosome-
Mtb, HIV
lysosome fusion
Survive in
Coxiella burnetti
phagolysosome
Homework - Read about

Intracellular • Oxygen-dependent killing

killing of
• Oxygen-independent killing
antigens by
• Nitric oxide-dependent killing
macrophages

Non-specific
• NK cells, Eosinophils & Mast
killing of cells
antigens by
 Inflammation
Tissue damage leads to inflammatory response
Purpose:
▪ Destroy pathogen
▪ limit spread of infection
▪ pave way for tissue repair
4 cardinal signs:?
Acute-phase proteins (Chemical mediators)
activated:
▪ Complement proteins
▪ Cytokines
▪ Specialized proteins such as fibrinogen and
bradykinin
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Signs of
The Three Stages of Inflammation

1. Vasodilation and increased vessel permeability

due to histamine (and other cytokine) release 
edema
2. Phagocyte migration and phagocytosis
❑ Margination and diapedesis (emigration)
❑ Chemotaxis(due to various cytokines and
components of complement system)
❑ Pus formation
❑ Factors challenging effectiveness of
phagocytosis
3. Tissue repair and regeneration depends on type
of tissue
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Inflammatory Process

Margination

Diapedesis
Treatment of abscess?
Fever: Abnormally High Body Temperature

▪ Hypothalamus acts as body’s thermostat

▪ Endotoxin causes phagocytes to release
interleukin–1 (IL–1). IL-1 is an endogenous
pyrogen
▪ Hypothalamus releases
prostaglandins that reset the
thermostat
▪ Body reacts to raise the
temperature.
▪ When no more IL–1, body
temperature falls (crisis).
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Beneficial effects of moderate fever:
Inhibited pathogen growth
Increased cellular metabolism  e.g.:
▪ Increased transferrin production
▪ Increased IL–1 activity  T cell production 
▪ Faster repair mechanisms

Problematic effects of high fever:

> 40.7C (105F) can be dangerous (Tachycardia,
acidosis, dehydration)
Death at temp. > 44 - 46C
Antimicrobial Substances

1. The complement system

2. Interferons
3. Transferrins: bind serum iron
4. Antimicrobial peptides: cause bacterial
cell lysis. Produced by mucous
membrane cells and phagocytes.

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The
Complement
System
 Complement system
• The complement system is a part of the immune system that
enhances (complements) the ability of antibodies and
phagocytic cells to clear microbes and damaged cells from an
organism, promotes inflammation, and attacks the pathogen's
cell membrane

• Complement – A series of serum and membrane expressed

proteins involved in the effector role of the immune response
to pathogens

• Made up of approximately 30 circulating and membrane-bound

proteins.

• Complement is a protein (globulin) present in normal serum.

 Complement proteins
• Synthesized in the liver and by cells involved in the inflammatory
response.

• Whole complement system is made up of nine components: C1 to C9

• Complement proteins are heat labile and are destroyed by heating at

56°C for 20 – 30 minutes

• Work with both innate and adaptive immunity to eliminate pathogens and
dead or dying cells
 Complement system:
Key role in defense against many foreign
invaders.

• Most important functions are:

• Production of opsonins

• Production of anaphylatoxins

• Direct killing of organisms

• Enhancing antigen-specific immune response

• Maintaining homeostasis
 Complement system:
Biological Activities of Complement

• Production of Opsonins
• Production of Anaphylatoxins
• Lysis of Cells
• Enhancing B Cell Response to Antigens
• Controlling the Formation and Clearance of Immune Complexes
• Removing Dead and Dying Cells
• Responses to Viruses
 Complement system:
Major functions

• Control of inflammatory reaction and

chemotaxis

• Clearance of the immune complexes

• Cellular activation and antimicrobial defense

• It is a major effector in immuno-pathological

diseases
Functions of complement
 Complement activation

1. classical pathway which is activated by Ab bound

to Ag

2. the lectin pathway activated by carbohydrates

3. Alternative pathway activated in the presence of

various microbial pathogen

• The protein of the system act in enzyme cascade

Complement activation
 Complement system:
The Classical Pathway
• Antigen-Antibody complexes are main activators of
this pathway.

• Activated by the formation of soluble Ag-Ab

complexes or binding of Ab (IgM or IgG) to Ag on a
target cell.

• C-reactive protein binds to the surface of many

bacteria and are also activators.
Classical pathway of complement activation
Membrane attack complex
Formation of the membrane
attack
complex (MAC).The formation of
the MAC showing the
addition of C6, C7, C8, and C9
components to the C5b component.
 Complement system:
The Lectin Pathway
• Antibody-independent pathway

• Activated by mannose-binding lectin to mannose

residues on foreign surface

• Binding activates MASP-1 and MASP-2 that cleave

MASP = MBL-associated
and activate C4 and C2 serine proteases

• Cleaved C4 and C2 generate C3 convertase

• Converges with the classical pathway at activation

of C3
• MB-lectin forms a
complex with two
protease : MBL
associated serine
protease; MASP-1
and MASP-2
• Closely homologous
to C1r and C1s and
activated to
cleave C4 and C2
 Complement system:
The Alternative Pathway
• Does not require Ag-Ab complex
formation
• Initiated by foreign cell surface proteins
• Produces active C3 and C5 convertase
• Active C3 is generated spontaneously
• Host cells regulate the progression
Complement System Summary
Series of  30 plasma (serum) proteins,
activated in a cascade
Three effects of complement system:
1. Enhances inflammatory response, e.g.:
attracts phagocytes
2. Increases phagocytosis through
opsonization or immune adherence
3. Creates Membrane Attack Complexes (MACs)
 Cytolysis
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Opsonins (complement proteins or
antibodies) coat bacteria and promote
attachment of micro-organism to phagocyte 
Opsonization
Some Bacteria Evade Complement

▪ Capsules prevent Complement activation.

▪ Surface lipid-carbohydrates of some Gram-

negatives prevent MAC formation.

▪ Enzymatic digestion of C5a by Gram-

positives.

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 Interferons in immunity
▪ Interferons (IFNs) are natural proteins produced by
the cells of the immune system of most vertebrates in
response to challenges by foreign agents such as
viruses, parasites and tumour cells.

▪ Interferons belong to the large class of glycoproteins

known as cytokines

▪ Interferons are more useful than Antibodies

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 Interferons (IFNs)

▪ Family of glycoproteins
▪ Host-cell-specific but not virus-specific
▪ -IFN and -IFN: Produced by virus infected cells.
Mode of action is to induce uninfected cells to produce
antiviral proteins (AVPs) that inhibit viral replication.
▪ -IFN: Produced by lymphocytes. Causes
neutrophils and macrophages to phagocytize
bacteria. Also involved in tumor immunology.
▪ Recombinant interferons have been produced. However
short-acting and many side-effects. No effect on already
infected cells.
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Interferons (IFNs)

Fig 16.15
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 Interferon  and  function

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Measurement of Immunity

▪ It is not possible to measure the immunity

accurately
▪ Detection of antibodies
▪ Detected by agglutination tests, Precipitation tests,
complement fixation, HI, ELISA
▪ Skin Tests, Schick test , Dick Tests
▪ Tuberculin Test – Delayed Hypersensitivity tests in
Tuberculosis

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Local Immunity

▪ Can be produced by Oral Vaccines

▪ Locally produced Antibodies IgA protect the gut

from entry of pathogens

▪ Local immunity antigen protects the individuals

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Herd Immunity

▪ This indicates the overall level in the community and

important in control of infections in the community
(HERD )

▪ When Herd immunity is low epidemics occur.

▪ Eradication of communicable diseases depends on

the development of high level of herd immunity
rather than high level of Individual Immunity
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