CONCEPT OF IMMUNOLOGY

&

HISTORICAL PERSPECTIVE
 Concept of Freedom from disease

The immune system evolved to protect multicellular organisms from

pathogens. Highly adaptable, it defends the body against invaders as
diverse as the tiny (~30 nm), intracellular virus, and as large as the
giant parasitic kidney worm (~ over 100 cm in length and 10 mm in
width).

This diversity of potential pathogens requires a range of recognition and

evolving a complicated and dynamic network of cells, molecules, and
pathways.

So, the study of immunology has produced amazing and fascinating stories,
where host and microbe engage in battles paid for both minutes and millennia.
The immune system is much more than an isolated component of the body,
merely responsible for search-and-destroy missions.
 Concept of Immunity

1) Traditional concept :

Immunity refers to protection against infectious

diseases.

2) Modern concept :

Immunity is a function of which an individual

recognizes and excludes antigenic foreign
substances. It is normally beneficial, but some
times, it is injurious.
 Concept of Immunology

1) Tranditional concept----anti-infection immunity

to different types of pathogenic microorganisms.

2) Modern concept----Immunology is an independent

subject about composition, functions of immune
system; mechanism of immune response and the
disease associated with immunity.
 Historical Approach to Immunology

History of Immunology

Looking at the history and development of immunology will help us to

understand present concepts in immunology. This historical approach
gives us all a chance to appreciate the large amount of Nobel Prizes that
have been given out since the beginning of the 20th century won by
immunologists, an amount “disproportionate” to the amount of trophies
other scientific fields win. Many of these discoveries are hugely
important.
How is disease transmitted and prevented?

This question was a revolution in thinking in the creation of immunology. They didn’t
even know what bacteria was, and so it is an amazing feat how scientists discovered
disease mechanisms and prevention.

Keen Observation was basis of Immunity

The discipline of immunology grew out of the observation
that individuals who had recovered from certain
infectious diseases were there after protected from the
disease. The Latin term immunis, meaning “exempt,” is the
source of the English word immunity, a state of
protection from infectious disease.

Perhaps the earliest written reference to the phenomenon

of immunity can be traced back to Thucydides, the great
historian. In describing a plague in Athens, he wrote in
430 BC that only those who had recovered from the
plague could nurse the sick because they would not
contract the disease a second time.
The word “immunity” (L: immunis – free of) was used in the context of being free of the
burden of taxes or military conscription. The history of immunology is really slightly more
than 100 years if you consider Louis Pasteur as the “Father of immunology” as most do. If one
thinks about cellular immunology, the “real” history begins in the late 1950’s.

From early writings, it is clear that primitive man knew about disease and its ravages . One
finds in the Babylonian Epic of Gilgamesh (2000 B.C. – Mesopotamian hero) records of the
presence of pestilence and disease. Recall that, in those days, disease and pestilence was
punishment rendering as a result of “bad deeds” or “evil thoughts”. Even the old testament is
filled with pestilence that God wrought upon those who “crossed” him. From these writings, it
is equally apparent that man knew that once he had been afflicted with disease, if he
survived, he was normally not able to contract it again.

The science of immunology grew from the common knowledge that those who survived many of
the then common infectious diseases, rarely contracted that disease again. This was an
observation that was made long before the establishment of the germ theory of
disease. Louis Pasteur and Robert Koch were instrumental in defining microorganisms as the
etiological agents of a large number of diseases.
Early Vaccination studies led the way to Immunology
Beginning around 1000 A.D., the ancient Chinese practiced a form of immunization
by inhaling dried powders derived from the crusts of smallpox lesions. Around the
fifteenth century, a practice of applying powdered smallpox "crusts" and inserting them
with a pin or “poking” device into the skin became commonplace. The process was referred
to as variolation and became quite common in the Middle East. However, the primary
intent of variolation was that of “preserving” the beauty of their daughters and no
mention was made of saving lives.

From Turkey, the process of variolation can be traced to the inhabitants of a country
called Arcassia. The people that populated this land were poor but were blessed with
large number of beautiful women, which unfortunately was the chief trade and very
important to the Arcassian economy. Most sales were to the Sultan of Turkey.

Eventually, the process was popularized in Great Britain, largely through the efforts of
Mary Wortley Montagu. It was vehemently opposed by the Church and was highly
discouraged, particularly if one were Christian. The clergy stated that it could only work
of an "UnChristian" who was an infidel in the eyes of the Lord. In 1721, Mary Wortley
Montagu’s daughter was the first person to be engrafted in Great Britain .

The first step to a safer procedure was to substitute material derived from the lesion of
a cowpox (vaccinia) for the inoculation. Cowpox is a benign disease due to infection with a
virus closely related to the smallpox (variola) virus.
Louise Pasteur worked on vaccines .He called this attenuated Fowl cholera strain a
vaccine (from the Latin vacca, meaning “cow”), in honor of Jenner’s work with
cowpox inoculation.

Wood engraving of Louis Pasteur watching

Joseph Meister receive the rabies vaccine
 Immunology time line
•1774- Benjamin Jesty, a farmer who inoculated his wife with the vaccinia virus obtained from
“farmer Elford of Chittenhall, near Yetminster”. First record of anyone using vaccinia virus to
"protect" against smallpox.

•1798 Edward Jenner, Smallpox vaccination

•1862 Ernst Haeckel, Recognition of phagocytosis

•1877 Paul Erlich, recognition of mast cells
•1879 Louis Pasteur, Attenuated chicken cholera vaccine development
•1883 Elie Metchnikoff Cellular theory of vaccination
•1885 Louis Pasteur, Rabies vaccination development
•1888 Pierre Roux & Alexandre Yersin, Bacterial toxins
•1888 George Nuttall, Bactericidal action of blood
•1891 Robert Koch, Delayed type hypersensitivity
•1894 Richard Pfeiffer, Bacteriolysis
•1895 Jules Bordet, Complement and antibody activity in bacteriolysis
•1900 Paul Erlich, Antibody formation theory
•1901 Karl Landsteiner, A, B and O blood groupings
•1901-8 Carl Jensen & Leo Loeb, Transplantable tumors
•1902 Paul Portier & Charles Richet, Anaphylaxis
•1903 Almroth Wright & Stewart Douglas, Opsonization reactions
•1906 Clemens von Pirquet, coined the word allergy
•1907 Svante Arrhenius, coined the term immunochemistry
•1910 Emil von Dungern, & Ludwik Hirszfeld, Inheritance of ABO blood groups
•1910 Peyton Rous, Viral immunology theory
•1914 Clarence Little, Genetics theory of tumor transplantation
•1915-20 Leonell Strong & Clarence Little, Inbred mouse strains
•1917 Karl Landsteiner, Haptens
•1921 Carl Prausnitz & Heinz Kustner, Cutaneous reactions
•1924 L Aschoff, Reticuloendothelial system
•1926 Lloyd Felton & GH Bailey, Isolation of pure antibody preparation
•1934-8 John Marrack, Antigen-antibody binding hypothesis
•1936 Peter Gorer, Identification of the H-2 antigen in mice
•1940 Karl Lansteiner & Alexander Weiner, Identification of the Rh antigens
•1941 Albert Coons, Immunofluorescence technique
•1942 Jules Freund & Katherine McDermott, Adjuvants
•1944 Peter Medwar, Immunological hypothesis of allograft rejection
•1948 Astrid Fagraeus, Demonstration of antibody production in plasma B cells
•1948 George Snell, Congenic mouse lines
•1949 Macfarlane Burnet & Frank Fenner, Immunological tolerance hypothesis
•1950 Richard Gershon and K Kondo, Discovery of suppressor T cells
•1953 Morton Simonsen and WJ Dempster, Graft-versus-host reaction
•1953 Rupert Billingham, Leslie Brent, Peter Medwar, & Milan Hasek, Immunological tolerance hypothesis
•1955-1959 Niels Jerne, David Talmage, Macfarlane Burnet, Clonal selection theory
•1957 Ernest Witebsky et al., Induction of autoimmunity in animals
•1957 Alick Isaacs & Jean Lindemann, Discovery of interferon (cytokine)
•1958-62 Jean Dausset et al., Human leukocyte antigens
•1959-62 Rodney Porter et al., Discovery of antibody structure
•1961-62 Jaques Miller et al., Discovery of thymus involvement in cellular immunity
•1961-62 Noel Warner et al., Distinction of cellular and humoral immune responses
•1963 Jaques Oudin et al., antibody idiotypes
•1964-8 Anthony Davis et al., T and B cell cooperation in immune response
•1965 Thomas Tomasi et al., Secretory immunoglobulin antibodies
•1967 Kimishige Ishizaka et al., Identification of IgE as the reaginic antibody
•1971 Donald Bailey, Recombinent inbred mouse strains
•1974 Rolf Zinkernagel & Peter Doherty, MHC restriction
•1975 Kohler and Milstein, Monoclonal antibodies used in genetic analysis
1980-1983 - Discovery and characterization of the first interleukins, 1 and 2 IL-1 IL-2 (Kendall A. Smith)
1981 - Disovery of the IL-2 receptor IL2R (Kendall A. Smith)
1983 - Discovery of HIV (Luc Montagnier)
1985-1987 - Identification of genes for the T cell receptor
•1985 Tonegawa, Hood et al., Identification of immunoglobulin genes
•1985-7 Leroy Hood et al., Identification of genes for the T cell receptor
•1990 Yamamoto et al., Molecular differences between the genes for blood groups O and A and between those for A and B
1986 - Hepatitis B vaccine produced by genetic engineering
1986 - Th1 vs Th2 model of T helper cell function (Timothy Mosmann)
1990 - Gene therapy for SCID
1995 - Regulatory T cells (Shimon Sakaguchi)
1996-1998 - Identification of Toll-like receptors
2005 - Development of human papillomavirus vaccine (Ian Frazer)
 Functions of Immunity

➢Immune defense

➢Immune homeostasis

➢Immune surveillance
 Types of Immunity

I. Innate Immunity
(or native immunity/ non-specific immunity
/congenital immunity)
II. Adaptive Immunity
(or acquired immunity/specific immunity)
 I. Innate immunity
( natural immunity/ non-specific immunity )

Innate immunity:
Protection against infection that relies on
mechanisms that exist before infection,are
capable of a rapid response to microbes,and
react in essentially the same way to repeated
infections.
➢ Exists at birth
➢ Be the first line of defense against infection
 Innate immunity

1. Characteristics

➢ Exists naturally
➢ Non–specific
➢ No immune memory (innate immunity can’t
be enhanced by the second stimulation of
the same antigen)
Immune memory: Exposure of the immune
system to a foreign antigen enhances its
ability to respond again to that antigen.
➢ Hereditable
➢ No racial difference
 2. Composition

(1) Barriers
➢ Physical barrier : skin and mucosa
➢ Chemical barrier: antimicrobial substances in
secretion of skin and mucosa
➢ Biotic barrier: normal flora existing on the surface
of skin and mucosa
➢ Anatomic barrier
. blood- brain barrier
. blood- placental barrier
. blood- tymus barrier
 • 4 barriers to infection:
– Anatomic
– Physiologic
– Phagocytic
– Inflammatory

•1st line of defense

•includes chemicals,
structure of skin/other
epithelia, and mechanisms
as well as cells – mainly
neutrophils and
macrophage
Most MO’s are quickly cleared within a few days by innate
immunity – before adaptive immunities are activated
Innate barriers to infections…

Intestinal
1) Anatomic
epithel. skin -> epidermis w/ keratin
mucus memb. ->inner surfaces
2) Physiological
temperature, pH, soluble
subst.
3) Phagocytes
blood monocytes, tissue MØ,
and neutrophils
4) Inflammatory response
triggered by wound/foreign
particle
5 Cardinal signs reflect 3 major
events of inflam response:
-vasodilation
- >capillary permeability
-influx of phagocytes
The Inflammation Process

Fig 1-4 Kuby 5e

(2) Humoral factors

➢ Complement
➢ Lysozyme
➢ Interferons(IFN)
➢ C-reactive protein
(3)Cells participating in innate immunity

➢ Phagocyte: endocytosis and phagocytosis

mononuclear phagocytes
----Monocytes,Macrophages (M Φ)----PRR
Neutrophils
➢ Nature killer cells (NK)—KAR/KIR,IgG Fc
receptor
➢ Dentritic cells(DC)
➢ γδ T cells
➢ B1 cells
➢ Other cells participating in innate immunity
 Phagocytosis
Lipid
Mannose mediators
receptor
Lysosome
Phagosome
Scavenger
receptor
LPS receptor
(CD14) Cytokines

Bacteria binding to
macrophage receptors Phagolysosome
The macrophage initiate the release of
expresses receptors for cytokines and small lipid
many bacterial mediators of inflammation Macrophages engulf and
digest bacteria to which
constituents
they bind
 Cell killing – NK cells
◼ NK cells do not require prior
immunization or activation
◼ They attach to ‘target’ cells
(ADCC)
◼ Cytotoxic granules are
released onto surface of cell
◼ Effector proteins penetrate
cell membrane and induce
programmed cell death
 Inflammation

Chemokines Inflammatory cells

migrate into tissue,
releasing inflammatory
mediators that cause
Cytokines
pain

Bacteria
trigger
macrophages
to release
Proteins
cytokines and
chemokines Fluids
Vasodilation and
increased vascular
premeability cause
redness, heat, and
swelling
Cytokines
◼ Low molecular weight, soluble proteins that are
produced in response to an antigen and function as
chemical messengers for regulating the innate and
adaptive immune system
◼ Innate immune system
◼ Macrophages and Dendritic cells
◼ Tumor necrosis factor-alpha (TNF-)
◼ Interleukin-1 (IL-1)
◼ Interleukin-12 (IL-12)
◼ Adaptive immune system
◼ T-lymphocytes
◼ Interleukin-2 (IL-2)
◼ Interleukin-4 (IL-4)
 Adaptive immunity
( acquired immunity/specific immunity)

Adaptive immunity:
The form of immunity that is mediated by
T or B lymphocytes and stimulated by
exposure to infectious agents.
➢ Take effects after innate immune response
➢ Be the second line of defense against
infection
Fig 1-7, Kuby, 4e
 1.Characteristics

➢ Specificity
➢ Acquired (set up after birth )
➢ Immune memory
(Adaptive immunity can be enhanced by the
second stimulation of the same antigen)
➢ Transferable
➢ Self-limitation
 2.Composition

➢T cell : Cell-mediated immunity (CMI)

➢B cell : Humoral immunity(HI) or
antibody-mediated immunity
 3.The process of immune
response
in adaptive immunity

➢Recognition of antigens
➢Activation,proliferation and
differenciation of T or B lymphocytes
➢Effector phase of immune response
----Elimination of antigens
 Adaptive Immunity requires 2 major groups of cells:
a. B and T Lymphocytes (B or T cells)

b. Antigen presenting cells

(APC’s)
-macrophage (MØ)
-dendritic cells (DC)
-B cells
B Lymphocytes:
• Form and mature in bone marrow
• Exhibit antibody receptors on
membrane
• Once naïve B cells bind Ag, they
divide rapidly to produce:
– Plasma cells (effector B cells)
– Memory cells

Plasma cells are secretory; live

Humoral Immunity only a few days (produce >
2,000 molecules of Ig/sec)
Memory cells have longer life
span than naïve B cells
T Lymphocytes • Formed in bone marrow;
migrate to and mature in
Thymus gland
• Exhibit unique T-cell Antigen
receptors (TCR’s) on surface
• TCR’s can only recognize Ag
with associated with MHC
glycoproteins
– MHC I – found on nearly all
nucleated cells
– MHC II – found only on APC’s

Once T cell binds to Ag, it

triggers cell division to
form both memory T cells
and
effector T cells
There are 2 populations of T
cells characterized by the
type of CD glycoprotein
found on surface:
TH – exhibits CD4
TC – exhibits CD8
 The Antigen presentation scenario:

Fig 1-8 Kuby, 4e

Different patterns of cytokines determines types of IR:

-if TC cell recognizes an Ag/MHC I complex, it divides
and differentiates to become CTL
if TH cell recognizes Ag/MHC II complex, it divides
and stimulates B cells, TC cells, and MØ
 Humoral vs Cell-mediated Immune Response:

Humoral IR: occurs when Ag becomes coated with

Ab which brings about the elimination
of the foreign body
-cross-link several Ag’s to form clumps -> more easily
phago’d
-bind complement proteins
-neutralize toxins, viruses, and bacteria from binding
target cells
Cell-Mediated IR: occurs when effector T cells are
activated
-activated TH cells → activate phagocytic cells
activate B cells to produce Ab
-activated TC cells → kill altered self cells (viral infected
and tumor
cells)
 Cardinal Features of Adaptive Immunity:

1) antibody specificity – distinguishes minute

differences in molecular structure to determine non-
self antigens.
2) diversity – the immune system can produce a
hugely diverse set of recognition molecules which allows
us to recognize literally billions of molecular shapes
3) memory – once it has responded to an antigen,
the system maintains a memory of that Ag
4) self-nonself recognition –the system typically
responds only to foreign molecules

*adaptive IR is not independent of innate IR – they’re connected

 Comparison of Adaptive and Innate
Immunity

Innate immunity Adaptive immunity

Characteristics Exists naturally Acquired by antigen stimulation after birth

Responds rapidly in the early develops slowly
stage of infection
No antigen specificity Has antigen specificity
No immune memory Has immune memory
Participates in natural defence Participates in specific immune response
Cells Neutrophil,Phagocytes,NK cell et al. T cell, B cell, APC
Molecules Complement.lysozyme,cytokines et al Antibody,cytokines
 Immunology Terms
• Antigen
– Any molecule that binds to immunoglobulin or T cell receptor
• Pathogen
– Microorganism that can cause disease
• Antibody (Ab)
– Secreted immunoglobulin
• Immunoglobulin (Ig)
– Antigen binding molecules of B cells
• Vaccination
– Deliberate induction of protective immunity to a pathogen
• Immunization
– The ability to resist infection