Transcript IMMUNITY

Introduction to Infection
and Immunity
Reference textbooks
中文
医学免疫学
细胞与分子免疫学
英文
Meidical Immunology
Fundamental Immunology
Cellular and Molecular Immunology
相关研究杂志
Nature Immunology, Immunology etc.
Section I Immunology
1 Introduction to Immunity and Immune System
11
Summary of Function of Immunity
Function
Normal
VS
Abnormal
Immune defense
Resistance
microbial infection
Hypersensitivity
Immunodeficiency
Immune
self-stability
Clear the damage
/aging cells
Autoimmune disease
Immune
surveillance
Prevention of
malignant cells
Tumor
Immunoregulatory Regulation immune
function of the body
Immune system
disorder
Immune tolerance Tissue tolerance
Autoimmune disease
Immune ?
• Immune (Latin- “immunus”)
– Exemption from a service, obligation , etc.
– Freedom from liability to jurisdiction, etc.
– Privilege granted to exempt from certain taxes , etc.
– The term “immunity” was first used in 1775 by Van
Sweiten, a Dutch physician, as“immunitas” to
describe the effects induced by an early attempt at
variolization (人痘接种 )
IMMUNITY
The term Immunity is derived from the Latin word
Immunitae, which referred to the protection from the legal
prosecution offered to Roman Senators during their tenure in
office.
Refers to the resistance exhibited by the host towards injury
caused by microorganisms and their products.
Protection against infectious diseases
Distinguishes self from non-self
Eliminate potentially destructive foreign substances from
body
Innate Immunity
Adaptive Immunity
(acquired)
Humoral immunity & Cell
Mediated Immunity
17
INNATE IMMUNE SYSTEM
The innate immune mechanisms provide the first line of
defense against infectious diseases.
It consists of cellular and biochemical defense
mechanisms that are in place even before infections and
poised to respond rapidly to infections. These
mechanisms react only to microbes and not to noninfectious substances
Innate Immunity
Species
Racial
Individual
Species immunity
 Refers to the total or relative refractoriness to a pathogen, shown
by all members of species.
 Person obtains by virtue of being a part of the human species.
 Determines whether or not a pathogen can multiply in them.
For e.g.
 All human beings are totally unsusceptible to plant pathogens and to,
many animal pathogens, such as render pest or distemper.
Pasteur’s experiments on anthrax in frogs, which are naturally
resistant to the disease but become susceptible when their body
temperature is raised from 25° to 35°C.
Racial immunity
 Racial differences are known to be genetic in origin
For e.g.
 People of Negroid origin in USA are more susceptible than the
Caucasians to tuberculosis.
 Genetic resistance to Plasmodium falciparum Malaria seen in
some parts of Africa and Mediterranean coast. A hereditary
abnormality of red cells (sickling) prevalent in the area, confer
immunity to infections by malarial parasite.
Individual immunity
 The difference in innate immunity exhibited by different
individuals in a race
 The genetic basis of individual immunity is seen in twins.
For e.g.
Homozygous twins exhibit similar degrees of resistance or
susceptibility to Lepromatous leprosy and Tuberculosis.
Innate immunity does not recognize every possible antigen
instead it recognizes pathogen-associated molecular patterns.
Receptors enable the phagocyte to attach to these patterns so it
can be engulfed and destroyed by lysosomes.
Pathogen-Associated Molecular Patterns Binding to Endocytic PatternRecognition Receptors on Phagocytes
Determinants of innate immunity
I. Species and strains
II. Age
III.Hormonal Influences
IV.Nutrition
MECHANISMS OF INNATE IMMUNITY
I.
Epithelial surfaces
Skin
Mucosa of the respiratory tract
Human eye.
Flushing action of urine
II. Antibacterial substances in Blood and tissues
III. Inflammation
IV. Fever
V. Cellular factors
ADAPTIVE IMMUNE SYSTEM
A person is said to be immune when he possesses specific
protective antibodies or cellular immunity as a result of
previous infection or immunization or is so conditioned by
such previous experience as to respond adequately to
prevent infection. Because this form of immunity develops
as a response to infection and is adaptive to the infection, it
is called adaptive immunity.
The characteristics of adaptive immunity are
 Specificity for distinct molecules.
 An ability to remember and respond more vigorously to
repeated exposure to the same microbe.
Hence it is also called as specific immunity.
Adaptive (specific) immunity
The adaptive immune response accounts for
specificity in recognition of foreign substances ,
or antigens, by functional receptors residing on
the surface of T and B lymphocytes.
ACTIVE IMMUNITY
PASSIVE IMMUNITY
1. Produced actively by host’s immune Received passively by the host
system
2. Induced by infection or by contact
with immunogens (vaccines,
allergens etc).
No participation by the host’s immune
system
3. Affords desirable and effective
protection
Conferred by introduction of
readymade antibodies
4. Immunity effective only after a lag
period (time required for generation
of antibodies).
Protection transient and less effective
Immunity effective immediately
5. Immunological memory present;
subsequent challenge more
effective (booster effect)
No immunological memory
subsequent administration of
antibodies less effective due to
immune elimination
6. Negative phase may occur
No negative phase
7. Not applicable in immunodeficient
hosts
Applicable in immunodeficient hosts
Natural Active immunity
 This results from either a clinical or in-apparent
infection.
 Immunity following chicken pox and measles infection
is usually life long
Artificial Active Immunity
This is the resistance induced by vaccines.
Vaccines are preparations of live or killed
microorganisms or their products used for immunization.
Types of Vaccine:
Immunizing agents that are used for immunoprophylaxis
 Bacterial vaccines:
Live (BCG vaccine for T.B.).
Killed (Cholera vaccine).
Subunit (Typhoid Vi antigen).
Bacterial products (Tetanus Toxoid).
 Viral Vaccine:
Live (Oral polio vaccine – Sabin).
Killed (Injectable polio vaccine – Salk).
Subunit (Hepatitis B-vaccine).
 Combinations
If more than one kind of immunizing agent is included in the vaccine, it is
called a mixed or combined vaccine.
DPT (Diphtheria – pertussis - tetanus)
MMR (Measles, mumps and rubella).
DPTP (DPT plus inactivated polio).
Natural Passive immunity
 This is the resistance passively transferred from the mother to
the baby. In human infants, maternal antibodies are transmitted
predominantly through the placenta.
 Human colustrum, which is also rich in IgA antibodies and
resistant to intestinal digestion.
Synthesis of antibodies (IgM) occurs at 20th week of IUL but its
immunogenic capacity is still inadequate at birth. It is only by
about the age of three month that the infants acquire a satisfactory
level of immunological independence.
Artificial passive immunity
This is the resistance passively transferred to a recipient by
administration of antibodies.
Passive immunization is indicated for immediate and temporary
protection in a non-immune host
Employed for the suppression of active immunity, when the latter
may be injurious.
Used as treatment of some infections.
Hyper immune sera of animal or human origin, convalescent sera
and pooled human gamma globulins are used for prophylaxis and
therapy.
SPECIFICITY OF ADAPTIVE RESPONSE BY
LYMPHOCYTE RECEPTORS
• Long-term good health requires continued
discrimination against foreign agents and
depends on immunologic memory, which allows
the adaptive immune system to respond more
efficiently to previously encountered antigens.
TIGHT REGULATON OF THE IMMUNE SYSTEM
AND ASSOCIATED RESPOSES
2、History and historians of
immunology
Pestilence record
Plague in Athens
2000 BC
430 BC
165-180
Plague in Rome
Plague in
Mediterranean
三个时期
541-542
1347-1352
16世纪
1518-1568
Plague in Europe
1556-1560
Plague in Mexico
经验免疫学
Plague in Europe
One who had recovered from the
disease could
nurse the sick without
Death
causes:
Individuals
having
survived
getting
the disease
a second
timea
pestilence
disease might often be spared further
poison.
involvement on the return,
a phenomenon known as Immunity
19世纪末
实验免疫学
20世纪中
科学免疫学
(1)Experience immunology stage
• Smallpox
------Severe infectious diseases
–
–
–
–
–
–
Variola virus
Enters the body through the lungs
Multiplies in Internal organs and skin
Leave sunken scars in skin in mild cases.
Kill 10 to 30% of the total population
First recorded infection was in Egypt in 1350.
1day－7day
• Smallpox
– Smallpox is the earliest disease found to
induce lifelong immunity.
– Variolation is the form of vaccination.
– Smallpox vaccine is the first vaccine to be
used and the first vaccine to be discontinued.
Early forms of smallpox vaccine---variolation
• 唐代：痘神
• 宋代：998-1022年
Early forms of smallpox vaccine---variolation
• 明代：随着治疗痘疹经验的丰富和完善，发明人痘术
• 清代： 朱纯嘏《痘疹定论》 俞茂鲲在《痘科金镜赋集解》
张璐《医通》
张琰《种痘新书》
其苗传种愈久，则药力之提拔愈清，人工之选炼愈熟，
火毒汰尽，精气独存，万全而无害也
Early forms of smallpox vaccine---variolation
痘浆法
旱苗法
痘衣法
水苗法
Variolation to Europe
–
Silk road ：17 century, the practice from China was
slowly introduced into Europeans neighboring
countries via Turkey along with the Silk Road
Edward Jenner -----Smallpox vaccine
1749-1823, in England
• Thinking: As a teenager, while learning to be a physician, he
heard a young farm girl tell a doctor that she could not contract
smallpox because she had once had cowpox (a very mild disease).
This started him thinking about a vaccine.
• Investigation：After observing cases of cowpox and
smallpox for a quarter century
• (18th century, Europe (400,000/year, and 1/3 blind )
?
?
Sarah Nelmes’ hand
• Experimented vaccination：In 1789 he had already
experimented vaccination on his own son, then aged oneand-a-half, with the swine pox, followed by conventional
smallpox inoculation
Edward Jenner -----First test
• First test on an boy： On May 14, 1796, Edward Jenner carried
out a famous experiment on a healthy 8-year-old boy, James
Phipps, with cowpox (from burst pustule on the arm of Sarah
Nelmes).
• Material:
• Virulent test：variola virus was injected.
Edward Jenner inoculating James Phipps with cowpox
• Inquiry: In 1798, published
his findings( 2 cases)
• Vaccination :Jenner called
his idea " vaccination"
from the word vaccinia
which is latin for cowpox.
• Jenner also introduced the
term virus.
Edward Jenner -----Publish his paper
• Paper: Jenner wrote a paper in 1798 explaining
his experiments, and wanted to report his first
case study in the “Transactions of the Royal
Society of London” His study was rejected.
• Publish his paper: After
improvement and further
work, he published a report of
23 cases
First use of biological warfare???
• 1754-1763---French（British and French）-Indian war
Some people believe that Lord Jeffrey Amherst,
Commander-in-Chief, may have used Smallpox
Blankets against the Indians
•
1870-1871--The Franco-Prussian War
Smallpox epidemic
French army was not vaccinated; 23,400 died
German army was vaccinated; only 278 died
Why do they not want to play with my kids?
They should be vaccinated first
Milestone
• 1979: WHO declared "the
world and its peoples" free
from endemic smallpox
Why？
(2) Experiment immunology stage
Development of Ideas in Immunology
Aims
Peroids
Pioneers
Applications 1870-1890 Pasture & Metchnikoff
Notions
Immunization &
Phagocytosis
Description 1890-1910 Behring & Ehrlich
Antibodies & Cell Receptors
1910-1930 Bordet & Landsteiner Specificity & Haptens
Mechanisms 1930-1950 Subcellular
1950-1970 Cellular
Ab synthesis & Ag
Clonal selection
Systemic Analysis 1970-1983 Multicellular
Network Cooperation
Immune regulation
Modern Immunol. 1983-present Post-TCR Era
Molecular Mechanisms
Robert Koch 1843-1910, (German physician)
•
•
•
•
Bacterial growth media
Purification techniques: tubercle bacillus etc.
Henle-Koch postulates
Discovered the tubercle bacillus and tuberculin.
---------Detailed tuberculin skin test (DTH)
Nobel Prize in 1905 for
his work on tuberculosis,
Anthrax, Cholera,
Tubercule bacillus
Louis Pasteur (1822-1895)
• Stereochemistist: molecular asymmetry
(Tartaric acid)
• Fermentation : caused by the growth of
micro-organisms (biogenesis)
• Pasteurisation
• Germ Theory of disease
----Thus started microbilogy
Pasteur’s Swan Neck Experiment
• Vaccines:
A aged culture of the
responsible bacteria had
failed to induce the
disease in some chickens.
• Attenuated vaccines:
cholera
Anthrax
rabies
Emil von Behring 1854 – 1917 (German)
•
•
1890, Behring and S Kitasato were the
discoverer of diphtheria antitoxin
1891, developing a serum therapy
against diphtheria
After during 10 years：
Antibody, Antigen, Serology, Humoral immunity etc.
Antibody--- humoral immunity is major ？
Nobel Prize in 1901 for demonstrating that circulating antitoxins
against diphtheria and tetanus toxins conferred immunity.
Elie Metchnikoff (1845-1916)
Embryologist ：studying starfish development
• Found phagocytosis:
•
• Birth of cellular immunology
Phagocytes－cellular immunology is major？
1883 – Phagocytosis; Shared Nobel Prize with Ehrlich in 1908
Paul Ehrlich (1854 – 1915)
Paul Ehrlich and antibody
 Developed a series of tissue-staining
dyes including that for tubercle
bacillus.
 Worked with Koch：Developed
anti-toxin (Diphtheria) and
hemalysis
 Side-chain theory of antibody
formation
Shared 1908 Nobel Prize with Metchnikoff for production of antibody
surface receptors bound by lock & key;
Ag stimulated receptors
Antibody
（侧连）
Antigen）
ABO blood group antigens &
immunochemistry
•
Landsteiner (1868 –1943, Austrian)
1900-- The agglutination of two people blood
----succeeded in identifying the ABO blood groups
----Found out the blood transfusion






1910(Landsteiner)--Artificial antigen--Antigen&immunochemistry
1917(Landsteiner)--Artificial antigen --Specificity
1934(Marrack)-----Lattice theory--Antigen & antibody reaction
1938(Tiselius & Kabat )--Serum protein electrophoresis--Antibody
1942(JT Freund)-----Adjuvant
1953(Grubar )--Immunoelectrophoresis--Heterogeneity of antibody
Antibody & Complement
•
•
•
•
1897(P Kraus)---Precipitation
1896(M von Gruber & HE Durham)---Agglutination
1906(AP von Wassermann)---Complement fixation
1930 (F Haurowitz)- Antibody product template theory
 1894(R Pfeiffer)--Bacteriolytic phenomenon- Complement
 1895(J Bordet) ---Complement and antibody
in bacteriolytic phenomenon
 1903(Wright & Douglas)---Opsonization (C and Ab)
Clinical immunological phenomenon
•
•
•
•
1951(C von Pirquet & B Schick )---Serum Sickness
1942(MW Chase)--Transfer of cutaneous sensitivity
(Cell transfer & delayed type hypersensitivity )
1945 (RD Owen )--Phenomenon of natural tolerance
1953(RE Billingham & PB Medawar)--Immune
tolerance provesion--Organ transplants(skin grafts)
(3) Science immunology stage
Sir Frank Macfarlane Burnet
(1899-1985 Australian virologist )
• Important work on influenza
• Discovery of an influenza viral enzyme
with the specificity for particular forms
of neuramic acid. Used today for
detection.
• 1959----Clonal selection theory to
explain tolerance
1960 Nobel Prize for the discovery of acquired immunological tolerance.
Rejection of donor grafts was due to an immunological reaction and that
tolerance can be built up by injections into embryos
•Chemical structure of Ab
Gerald Edelman Rodney Porter
1917-1985
1929 --
Nobel Prize
in 1972
•Immunoglobulin：IgG，IgM，IgA，IgD，IgE
Nobel Prize in 1984
•Immunoglobulin function
•Products of mAb and pAb
Georeges Kohler
Cesar Milstein 1927-- 1946--1995
•Immunoglobulin gene(antibody diversity (BCR/TCR))
Antibody Engineering and Immunoassay
Susumu Tonegama
Nobel Prize 1987
MHC
Discovered genes that regulate immune responses (Ir gene),
Now known as the major histocompatibility antigens
MHC I
BARUJ BENACERRAF
JEAN DAUSSET
MHC II
a2
a1
a1
b1
肽结合单位
a3
b 2m
a2
b2
Ig样单位
跨膜单位
1980
Noble
prize
GEORGE D. SNELL
Immunogenetics
Transplantation immunology
Immune system
Miller and Good----thymus immune function (60s)
Claman and Mitchell----T / B sub-group (1969)
Gowan----lymphocyte function (1965)
Cooper----the distribution of lymphocytes in peripheral
lymphoid tissue
Mitchison and Gershon----T sub-group (70s)
Immune Biology
Antigen epitope
Nobel Prize, 1984
 Antibody avidity maturation
 Plaque forming assay
 Idiotype network
Niels K. Jerne
(1912-1994)
Epitope
Vaccinology
Diseases & Immunology
•
•
•
•
•
•
•
•
Organ Transplantation & Immune
Respiratory diseases & immune
Infectious diseases & immune
Blood system diseases & immune
Connective tissue disease & immune
Nerve system and endocrine system & immune
Tumor and immune
… … Etc.
Clinical Immunology
Other … …
•
•
•
•
•
Behavior and Immunity
Psychological and immune
Nutrition and Immunity
Obesity and immunity
… … Etc.
Timeline of immunology (wikipedia)
•1718 - Lady Mary Wortley Montagu, the wife of the British ambassador to Constantinople, observed the
positive effects of variolation on the native population and had the technique performed on her own children.
•1798 - First demonstration of vaccination smallpox vaccination (Edward Jenner)
•1837 - First description of the role of microbes in putrefaction and fermentation (Theodore Schwann)
•1838 - Confirmation of the role of yeast in fermentation of sugar to alcohol (Charles Cagniard-Latour)
•1840 - First "modern" proposal of the germ theory of disease (Jakob Henle)
•1850 - Demonstration of the contagious nature of puerperal fever (childbed fever) (Ignaz Semmelweis)
•1857-1870 - Confirmation of the role of microbes in fermentation (Louis Pasteur)
•1862 - phagocytosis (Ernst Haeckel)
•1867 - First aseptic practice in surgery using carbolic acid (Joseph Lister)
•1876 - First demonstration that microbes can cause disease-anthrax (Robert Koch)
•1877 - Mast cells (Paul Ehrlich)
•1878 - Confirmation and popularization of the germ theory of disease (Louis Pasteur)
•1880 - 1881 -Theory that bacterial virulence could be attenuated by culture in vitro and used as vaccines.
Proposed that live attenuated microbes produced immunity by depleting host of vital trace nutrients. Used to
make chicken cholera and anthrax "vaccines" (Louis Pasteur)
•1883 - 1905 - Cellular theory of immunity via phagocytosis by macrophages and microphages
(polymorhonuclear leukocytes) (Elie Metchnikoff)
•1885 - Introduction of concept of a "therapeutic vaccination". First report of a live "attenuated" vaccine for
rabies (Louis Pasteur).
•1888 - Identification of bacterial toxins (diphtheria bacillus) (Pierre Roux and Alexandre Yersin)
•1888 - Bactericidal action of blood (George Nuttall)
•1890 - Demonstration of antibody activity against diphtheria and tetanus toxins. Beginning of humoral theory
of immunity. (Emil von Behring) and (Shibasaburo Kitasato)
•1891 - Demonstration of cutaneous (delayed type) hypersensitivity (Robert Koch)
•1893 - Use of live bacteria and bacterial lysates to treat tumors-"Coley's Toxins" (William B. Coley)
•1894 - Bacteriolysis (Richard Pfeiffer)
•1896 - An antibacterial, heat-labile serum component (complement) is described (Jules Bordet)
•1900 - Antibody formation theory (Paul Ehrlich)
•1901 - blood groups (Karl Landsteiner)
•1902 - Immediate hypersensitivity anaphylaxis (Paul Portier) and (Charles Richet)
•1903 - Intermediate hypersensitivity, the "Arthus reaction" (Maurice Arthus)
•1903 - Opsonization
•1905 - "Serum sickness" allergy (Clemens von Pirquet and (Bela Schick)
•1911 - 2nd demonstration of filterable agent that caused tumors (Peyton Rous)
•1917 - hapten (Karl Landsteiner)
•1921 - Cutaneous allergic reactions (Carl Prausnitz and Heinz Küstner)
•1924 - Reticuloendothelial system
•1938 - Antigen-Antibody binding hypothesis (John Marrack)
•1940 - Identification of the Rh antigens (Karl Landsteiner and Alexander Weiner)
•1942 - Anaphylaxis (Karl Landsteiner and Merill Chase)
•1942 - Adjuvants (Jules Freund and Katherine McDermott)
•1944 - hypothesis of allograft rejection
•1946 - identification of mouse MHC (H2) by George Snell and Peter A. Gorer
•1948 - antibody production in plasma B cells
•1949 - growth of polio virus in tissue culture, neutralization with immune sera, and demonstration of attenuation of
neurovirulence with repetitive passage (John Enders) and (Thomas Weller) and (Frederick Robbins)
•1949 - immunological tolerance hypothesis
•1951 - vaccine against yellow fever
•1953 - Graft-versus-host disease
•1953 - immunological tolerance hypothesis
•1957 - Clonal selection theory (Frank Macfarlane Burnet)
•1957 - Discovery of interferon
•1958-1962 - Discovery of human leukocyte antigens (Jean Dausset and others)
•1959-1962 - Discovery of antibody structure (independently elucidated by Gerald Edelman and Rodney Porter)
•1959 - Discovery of lymphocyte circulation (James Gowans)
•1960 - Discovery of lymphocyte "blastogenic transformation" and proliferation in response to mitogenic lectinsphytohemagglutinin (PHA) (Peter Nowell)
•1961-1962 Discovery of thymus involvement in cellular immunity (Jacques Miller)
•1961- Demonstration that glucocorticoids inhibit PHA-induced lymphocyte proliferation (Peter Nowell)
•1963 - Development of the plaque assay for the enumeration of antibody-forming cells in vitro (Niels Jerne) (Albert Nordin)
•1964-1968 T and B cell cooperation in immune response
•1965 - Discovery of the first lymphocyte mitogenic activity, "blastogenic factor" (Shinpei Kamakura) and (Louis Lowenstein)
(J. Gordon) and (L.D. MacLean)
•1965 - Discovery of "immune interferon" (gamma interferon) (E.F. Wheelock)
•1965 - Secretory immunoglobulins
•1967 - Identification of IgE as the reaginic antibody (Kimishige Ishizaka)
•1968 - Passenger leukocytes identified as significant immunogens in allograft rejection (William L. Elkins and Ronald D.
Guttmann)
•1969 - The lymphocyte cytolysis Cr51 release assay (Theodore Brunner) and (Jean-Charles Cerottini)
•1971 - Peter Perlmann and Eva Engvall at Stockholm University invented ELISA
•1972 - Structure of the antibody molecule
•1974 - T-cell restriction to major histocompatibility complex (Rolf Zinkernagel and (Peter Doherty)
•1975 - Generation of the first monoclonal antibodies (Georges Köhler) and (César Milstein)
•1976 - Identification of somatic recombination of immunoglobulin genes (Susumu Tonegawa)
•1979 - Generation of the first monoclonal T cells (Kendall A. Smith)
•1980-1983 - Discovery and characterization of the first interleukins, 1 and 2 IL-1 IL-2 (Kendall A. Smith)
•1981 - Discovery of the IL-2 receptor IL2R (Kendall A. Smith)
•1983 - Discovery of the T cell antigen receptor TCR (Ellis Reinherz) (Philippa Marrack) and (John Kappler) (James Allison)
•1983 - Discovery of HIV (Luc Montagnier)
•1984 - The first single cell analysis of lymphocyte proliferation (Doreen Cantrell) and (Kendall A. Smith)
•1985-1987 - Identification of genes for the T cell receptor
•1986 - Hepatitis B vaccine produced by genetic engineering
•1986 - Th1 vs Th2 model of T helper cell function (Timothy Mosmann)
•1988 - Discovery of biochemical initiators of T-cell activation: CD4- and CD8-p56lck complexes (Christopher E. Rudd)
•1990 - Gene therapy for SCID
•1994 - 'Danger' model of immunological tolerance (Polly Matzinger)
•1995 - Regulatory T cells (Shimon Sakaguchi)
•1996-1998 - Identification of Toll-like receptors
•2001 - Discovery of FOXP3 - the gene directing regulatory T cell development
•2005 - Development of human papillomavirus vaccine (Ian Frazer)
•1961-1962 Discovery of thymus involvement in cellular immunity (Jacques Miller)
•1961- Demonstration that glucocorticoids inhibit PHA-induced lymphocyte proliferation (Peter Nowell)
•1963 - Development of the plaque assay for the enumeration of antibody-forming cells in vitro (Niels Jerne) (Albert Nordin)
•1964-1968 T and B cell cooperation in immune response
•1965 - Discovery of the first lymphocyte mitogenic activity, "blastogenic factor" (Shinpei Kamakura) and (Louis Lowenstein)
(J. Gordon) and (L.D. MacLean)
•1965 - Discovery of "immune interferon" (gamma interferon) (E.F. Wheelock)
•1965 - Secretory immunoglobulins
•1967 - Identification of IgE as the reaginic antibody (Kimishige Ishizaka)
•1968 - Passenger leukocytes identified as significant immunogens in allograft rejection (William L. Elkins and Ronald D.
Guttmann)
•1969 - The lymphocyte cytolysis Cr51 release assay (Theodore Brunner) and (Jean-Charles Cerottini)
•1971 - Peter Perlmann and Eva Engvall at Stockholm University invented ELISA
•1972 - Structure of the antibody molecule
•1974 - T-cell restriction to major histocompatibility complex (Rolf Zinkernagel and (Peter Doherty)
•1975 - Generation of the first monoclonal antibodies (Georges Köhler) and (César Milstein)
•1976 - Identification of somatic recombination of immunoglobulin genes (Susumu Tonegawa)
•1979 - Generation of the first monoclonal T cells (Kendall A. Smith)
•1980-1983 - Discovery and characterization of the first interleukins, 1 and 2 IL-1 IL-2 (Kendall A. Smith)
•1981 - Discovery of the IL-2 receptor IL2R (Kendall A. Smith)
•1983 - Discovery of the T cell antigen receptor TCR (Ellis Reinherz) (Philippa Marrack) and (John Kappler) (James Allison)
•1983 - Discovery of HIV (Luc Montagnier)
•1984 - The first single cell analysis of lymphocyte proliferation (Doreen Cantrell) and (Kendall A. Smith)
•1985-1987 - Identification of genes for the T cell receptor
•1986 - Hepatitis B vaccine produced by genetic engineering
•1986 - Th1 vs Th2 model of T helper cell function (Timothy Mosmann)
•1988 - Discovery of biochemical initiators of T-cell activation: CD4- and CD8-p56lck complexes (Christopher E. Rudd)
•1990 - Gene therapy for SCID
•1994 - 'Danger' model of immunological tolerance (Polly Matzinger)
•1995 - Regulatory T cells (Shimon Sakaguchi)
•1996-1998 - Identification of Toll-like receptors
•2001 - Discovery of FOXP3 - the gene directing regulatory T cell development
•2005 - Development of human papillomavirus vaccine (Ian Frazer)
Highlights of 10 years of immunology
2001 The discovery of TLRs:
fundamental insights into the biology
of the innate immune system
2002 Treg cells
many unanswered questions remain
2003 The IL-12 family
IL-23 and IL-27 were reported
2004 IDO (Indoleamine 2,3-dioxygenase,吲哚胺2,3-二氧酶)
control local innate immunity & regulate adaptive immunity
2005 Macrophage heterogeneity
so-called M1 and M2 phenotypes
still missing the point
2006 The immune response in atherosclerosis a double-edged sword
2007 Dendritic cell development
conventinal DC generated in bonr marrow
plasmacytoid DC( pDC) & macrophage–DC precursor
2008 TH17 cell
TH17 cell lineage specification
2009 the crucial role of MDSC
myeloid-derived suppressor cells (MDSCs)
control immune responses.
2010 IL-10 production
the regulation of IL-10 production in immune cells
Nature Reviews Immunology 11, 693-702 (October 2011)
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.
Properties of Ag
-⑴immunogenicity: Induction of an immune response
免疫原性
T
T
致敏T细胞
Ag
B
浆细胞
抗
体
-⑵antigenicity or immunoreactivity (react with the
products of a specific immune response)
抗原性
T
T
致敏T细胞
Ag
B
浆细胞
抗体
ANTIGENS
Based on the ability of antigens to carry out these two functions, they
may be classified into different types:
• Complete Ags：is able to induce antibody formation
and produce a specific and observable reaction with the
antibody so produced, have the properties of
immunogenicity and immunoreactivity.
• Hapten （ 半 抗 原 ） ： are substances, which are
incapable of inducing antibody formation by themselves,
but can react specifically with antibody. have the property
of immunoreactivity but not immunogenicity .
Haptens are small molecules which could never
induce an immune response when administered by
themselves but which can when coupled to a
carrier molecule.
hapten + carrier → complete Ag
FACTORS INFLUENCING IMMUNOGENICITY :
Contribution of the Immunogen
Foreignness
The immune system normally discriminates between self and nonself such that only foreign molecules are immunogenic.
Size
There is not absolute size above which a substance will be
immunogenic. However, in general, the larger the molecule the more
immunogenic it is likely to be.
Chemical Composition
In general, the more complex the substance is chemically the more
immunogenic it will be. The antigenic determinants are created by
the primary sequence of residues in the polymer and/or by the
secondary, tertiary or quaternary structure of the molecule.
Physical form
In general particulate antigens are more immunogenic than soluble
ones and denatured antigens more immunogenic than the native form.
Degradability
Antigens that are easily phagocytosed are generally more
immunogenic. This is because for most antigens (T-dependant
antigens, see below) the development of an immune response
requires that the antigen be phagocytosed, processed and presented to
helper T cells by an antigen presenting cell (APC).
Contribution of the Biological System
Genetic Factors
Some substances are immunogenic in one species but not in another.
Similarly, some substances are immunogenic in one individual but
not in others (i.e. responders and non-responders). The species or
individuals may lack or have altered genes that code for the receptors
for antigen on B cells and T cells or they may not have the
appropriate genes needed for the APC to present antigen to the helper
T cells.
Age
Age can also influence immunogenicity. Usually the very young and
the very old have a diminished ability to mount and immune response
in response to an immunogen.
Method of Administration
Dose
The dose of administration of an immunogen can influence its
immunogenicity. There is a dose of antigen above or below which the
immune response will not be optimal.
Route
Generally the subcutaneous route is better than the intravenous or
intragastric routes. The route of antigen administration can also alter
the nature of the response
Adjuvants
Substances that can enhance the immune response to an immunogen
are called adjuvants. The use of adjuvants, however, is often
hampered by undesirable side effects such as fever and inflammation.
antigenic determinant (epitope)
抗原决定簇（基），表位
- the portion of the antigen that binds
specifically with the binding site of an
antibody or a receptor on a lymphocyte.
- the size of an epitope is approximately
equivalent to 5-15 amino acids.
epitope
Tolerogen, allergen
• Tolerogen: an antigen that induces a state
of specific immunological unresponsiveness
• Allergen: a substance capable of inducing
allergy or specific hypersensitivity.
pollens, dust, drugs, and foods…
SUPERANTIGENS
• When the immune system encounters a
conventional T-dependent antigen, only a
small fraction (1 in 104 -105) of the T cell
population is able to recognize the antigen
and become activated
(monoclonal/oligoclonal response).
However, there are some antigens which
polyclonally activate a large fraction of the
T cells (up to 25%). These antigens are
called superantigens.
• Examples of superantigens include:
Staphylococcal enterotoxins (food
poisoning), Staphylococcal toxic shock toxin
(toxic shock syndrome), Staphylococcal
exfoliating toxins (scalded skin syndrome)
and Streptococcal pyrogenic exotoxins
(shock). Although the bacterial
superantigens are the best studied there are
superantigens associated with viruses and
other microorganisms as well.
Antigen reacting only with particular Immunocytes
B-lymphocytes have sIg molecules on their surface that recognize epitopes
directly on antigens. Different B-lymphocytes are programmed to produce
different molecules of sIg, each specific for a unique epitope.