1. Introduction of immunology
Tel: ； (lab)
Institute of Immunolgy, weifang Medical University
02704

2. Introduction of immunology
Contents:
brief introduction
I. Concept
II. Composing of Immune system
III. Function of Immune system
IV. Two types of Immunity
I. History of immunology
II. Prospect of immunology
Part I
Part II

3. Part I
Immunity
Origin
The Latin term immunis, meaning “exempt”, is the source of the English word Immunity, meaning the state of protection from infectious disease.
• The earliest reported in 430 BC by Thucydides:
“only those who had recovered from the plague could nurse the sick because they would not contract the disease a second time”
Immunity = state of protection from infection

4. New Concept of immunity
(Traditional concept: anti-infection)
Definition of Immunitiy
The ability of the immune system that can recognize and eliminate the antigenic non-self substances is called immunity.
recognize “self” or “non self”
. normally beneficial
.sometime injurious

5. Immunology
Immunology is the study of our protection from foreign macromolecules or invading organisms and our responses to them.
Foreign macromolecule, antigen – e.g. virus protein, worm, parasite (Everything that should not be in my body)

6.                                 
Smallpox
Rabies 
The ability people used to protect themselves from outer invasions are contributed by :
Pertussis
Hepatitis B
Rubella
Immune System
Rotavirus
Polio
Influenza
diphtheria

7. Basic Components of the Immune System
Immune system: a system that protects the body from foreign substances and pathogenic organisms by producing the immune response.
Basic Components of the Immune System
Immune tissue and organs
Immune cells
Immune molecules

8. Immune tissue and organs:
Primary organs(central) 2º 1º
Thymus;
Bone marrow;
bursa of Fabricius (bird)
Secondary organs(peripheral)
Spleen;
lymph nodes;
other diffused lymphoid tissues
mucosal-associated lymphoid tissue

10. Functions of immune system
1)  immune defense
2)  immune surveillance
3) immune homeostasis

11. Immune defense: anti-infection

12. immune surveillance: remove the denatured cell

13. remove the dead or decayed cell
Immune tolerance Immune regulation
Immune homeostasis:
Immune S
Endocrine S
Nervous S

14. Two types of immunity
     . Innate immunity
(or natural immunity/ non-specific immunity )
. Adaptive Immunity
(or acquired immunity/specific immunity)

15. Innate immunity
Definition ：innate immunity refers to any inborn immunity that is already present the first time a pathogen is encountered; it does not require prior exposure and is not modified significantly by repeated exposures to the pathogen over the life of an individual.
Barriers ： Skin & Mucous membranes
Cell： Granulocytes 、Mast cell、
Macrophage、Natural killed cells
molecules ：complement、cytokine
Components

16. Adaptive immunity Definition
Adaptive immunity refers to immunity that is weak or absent on first exposure, but that increases dramatically with subsequent exposure to the same specific pathogen.
(Acquired immunity; specific immunity)
Cells: T、B lymphocytes
molecules ：Antibody, MHC,
Components

17. immunity

18. Immune disease Hypersensitivity( anaphylaxis) Autoimmune disease
Systemic Lupus Erythematosus,SLE
Hypersensitivity( anaphylaxis)
Autoimmune disease
Immunodeficiency D
allergic rhinitis
rheumatoid arthritis;RA

19. clinical application immuno-diagnosis ： Ag-Ab interaction---
prophylaxis
immuno-prevention---smallpox、polio
Hepatitis B , SARS, AIDS, bird-flu, H1N1
immuno-therapy
mAb, immune cells and molecules

20. ??? A
help B
Anti-venom

21. History of Immunology Part II Immunology has a short history,
but human beings have learning it for a very long time:
Experience period (the 17th century- the middle of 19th century)
Scientific period(the middle of 19th century-the middle of 20th century)
Modern period (the middle of 20th century-the 21th century)

22. Do you know ? Plague !!! --- Black Death Disease

23. Plagues spread all over the world
Black death is an infection of rodents caused by Yersinia pestis and accidentially transmitted to humans by the bite of infected fleas.
Plague or black death is an infection of rodents caused by Yersinia pestis and accidentially transmitted to humans by the bite of infected fleas.
The Black Death was one of the great epidemic scourges of mankind. It swept across Europe and Asia in a series of devastating pandemics during the Middle Ages. This disease was  responsible for the death of one-third of the world's population at that time. For largely unknown reasons, bubonic plague ceased to be an important pandemic disease. No major epidemics have occurred in Europe or North America in more than a century.
The organisms then kill the macrophage and are released into the extracellular environment, where they resist phagocytosis (YopH and YopE; Yersinia outer membrane protein) by the polymorphs. The Y. pestis quickly spread to the draining lymph nodes, which become hot, swollen, tender, and hemorrhagic. This gives rise to the characteristic black buboes responsible for the name of this disease.
The Black Death was one of the great epidemic scourges of mankind. It swept across Europe and Asia in a series of devastating pandemics during the Middle Ages. This disease was  responsible for the death of one-third of the world's population at that time.

24. Smallpox, a disfiguring and fatal disease

25. Progression of Smallpox
Day 3
Day 5
Day 7

26. Smallpox was a scourge.  It infected whole population centers throughout the world. The pustules of the disease caused massive disfigurement, in its worse case blindness, and in many cases killed its victims.

27. Smallpox
Caused by the variola virus. It enters the body through the lungs and is carried in the blood to the internal organs and skin where it multiplies. It can kill 10 to 30% of the total population, the most feared and greatest killer in human history. The first recorded infection was in Egypt in The first real epidemic might have been much earlier.
Leave sunken scars in skin in mild cases. In severe case, it causes blood poisoning, secondary infections or internal bleeding. There is no treatment. It affected societies dramatically. Prince William died at 11. Mozart, George Washington and Abraham Lincoln were all infected. Beauty decorations such as veils were believed to hide scars.
Smallpox is the earliest disease found to induce lifelong immunity. Variolation is the form of vaccination. Stopped in Currently, there should be enough doses available in the US.
Smallpox vaccine is the first vaccine to be used and the first vaccine to be discontinued.

28. Chinese medical practitioners : variolation
I. Experience period
(the 17th century—to the middle of 19th century)
Chinese medical practitioners : variolation

29.   
·    Song dynasty ( ), Chinese used "Yi Miao": wearing an infected person’s clothes who had just recently died.
·    Inoculation against smallpox in China did not become widely known and practiced until the period Vivid descriptions of the practice are recorded by Yu Chang in his book Miscellaneous Ideas in Medicine, of 1643.”
·    Ming dynasty ( ), Variolation: inserting scabs from patients under the skin of healthy individuals or blowing dried scab material up the noses of the individuals with a silver tube ("Gan Miao": dry vaccine) or using water to make a paste from scabs to insert into the nostrils ("Shi Miao": wet vaccine).
·    A more systemic summary of the Chinese smallpox vaccination was done by Chang Yen in 1741 in his "Zhong Miao Xin Shu" (a new book about vaccination).

31. Smallpox Vaccination to Europe
·   During the seventeenth century, the practice from China was slowly introduced into neighboring countries along with the “Silk Road”, and it was in Turkey that it came to the attention of Europeans.
English merchant John Lister reported the Chinese method to the Royal Society in 1700.
The wife of the British Ambassador to Constantinople (Istanbul), Lady Mary Wortley Montagu ( ) allowed her family to be 'variolated' in 1718. 31

32. Lady Mary Wortley Montagu (1689-1762)
· Herself a smallpox victim;
In December 1715 smallpox ruined her good looks and left her without eyelashes and with deeply pitted skin
Lady Mary was the wife of the British Ambassador to Turkey ( ). Learned how to variolate persons in Turkey and variolated her son in 1717 and her daughter in England in 1721.
· Although there was much resistance to the acceptance of this vaccination method and Lady Mary was heavily criticized by the higher society in England, the permission to vaccinate the children of the Prince and Princess of Wales in 1772 dramatically promoted the adaptation of this method in England and in other part of Europe. 32

33. ·  By the second half of the 18th century, Europe was being ravaged by smallpox epidemics.
By this time, in rural England, it was noticed that women who milked cows were frequently spared clinical smallpox disease and several undocumented accounts suggest that the connection was made between contact with cowpox virus and protection from smallpox.

34. Milestones in immunology
1780AD
Edward Jenner discovers small pox vaccine in May 14, 1796

35. 1796 Edward Jenner an English country doctor Observation:
Milkmaids who contracted
cowpox (a mild disease)
were subsequently immune
to small pox

36. A small sore at the site of injection. No disease developed.
1798 Edward Jenner
Testing:
Inoculating an 8-yr old boy with fluid from a cow pox pustule and few months later intentionally infected the child with small pox.
Immediate result:
A small sore at the site of injection.
No disease developed.
A CRIME??

37. Edward Jenner Among patients awaiting small pox vaccination
The method was significantly improved by the English physician
Edward Jenner, in Intrigued by the fact that milkmaids
who had contracted the mild disease cowpox were subsequently
immune to smallpox, which is a disfiguring and often
fatal disease, Jenner reasoned that introducing fluid from
a cowpox pustule into people (i.e., inoculating them) might
protect them from smallpox. To test this idea, he inoculated
an eight-year-old boy with fluid from a cowpox pustule and
later intentionally infected the child with smallpox. As predicted,
the child did not develop smallpox.

38. ·    The Franco-Prussian War (1870-71).
Smallpox epidemic
French army was not vaccinated; 23,400 died.
German army was vaccinated; only 278 died.
Vaccination enabled the WHO to announce in 1980 that smallpox had been eradicated, arguably the greatest triumph in modern medicine.

39. Jenner knew nothing of the infectious agents which caused disease。
Jenner’s technique of inoculating with cowpox to protect against smallpox spread quickly throughout Europe. However, for many reasons, including a lack of obvious disease targets and knowledge of their causes, it was nearly a hundred years before this technique was applied to other diseases.
What causes smallpox？
Chinese
Jenner knew nothing of the infectious agents which caused disease。
Experience period

40. II. Scientific period Experimental science
Explanations of immunologic phenomena are
based on experimental observations
and the conclusions drawn from them
19th century
Firstly leeuwenhoek developed the microscope .

41. Anti-cholera and rabies vaccines
Louis Pasteur ,
Anti-cholera and rabies vaccines
Cholera grown in culture can made chicken die
Old cultural cholera only made chicken sick and protect from freshly cholera infection.
Pasteur called the attenuated strain as “Vaccine”.
The latin word “vacca=cow” in honor of Jenner’s work.
France Chemist, microbiologist
and immunologist
Father of immunology, attenuated bacteria and viruses as vaccine against anthrax …..

42. Louis Pasteur 1879 Fowl cholera
Old cultural cholera only made chicken sick and protect from freshly cholera infection.

43. Experiment of Louis Pasteur
In May 5, 1882, Pasteur was first time to test the concept of vaccine by immunizing sheep with heat-attenuated anthrax bacillus.
cholera（霍乱）
anthrax bacillus (炭疽杆菌)
rabid dog disease (狂犬病
in May Sixty sheep used in the test. Pasteur kept ten as they were and divided the other fifty into two groups of twenty-five. One group was inoculated with his vaccine while twenty-five were not. All fifty were then injected with the anthrax virus. Those that were not inoculated died within two days. The inoculated group suffered no ill-effects
The great German physician/scientist Robert Koch, isolated the anthrax bacillus
Vaccinating sheep at Pouilly-le-fort.
At this time, anthrax, a fatal disease of sheep and cattle, was decimating the sheep industry and the economy of France.

44. Vaccinating sheep with heat attenuated Anthrax Bacillus
Rest for several weeks
Inject virulent
Anthrax Bacillus
Sheep dies
Rest for several weeks
Inject attenuated
Anthrax Bacillus
Inject virulent
Anthrax Bacillus
Sheep lives
Louis Pasteur:
Vaccinating sheep with heat attenuated Anthrax Bacillus

45. 1885, Pasteur administered his first vaccine to a human, 9-year-old Joseph Meister was bitten repeatedly by a rabid dog. Pasteur treated him with his attenuated rabies vaccine two days later. Meister survived. he later become a gatekeeper for the Pasteur Institute.
In 1940, when he was ordered by the German occupiers to open Pasteur's crypt, Joseph Meister refused and committed suicide!
The experiment is marker of the beginning of Immunology.
It opened a new era that people began to help them by
active immunization

46. Active immunity:
The form of adaptive immunity that is induced by exposure to a foreign antigen and in which the immunized individual plays an active role in responding to the antigen.

47. Pasteur’s contributions
First, championed changes in hospital practices to minimize the spread of disease by microbes.
Second, discovered that weakened forms of a microbe could be used to immunize against more virulent forms of the microbe.
Third, found that rabies was transmitted by agents so small they could not be seen under a microscope, thus revealing the world of viruses. As a result he developed techniques to vaccinate dogs against rabies, and to treat humans bitten by rabid dogs.
And fourth, developed "pasteurization," a process by which harmful microbes in perishable food products are destroyed by heat, without destroying the food.

48. Robert Koch, 1843-1910 German physician and bacteriologist
 Also started to work on Anthrax in 1870's. Identified the spore stage. First time the causative agent of an infectious disease was identified.
Koch's postulates: conditions that must be satisfied before accepting that particular bacteria cause particular diseases.
Discovered the tubercle bacillus and tuberculin.
Detailed tuberculin skin test (DTH).
Robert Koch , Nobel Prize in 1905 for his work on tuberculosis, Anthrax, Cholera, Tubercule bacillus

49. Contributions of Koch
Microorganisms are the source of infectious diseases;
Each disease is caused by specific microbe.
Koch worked on anthrax, Cholera and tuberculosis (TB) and he further developed the work of Louis Pasteur;
He invented methods for culturing and isolating bacteria.
He discovered the cholera bacillus and the bacterial cause of anthrax. He won a 1905 Nobel Prize for developing tuberculin.

50. History of humoral and cellular immunity
Although Pasteur proved that vaccination worked, he did not understand how.
The experimental work of Emil von Behring and Shibasaburo Kitasato in 1890 gave the first insights into the mechanism of immunity, earning von Behring the Nobel prize in medicine in
Von Behring and Kitasato demonstrated that serum (the liquid, noncellular component of coagulated blood) from animals previously immunized to diphtheria could transfer the immune state to unimmunized animals.

51. Emil Adolf von Behring (1854 – 1917)
A Student of Koch
With Kitasato and Wernike, discovered anti-toxin
for Diphtheria and Tetanus and applied as therapy.
Awarded first Nobel Prize in physiology, 1901

52. von Behring and Kitasato experiment (1892)
diphtheria
healthy rabbit
Vaccinated
rabbit
diphtheria-resistant
toxoid
rabbit
isolate serum
from blood
rabbit lives
healthy rabbit
virulent x
diphtheria
rabbit dies
healthy rabbit
-> protective substances appeared in serum
-> Immunity could be passively acquired.

53. Contracted body of soldier suffering from tetanus- opistotonus
Tetanus- Clinical Findings
Symptoms
Spasm of the muscles---- typically jaw muscles
Spasm of neck muscles, difficulty in swallowing
Abdominal muscle stiffness
Autonomic instability
破伤风
Contracted body of soldier suffering from tetanus- opistotonus

54. The passive transfer of immunity to Tetanus by means of antibody
Tetanus toxin
The passive transfer of immunity to Tetanus by means of antibody

55. Serum ? (humoral immunity)
(the liquid, non-cellular component of coagulated blood)
Ab ?
Sero-therapy
Anaphylaxis ?
In 1894, Behring extracting serum from the immunized horse using a tap.
It could neutralize diphtheria toxin in other animals or humans
In the 1930s, a fraction of serum Ig (Ab), was responsible for these activities.
>>> Passive immunization

56. Passive immunity:
The form of immunity to an antigen that is established in one individual by transfer of antibody or lymphocytes from another individual who is immune to that antigen.

57. In search of the protective agent, various researchers during the next decade demonstrated that an active component from immune serum could neutralize toxins, precipitate toxins, and agglutinate (clump) bacteria. In each case, the active agent was named for the activity it exhibited: antitoxin, precipitin, and agglutinin, respectively.

58. Initially, a different serum component was thought to be responsible for each activity, but during the 1930s, mainly through the efforts of Elvin Kabat, a fraction of serum first called gamma-globulin (now immunoglobulin) was shown to be responsible for all these activities.
The active molecules in the immunoglobulin fraction are called antibodies. Because immunity was mediated by antibodies contained in body fluids (known at the time as humors), it was called humoral immunity.

59. 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:
"surface receptors bound by lock & key; Ag stimulated receptors"
·   Shared 1908 Nobel Prize with Metchnikoff.
Paul Ehrlich , Nobel Prize in 1908 for demonstrating production of antibody

60. History of humoral and cellular immunity
In 1883, even before the discovery that a serum component could transfer immunity, Elie Metchnikoff demonstrated that cells also contribute to the immune state of an animal.
He observed that certain white blood cells, which he termed phagocytes, were able to ingest (phagocytose) microorganisms and other foreign material. Noting that these phagocytic cells were more active in animals that had been immunized, Metchnikoff hypothesized that cells, rather than serum components, were the major effector of immunity.

61. Elie Metchnikoff and phagocytes
Phagocytosis
Microorganisms are engulfed & digested by phagocytic cells (macrophages)
• Phagocytosis in host defense
• Cellular elements of immunity
Nobel Prize in 1908

62. In due course, a controversy developed between those who held to the concept of humoral immunity and those who agreed with Metchnikoff ’s concept of cell-mediated immunity.
It was later shown that both are correct—immunity requires both cellular and humoral responses.
It was difficult to study the activities of immune cells before the development of modern tissue culture techniques, whereas studies with serum took advantage of the ready availability of blood and established biochemical techniques. Because of these technical problems, information about cellular immunity lagged behind findings that concerned humoral immunity.

63. In a key experiment in the 1940s,Merrill Chase succeeded in transferring immunity against the tuberculosis organism by transferring white blood cells between guinea pigs. This demonstration helped to rekindle interest in cellular immunity.
With the emergence of improved cell culture techniques in the 1950s, the lymphocyte was identified as the cell responsible for both cellular and humoral immunity.

64. Soon thereafter, experiments with chickens pioneered by Bruce Glick at Mississippi State University indicated that there were two types of lymphocytes: T lymphocytes derived from the thymus mediated cellular immunity, and B lymphocytes from the bursa of Fabricius were involved in humoral immunity.
The controversy about the roles of humoral and cellular immunity was resolved when the two systems were shown to be intertwined, and that both systems were necessary for the immune response.

65. Immunological tolerance
In 1945,owen made crucial observation suggesting that tolerance to self-Ags occurred because the immune system are exposed to these Ags during early development.
1945, Ray owen

66. cattle of dizygotic twin
Commonly use one placenta
Their blood types are different and form chimeras
Adult dizygoic twin cows each contained a mixture of their own and their twin’s blood cells, indicating that they were equally tolerant of their own and each other’s blood cells Ags.

67. Sir Frank Macfarlane Burnet (1899-1985)
·  Trained as MD
·   Important work on influenza. Discovery of an influenza viral enzyme with the specificity for particular forms of neuramic acid. Used today for detection.
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.

68. Clonal selection theory
(1) There are various lymphocyte clones come from one stem cell each of them bears a single type of Ag receptors (unique specificity).

69. Clonal selection theory
(2) Those clones whose receptors can recognize
self antigens will be destroy
or learn to tolerance to self Ags
(forbidden clones) at early stage
— Clone deletion

70. Clonal selection theory
(3) The interaction between Ag and Ag receptor will lead to the lymphocytes activation (amplification, proliferation ), and then produce effective cells (or Ab) and memory cells.---clone selection

71. Clonal selection theory
(4) forbidden clones can be revival and cause antoimmunity.

72. Burnet Clonal selection theory

73. 1972 Nobel Prize for their discoveries concerning the chemical structure of antibodies.
Rodney R. Porter
Gerald M. Edelman
1929-
4 peptides

74. Discovered genes that regulate immune responses (Ir gene),
BARUJ BENACERRAF
JEAN DAUSSET
GEORGE D. SNELL
Discovered genes that regulate immune responses (Ir gene),
Now known as the major histocompatibility antigens
1980 Noble prize

75. · Antibody avidity maturation
·     Pre-existing repertoire (in host DNA) theory helped the formation of clonal selection theory.
·   Host MHC is the driving force for the maturation and selection of T cells in the thymus.
·   **Idiotype network
Nobel Prize, 1984, for theories concerning "the specificity in development and control of the immune system" and the discovery of "the principle for production of monoclonal antibodies."
Niels K. Jerne ( )

76. Milstein (b. 1927) and Köhler (1946-1995)
·   Monoclonal antibody

77. Cloning of the Immunoglobulin gene
Susumu Tonegawa (b. 1939)
Cloning of the Immunoglobulin gene
1987 Nobel prize for his discovery of "the genetic principle for generation of antibody diversity".

78. ·       Two signals
·        1996 Nobel Prize for their discoveries concerning "the specificity of the cell-mediated immune defence".
                               
Peter C. Doherty and Rolf M. Zinkernagel

79. III. Modern period 1. Diversity of antigen receptors----TCR,BCR
2. Discovery of signal transduction pathway
3. Discovery of programmed cell death
4. Hematogenesis and development of immune cells

80. Other developments Cytokine Adhesion molecules Immune tolerance
  Apoptosis
  Protein engineering
  Cell signal transduction
Gene transfer animal and Gene knockout animal

81. Prospect of immunology
The completion of human genome project is one of the landmarks of science in the 21st century, and It will certainly have a major impact on immunology.
The disclosure of the human genome sequence and rapid advances in genomic expression profiling have revolutionized our knowledge about immune response.
The technology of microarray, proteomics, as well as bioinformation will help to study the mechanism of immune response.
Human Genome Project

82. Various transgenic and knockout mouse strains can be used to evaluate immune function in vivo.

83. Immunology deals mostly with acute infectious disease.
We have learnt that most of these disease are readily taken care of by vaccines.
But there are many diseases that eventually become debilitating but which cannot be controlled , particularly autoimmune diseases, tumors and graft rejections. So the future of immunology is in understanding more of these diseases.

84. Recent development in immunology are opening up a huge range of potential new approaches of prevention and therapy of diseases.
One promising area is vaccine development using DNA recombination technology and reverse immunology, which fights not only against HIV, tuberculosis, SARS and other infectious diseases, but also against cancer, autoimmune diseases such as diabetes