Introduction To Immunology

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Kasi.M.Kannan, Department of Microbiology V.H.N.S.N.College, Virudhunagar

What is immunology? 

Immune (Latin- “immunus”) 

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To be free, exempt People survived ravages 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 Fungi

- Viruses - Parasites

- Toxins

The word IMMUNITY Derives from the latin immunitas, meaning freedom from public service (i.e., the military draft). From Merriam-Webster dictionary: “a condition of being able to resist a particular  disease especially through preventing  development of a pathogenic microorganism or  by counteracting the effects of its products”

There are two kinds of immunity

HOST DEFENSE= Innate + adaptive immunity Resistance to infection can be learned or innate. It appears that many organisms lack learned immunity, but can have robust innate defenses. As we shall see, learned immunity is an evolutionary offshoot of innate immunity, and the human immune system combines both types in host defense.

The Triumph of Death ­ Pieter Brueghel the Elder ca. 1562

Big bugs have little bugs Upon their backs to bite ‘em Little bugs have littler bugs And so on ad infinitum -Ogden Nash

Every organism needs host defense Colonization of large organisms by smaller organisms or viruses is the “inverse food chain” Large complex organisms present a source of energy and a habitat for smaller organisms and viruses via colonization Colonization and defense against colonization is a fundamental principle in biology The immune system is principally and most importantly evolved to sculpt colonization to benefit the host

The notion of immunity to disease is ancient Thucydides: “History of the Peloponnesian War” 5th century BCE He noted that during the plague of Athens (430 BCE) the sick were nursed by those who had recovered from the disease (caused by a bacterium, possibly Yersinia pestis) because they knew that they were safe from developing, or at least dying from, the disease a second time. It was also clear that this resistance was specific to the plague disease only. Thus the specificity and memory of immunity was recognized long ago.

Immunizations have been carried out for a long time Variolation was an ancient folk practice of vaccination to smallpox (infectious agent Variola major virus) practiced throughout Asia, Africa, and parts of Europe. Essentially, it followed a procedure in which blisters from diseased skin carrying virus from a smallpox victim was innoculated in the skin or nose. Variolation became a common practice in England after the Prince and Princess of Wales had their children innoculated in 1722. The precursor to the modern vaccine was based on the work of Jenner, who showed in 1798 that pustules from cows diseased with cowpox had the same smallpox protective effect. Hence vaccination (Latin vaccus, cow).

Germ theory and the scientific basis of immunity Jenner didn’t know why or how his vaccine worked. In the 1870s Robert Koch, Louis Pasteur, and others identified specific microbial agents of several human and animal diseases, including Anthrax (Bacillus anthracis), cholera (Vibrio cholerae), tuberculosis (Mycobacterium tuberculosis), Dyptheria (Corynebacterium diphtheriae) and the Plague (Yersinia pestis). A major breakthrough was Pasteur’s demonstration that injection of weakened pathogenic microbes of Anthrax or fowl cholera could protect animals from lethal infection of the same microbe. “Attenuated” vaccines are commonly used today. He later developed an effective rabies vaccine using ground up spinal tissue from diseased animals. However, vaccines against some microbes, such as tuberculosis, failed, and an effective vaccine is still not available for this and many other important diseases.

Immunology •

There have been various theories to explain acquired immunity, the formal explanation was provided by Edward Jenner’s reinfection studies (1780’s) •

The history of immunology is really slightly more than 100 years if you consider Louis Pasteur as the “Father of immunology” as some immunologists do. •

Cellular immunology, the “real” history begins after the World War II, along with the development of transplantation and the “clonal selection theory” formulated by the Australian immunologist, Sir Frank Macfarlane Burnet. Before that, most studies focused on the chemistry of the specificity.

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 1350. 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 1972. 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. President Bush was immunized with smallpox vaccine on Dec. 21, 2002.

Early forms of smallpox vaccine---variolation "The Genius of China: 3000 Years of Science, Discoveries and Inventions", Simon and Schuster, New York, by Robert Temple, 1986 "The origins of inoculation against smallpox in China are somewhat mysterious. We know that the technique originated at the southern province of Szechuan. In the south-west of that province there is a famous mountain called O-Mei Shan which is known for its connection with both Buddhism and the native Chinese religion of Taoism. The Taoist alchemists who lived as hermits in the caves of that mountain possessed the secret of smallpox inoculation in the tenth century AD. How long before that they had it we shall never know. The technique first came to public attention when the eldest son of the Prime Minister Wang Tan ( 王旦 , 9571017) died of smallpox. Wang desperately wished to prevent its happening to other members of his family, so he summoned physicians, wise men and magicians from all over the Empire to try to find some remedy. One Taoist hermit came from O-Mei Shan, described variously as a 'holy physician', a 'numinous old woman' (in which case a nun), and a 'ouija board immortal' (ouija boards or planchettes were widely used in China, where whole books were written through 'spirit dictation'). This monk or nun brought the technique of inoculation and introduced it to the capital.... ”

• Song dynasty (960-1279), 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 1567-72. Vivid descriptions of the practice are recorded by Yu Chang in his book Miscellaneous Ideas in Medicine, of 1643.” • Ming dynasty (1368-1644), 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).

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. • In pre-colonial India, “tika”, or dot, would be made on the sole of the foot by “tikadars”. • The wife of the British Ambassador to Constantinople (Istanbul), Lady Mary Wortley Montagu (1689-1762) allowed her family to be 'variolated' in 1718.

LADY MARY WORTLEY MONTAGU (1689-1762) • A famous poet • Herself a smallpox victim; Poem: THE SMALL-POX 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 (1716-1718). 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. • 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.

Edward Jenner •Born on May 17, 1749, in Berkeley, Gloucestershire, England, Died Jan. 26, 1823. • 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. • After years of experimenting, on May 14, 1796, Edward Jenner carried out a famous experiment on a healthy 8-year-old boy, James Phipps, with cowpox. He took material from a burst pustule on the arm of Sarah Nelmes who had apparently contracted cowpox. He then deliberately exposed the boy to virulent variola virus two months later and found that the child was protected, showing only a mild inflammation around the site where the variola was injected. • Some record shows that in 1789 he had already experimented vaccination on his own son, then aged one-and-a-half, with the swine pox, followed by conventional smallpox inoculation. A CRIME??

Sarah Nelmes’ hand

• 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. He then went to London to demonstrate his theory. No one would submit to his vaccination. Discouraged, Jenner returned to Berkeley. • In 1801, Jenner published “The Origin of the Vaccine Inoculation” describing how cowpox virus was prepared and used to protect ("vaccinate") healthy persons against smallpox. Material used as the vaccine was prepared from the arm of a vaccinated child, thus the distribution of vaccine involved the transportation of vaccinated children all over Europe. Orphans were often used for this purpose. Eventually, material from infected cows was used directly as vaccine. By 1840, the British government had banned other preventive treatments against smallpox. “Vaccination,” the word Jenner invented for his treatment (from the Latin, vacca, a cow), was adopted by Louis Pasteur for immunization against any disease.

An Inquiry into the causes and effects of the Variolae Vaccinae, a disease discovered in some of the western counties of England, particularly Gloucestershire, and known by the name of the cow-pox

Baxby D. 1999. Edward Jenner's Inquiry; a bicentenary analysis. Vaccine. 1999 Jan 28;17(4):301-7.

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The Franco-Prussian War (1870-71).

Smallpox epidemic French army was not vaccinated; 23,400 died. German army was vaccinated; only 278 died. • 1980: as a result of Jenner's discovery, the World Health Assembly officially declared "the world and its peoples" free from endemic smallpox. • 1996: 200 th anniversary of Edward Jenner's first experimental vaccination The Scientists: http://www.the-scientist.com/1996/04/01/14/1/ • Some people believe that Lord Jeffrey Amherst, Commander-in-Chief for America, may have used Smallpox Blankets against the Indians during the French & Indian war (1754-1763). First use of biological warfare???

The last reported case of smallpox, Ali Maakin, in the world was in Somalia, on October 26, 1977 • The last stocks of the smallpox virus were kept frozen in laboratories at the Centers for Disease Control and Prevention, in Atlanta, and the Russian State Research Center of Virology and Biotechnology, in Koltsovo, Russia. • •

First deliberate destruction of a species?

Monkeypox in Congo: a new threat? Between February 1996 and October 1997, there were 511 suspected cases of monkeypox in the Democratic Republic of the Congo (DRC, formerly Zaire). This outbreak, the largest ever, raised fears that the virus had mutated and become more infectious to humans.

Current Smallpox Vaccine It is live vaccinia virus. No longer produced in calves; is produced by a cultured human fibroblast in laboratories. Provides protection for about 10 years (only an estimate). The efficacy of vaccinia vaccine to prevent smallpox has never been measured precisely during controlled trials and the level of antibody required for protection against smallpox infection is unknown. Method: use a forked needle to repeatedly press into the skin of the upper arm. Adverse reaction rate: 250 per million (0.025%)

Development of Ideas in Immunology Aims

Peroids

Pioneers

Notions

Applications Phagocytosis

1870-1890

Pasture & Metchnikoff

Immunization &

Description

1890-1910 1910-1930

Behring & Ehrlich Bordet & Landsteiner

Antibodies & Cell Receptors

1930-1950 1950-1970

Subcellular Cellular

Ab synthesis & Ag temp. Clonal selection

Systemic Analysis1970-1983

Multicellular

Network Cooperation Immune regulation

Modern Immunol. 1983-present

Post-TCR Era

Molecular Mechanisms

Mechanisms

Specificity & Haptens

Louis Pasteur (1822-1895) Stereochemistist: molecular asymmetry Fermentation and silk worker disease, Pasteurisation , Germ Theory of disease Thus started microbilogy Attenuated vaccines for cholera, anthrax, and rabies On July 4, 1886, 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. Joseph Meister 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! • Another way to look at Louis Pasteur: THE DREAM AND LIE OF LOUIS PASTEUR by R. B. Pearson http://whale.to/a/b/pearson.html

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.

Robert Koch (1843-1910) German physician; 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).

Emil Adolf von Behring (1854 – 1917) •

A Student of Koch

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With Kitasato and Wernike, discovered anti-toxin for Diphtheria and Tetanus and applied as therapy. •

Awarded first Nobel Prize in physiology, 1901

Paul Ehrlich (1854 – 1915)

Developed a series of tissue-staining dyes including that for tubercle bacillus.

• Worked with Koch. Developed antitoxin (Diphtheria) and hemalysis • Side-chain theory of antibody formation: "surface receptors bound by lock & key; Ag stimulated receptors" • Shared 1908 Nobel Prize with Metchnikoff.

Elie Metchnikoff (1845-1916) · Embryologist studying starfish development. · Found phagocytosis. Phagocytes from larva stuck on thorn from a tangerine tree. Later he found a fungal spore attached to a phagocyte of Daphnia. Formed the basis of leukocyte phagocytosis. · Birth of cellular immunology Shared Nobel Prize with Ehrlich in 1908

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.

1972 Nobel Prize for their discoveries concerning the chemical structure of antibodies. Gerald M. Edelman 1929-

Rodney R. Porter 1917-1985

BARUJ BENACERRAF

JEAN DAUSSET

GEORGE D. SNELL

Discovered genes that regulate immune responses (Ir gene), Now known ad the major histocompatibility antigens 1980 Noble prize

Niels K. Jerne (1912-1994) • Antibody avidity maturation • Plaque forming assay • 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."

Milstein (b. 1927) and Köhler (1946-1995)

• Monoclonal antibody

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

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

Nobel Prizes in Immunology

1901 EMIL ADOLF VON BEHRING for his work on serum therapy, especially its application against diphtheria. 1905 ROBERT KOCH for his investigations and discoveries in relation to tuberculosis. 1908 ILYA ILYICH MECHNIKOV and PAUL EHRLICH in recognition of their work on immunity. 1913 CHARLES ROBERT RICHET in recognition of his work on anaphylaxis. 1919 JULES BORDET for his discoveries relating to immunity. 1930 KARL LANDSTEINER for his discovery of human blood groups. 1960 SIR FRANK MACFARLANE BURNET and SIR PETER BRIAN MEDAWAR for 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.

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1972 GERALD M. EDELMAN and RODNEY R. PORTER for their discoveries concerning the chemical structure of antibodies. 1980 BARUJ BENACERRAF, JEAN DAUSSET and GEORGE D. SNELL showed that so-called H antigens (histocompatibility antigens) determine the interaction of the multitude of different cells responsible for the body's immunological reactions - including the combat of infections and rejection of foreign matter. 1984 NIELS K. JERNE for the specificity in development and control of the immune system. 1987 SUSUMU TONEGAWA for discovery of the genetic principle for generation of antibody diversity. 1996 PETER C DOHERTY AND ROLF M ZINKERNAGEL for their discoveries concerning the Specificity of the Cell-Mediated Immune Defense. They found that white blood cells (lymphocytes) must recognize both the virus and certain self molecules -- the so-called major histocompatibility antigens -- in order to kill the virus-infected cells.

Looking back makes one know the path that leads to the future. A path is the foot prints of many, though only those walk in front are said heroes. When many walk together, a path comes into being.

Problem: Your friend made a big fortune in Atlantic City and asked you to help award any discovery ever made in the history of immunology. The recipient(s) could be dead or alive and the discovery could have or not have been awarded the Nobel prize. You have the great honor to nominate a candidate’s discovery. You are asked to provide a 3-page essay to support your nomination. Voluntary: Essay will not receive extra credit.