History of immunology

In Western society, it was not until the late eighteenth century that a rational approach to the origin of disease developed. Prior to the discovery that disease was the result of pathogenic organisms, it was commonly accepted that disease was a punishment from God (or the Gods), or even a witches curse. Eastern cultures perceived disease as an imbalance in the energy channels within the body. Later, the great plagues of Europe were assumed the result of virulent or noxious vapors. Nevertheless, there were intimations as early as 430 B.C. that if one survived a disease, the person thereafter became "immune" to any subsequent exposures. However, this was never recognized as evidence of some type of internal defense system until the later part of the seventeenth century.

Although most historical accounts credit Edward Jenner for the development of the first immunization process, a previous similar procedure had become established in China by 1700. The technique was called variolation. This was derived from the name of the infective agent—the variola virus . The basic principal of variolation was to deliberately cause a mild infection with unmodified pathogen. The risk of death from variolation was around two to three percent. Although still a risk, variolation was a considerable improvement on the death rate for uncontrolled infection. Immunity to smallpox was conferred by inserting the dried exudate of smallpox pustules into the nose. This technique for the transfer of smallpox, as a form of limited infection, traveled to the west from China along the traditional trade routes to Constantinople where it spread throughout Europe. Hearing of this practice, the Royal family of England had their children inoculated against the disease in 1721, but the practice aroused severe opposition as physicians felt it was far too risky.

In 1798, Edward Jenner, noticed that milkmaids were protected from smallpox if they had been first infected with cowpox . It was not his intention to make medical history, as his interests were mostly scholarly and involved the transfer of infections from one species to another, especially from animals to humans. However, Jenner's work led him to the conclusion, that inoculation with cowpox (a bovine analogue of smallpox) could confer immunity to smallpox. Thus, the concept of vaccination was initiated. (Incidentally, the Latin word for cow is vacca ). Jenner's ideas first made him a medical as well as a social pariah, as they were in opposition to both the church and popular beliefs. Because his method was much safer then variolation, however, the use of vaccinations gradually became widely accepted and most European countries had some form of compulsory program within fifty years of Jenner's discovery.

The idea that a pathogenic organism caused disease was not fully realized until certain technological advances had occurred. Initially, Antoni van Leeuwenhoek 's development of the microscope and the subsequent realization that entities existed that were not visible to the human eye, allowed the concept of germs to be appreciated. That these organisms were the causative agent of disease was not recognized until Louis Pasteur developed his germ theory of disease . His original interests were in fermentation in wine and beer, and he was the first to isolate the organisms that caused the fermentation process. Pasteur's work eventually led him to the development of pasteurization (heating) as a means of halting fermentation. While working with silk worms and anthrax , he was able to demonstrate that the same method for transferring the fermentation process also worked in transmitting disease from infected animals to unaffected animals. Finally, in 1878, Pasteur accidentally used an attenuated (weakened) chicken cholera culture and realized, when he repeated the experiment using a fresh culture, that the weakened form protected the chickens from the virulent form of the disease. Pasteur went on to develop an attenuated vaccine against rabies and swine erysipelas.

Pasteur was not the only proponent of the germ theory of disease. His chief competitor was Robert Koch . Koch was the first to isolate the anthrax microbe and, unaware of Pasteur's work, he was able to show that it caused the disease. Then in 1882, Koch was able to demonstrate that the germ theory of disease applied to human ailments as well as animals, when he isolated the microbe that caused tuberculosis . His "Koch's postulates" are still used to identify infective organisms.

Much of the basis for modern medicine, as well as the field of immunology , can be traced back to these two scientists, but the two major questions still to be answered were how did infection cause the degradation of tissue, and how did vaccines work? The first question was addressed in 1881 by Emile Roux and Alexander Yersin when they isolated a soluble toxin from diphtheria cultures. Later, Emil von Behring and Shibasaburo Kitasato were able to demonstrate passive immunity when they took serum from animals infected with diphtheria and injected into healthy animals. These same animals were found to be resistant to the disease. Eventually these serum factors were recognized in 1930 as antibodies. However, thirty years before antibodies were finally isolated and identified, Paul Ehrlich and others, recognized that a specific antigen elicited the production of a specific antibody . Ehrlich hypothesized that these antibodies were specialized molecular structures with specific receptor sites that fit each pathogen like a lock and key. Thus, the first realization that the body had a specific defense system was introduced. In addition, sometime later, he realized that this powerful effector mechanism, used in host defense would, if turned against the host, cause severe tissue damage. Ehrlich termed this horror autotoxicus. Although extremely valuable, his work still left a large gap in understanding how the immune system fights a pathogenic challenge. The idea that specific cells could be directly involved with defending the body was first suggested in 1884 by Élie Metchnikoff . His field was zoology and he studied phagocytosis in single cell organisms. Metchnikoff postulated that vertebrates could operate in a similar manner to remove pathogens. However, it was not until the 1940s that his theories were accepted and the cell mediated, as opposed to the humoral, immune response was recognized.

The clarification of the immune response and the science of immunology did not progress in a systematic or chronological order. Nonetheless, once scientists had a basic understanding of the cellular and humoral branches of the immune system, what remained was the identification of the various components of this intricate system, and the mechanisms of their interactions. This could not have been accomplished without the concomitant development of molecular biology and genetics.

Milestones in the history of immunology include:

• 1798 Edward Jenner initiates smallpox vaccination.
• 1877 Paul Erlich recognizes mast cells.
• 1879 Louis Pasteur develops an attenuated chicken cholera vaccine.
• 1883 Elie Metchnikoff develops cellular theory of vaccination.
• 1885 Louis Pasteur develops rabies vaccine.
• 1891 Robert Koch explored delayed type hypersensitivity.
• 1900 Paul Erlich theorizes specific antibody formation.
• 1906 Clemens von Pirquet coined the word allergy.
• 1938 John Marrack formulates antigen-antibody binding hypothesis.
• 1942 Jules Freund and Katherine McDermott research adjuvants.
• 1949 Macfarlane Burnet & Frank Fenner formulate immunological tolerance hypothesis.
• 1959 Niels Jerne, David Talmage, Macfarlane Burnet develop clonal selection theory.
• 1957 Alick Isaacs & Jean Lindemann discover interferon (cytokine).
• 1962 Rodney Porter and team discovery the structure of antibodies.
• 1962 Jaques Miller and team discover thymus involvement in cellular immunity.
• 1962 Noel Warner and team distinguish between cellular and humoral immune responses.
• 1968 Anthony Davis and team discover T cell and B cell cooperation in immune response.
• 1974 Rolf Zinkernagel and Peter Doherty explore major histocompatibility complex restriction.
• 1985 Susumu Tonegawa, Leroy Hood, and team identify immunoglobulin genes.
• 1987 Leroy Hood and team identify genes for the T cell receptor.
• 1985 Scientists begin the rapid identification of genes for immune cells that continues to the present.

See also Antibody and antigen; B cells or B lymphocytes; Germ theory of disease; History of the development of antibiotics; History of public health; Immunity, active, passive and delayed; Immunity, cell mediated; Immunity, humoral regulation; Infection and resistance; T cells or T-lymphocytes