World of Microbiology and Immunology

The immune system is the body's biological defense mechanism that protects against foreign invaders. Only in the last century have the components of that system and the ways in which they work been discovered, and more remains to be clarified.

The true roots of the study of the immune system date from 1796 when an English physician, Edward Jenner, discovered a method of smallpox vaccination. He noted that dairy workers who contracted cowpox from milking infected cows were thereafter resistant to smallpox. In 1796, Jenner injected a young boy with material from a milkmaid who had an active case of cowpox. After the boy recovered from his own resulting cowpox, Jenner inoculated him with smallpox; the boy was immune. After Jenner published the results of this and other cases in 1798, the practice of Jennerian vaccination spread rapidly.

It was Louis Pasteur who established the cause of infectious diseases and the medical basis for immunization. First, Pasteur formulated his germ theory of disease, the concept that disease is caused by communicable microorganisms. In 1880, Pasteur discovered that aged cultures of fowl cholera bacteria lost their power to induce disease in chickens but still conferred immunity to the disease when injected. He went on to use attenuated (weakened) cultures of anthrax and rabies to vaccinate against those diseases. The American scientists Theobald Smith (1859–1934) and Daniel Salmon (1850–1914) showed in 1886 that bacteria killed by heat could also confer immunity.

Why vaccination imparted immunity was not yet known. In 1888, Pierre-Paul-Emile Roux (1853–1933) and Alexandre Yersin (1863–1943) showed that diphtheria bacillus produced a toxin that the body responded to by producing an antitoxin. Emil von Behring and Shibasaburo Kitasato found a similar toxin-antitoxin reaction in tetanus in 1890. Von Behring discovered that small doses of tetanus or diphtheria toxin produced immunity, and that this immunity could be transferred from animal to animal via serum. Von Behring concluded that the immunity was conferred by substances in the blood, which he called antitoxins, or antibodies. In 1894, Richard Pfeiffer (1858–1945) found that antibodies killed cholera bacteria (bacterioloysis). Hans Buchner (1850–1902) in 1893 discovered another important blood substance called complement (Buchner's term was alexin), and Jules Bordet in 1898 found that it enabled the antibodies to combine with antigens (foreign substances) and destroy or eliminate them. It became clear that each antibody acted only against a specific antigen. Karl Landsteiner was able to use this specific antigen-antibody reaction to distinguish the different blood groups.

A new element was introduced into the growing body of immune system knowledge during the 1880s by the Russian microbiologist Elie Metchnikoff. He discovered cell-based immunity: white blood cells (leucocytes), which Metchnikoff called phagocytes, ingested and destroyed foreign particles. Considerable controversy flourished between the proponents of cell-based and blood-based immunity until 1903, when Almroth Edward Wright brought them together by showing that certain blood substances were necessary for phagocytes to function as bacteria destroyers. A unifying theory of immunity was posited by Paul Ehrlich in the 1890s; his "side-chain" theory explained that antigens and antibodies combine chemically in fixed ways, like a key fits into a lock. Until this time, immune responses were seen as purely beneficial. In 1902, however, Charles Richet and Paul Portier demonstrated extreme immune reactions in test animals that had become sensitive to antigens by previous exposure. This phenomenon of hypersensitivity, called anaphylaxis, showed that immune responses could cause the body to damage itself. Hypersensitivity to antigens also explained allergies, a term coined by Pirquet in 1906.

Much more was learned about antibodies in the mid-twentieth century, including the fact that they are proteins of the gamma globulin portion of plasma and are produced by plasma cells; their molecular structure was also worked out. An important advance in immunochemistry came in 1935 when Michael Heidelberger and Edward Kendall (1886–1972) developed a method to detect and measure amounts of different antigens and antibodies in serum. Immunobiology also advanced. Frank Macfarlane Burnet suggested that animals did not produce antibodies to substances they had encountered very early in life; Peter Medawar proved this idea in 1953 through experiments on mouse embryos.

In 1957, Burnet put forth his clonal selection theory to explain the biology of immune responses. On meeting an antigen, an immunologically responsive cell (shown by C. S. Gowans (1923– ) in the 1960s to be a lymphocyte) responds by multiplying and producing an identical set of plasma cells, which in turn manufacture the specific antibody for that antigen. Further cellular research has shown that there are two types of lymphocytes (nondescript lymph cells): B-lymphocytes, which secrete antibody, and T-lymphocytes, which regulate the B-lymphocytes and also either kill foreign substances directly (killer T cells) or stimulate macrophages to do so (helper T cells). Lymphocytes recognize antigens by characteristics on the surface of the antigen-carrying molecules. Researchers in the 1980s uncovered many more intricate biological and chemical details of the immune system components and the ways in which they interact.

Knowledge about the immune system's role in rejection of transplanted tissue became extremely important as organ transplantation became surgically feasible. Peter Medawar's work in the 1940s showed that such rejection was an immune reaction to antigens on the foreign tissue. Donald Calne (1936– ) showed in 1960 that immunosuppressive drugs, drugs that suppress immune responses, reduced transplant rejection, and these drugs were first used on human patients in 1962. In the 1940s, George Snell (1903–1996) discovered in mice a group of tissue-compatibility genes, the MHC, that played an important role in controlling acceptance or resistance to tissue grafts. Jean Dausset found human MHC, a set of antigens to human leucocytes (white blood cells), called HLA. Matching of HLA in donor and recipient tissue is an important technique to predict compatibility in transplants. Baruj Benacerraf in 1969 showed that an animal's ability to respond to an antigen was controlled by genes in the MHC complex.

Exciting new discoveries in the study of the immune system are on the horizon. Researchers are investigating the relation of HLA to disease; certain types of HLA molecules may predispose people to particular diseases. This promises to lead to more effective treatments and, in the long run, possible prevention. Autoimmune reaction, in which the body has an immune response to its own substances, may also be a cause of a number of diseases, like multiple sclerosis, and research proceeds on that front. Approaches to cancer treatment also involve the immune system. Some researchers, including Burnet, speculate that a failure of the immune system may be implicated in cancer. In the late 1960s, Ion Gresser (1928– ) discovered that the protein interferon acts against cancerous tumors. After the development of genetically engineered interferon in the mid-1980s finally made the substance available in practical amounts, research into its use against cancer accelerated. The invention of monoclonal antibodies in the mid-1970s was a major breakthrough. Increasingly sophisticated knowledge about the workings of the immune system holds out the hope of finding an effective method to combat one of the most serious immune system disorders, AIDS.

Avenues of research to treat AIDS includes a focus on supporting and strengthening the immune system. (However, much research has to be done in this area to determine whether strengthening the immune system is beneficial or whether it may cause an increase in the number of infected cells.) One area of interest is cytokines, proteins produced by the body that help the immune system cells communicate with each other and activate them to fight infection. Some individuals infected with the AIDS virus HIV (human immunodeficiency virus) have higher levels of certain cytokines and lower levels of others. A possible approach to controlling infection would be to boost deficient levels of cytokines while depressing levels of cytokines that may be too abundant. Other research has found that HIV may also turn the immune system against itself by producing antibodies against its own cells.

Advances in immunological research indicate that the immune system may be made of more than 100 million highly specialized cells designed to combat specific antigens. While the task of identifying these cells and their functions may be daunting, headway is being made. By identifying these specific cells, researchers may be able to further advance another promising area of immunologic research, the use of recombinant DNA technology, in which specific proteins can be mass-produced. This approach has led to new cancer treatments that can stimulate the immune system by using synthetic versions of proteins released by interferons.

World of Microbiology and Immunology | Immune System