Immune system

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

Since ancient times medical observers had noticed that the body seemed to have powers to protect itself and resist disease. In particular, people who survived some infectious diseases did not suffer from those diseases again duringtheir lifetime. This led to the practice of variolation in Asia, whereby people were injected with a mild case of smallpox to prevent the later development of a severe case of the disease. Lady Mary Wortley-Montague introduced variolation to Britain from the Ottoman Empire in 1720. The procedure was ratherdangerous, however, because the injected person could develop an acute rather than mild case of smallpox, which could lead to an epidemic.

The true roots of immunology--or the study of the immune system--date from 1796 when an English physician, Edward Jenner, discovered a method of smallpoxvaccination. 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 inoculatedhim with smallpox; the boy was immune. After Jenner published the results ofthis and other cases in 1798, the practice of Jennerian vaccination spread rapidly.

It was Louis Pasteur who established the cause of infectious diseases and themedical basis for immunization. First, Pasteur formulated his germ theory ofdisease--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 thedisease 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. He 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 cholerabacteria (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 combinewith antigens (foreign substances) and destroy or eliminate them. It becameclear 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 knowledgeduring 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 inthe 1890s; his "side-chain" theory explained that antigens and antibodies combine chemically in fixed ways, like a key fits into a lock. Until now, immuneresponses 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 thebody to damage itself. Hypersensitivity to antigens also explained allergies, a term coined by Pirquet in 1906.

By the early 1900s immunology had become an established medical field with its own journals, first in Germany in 1909 and then in the United States in 1916 (the latter published by the world's first immunology society, founded in 1913).

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 andare produced by plasma cells; their molecul ar 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 bymultiplying 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 chemicaldetails of the immune system components and the ways in which they interact.

Knowledge about the immune system's role in rejection of transplanted tissuebecame extremely important as organ transplantation became surgically feasible. Peter Medawar's work in the 1940s showed that such rejection was an immunereaction 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- MHC) discovered in mice a group of tissue-compatibility genes, that played an important role in controllingacceptance or resistance to tissue grafts. Jean Dausset found human MHC, a set of antigens to human leucocytes (white blood cells), called HLA. Matchingof 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 immunology 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 alsobe a cause of a number of diseases, like multiple sclerosis, and research proceeds on that front. Approaches to cancer treatment also involve theimmune system. Some researchers, including Burnet, speculate that a failureof 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 inthe mid-1970s was a major breakthrough. Increasingly sophisticated knowledgeabout 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 areato determine whether strengthening the immune system is beneficial or whetherit 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 possibleapproach 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.

For many years it was believed that the immune system responded only to invading antigens and was not influenced by psychological events. However, building on research that began in the mid-1960s, scientists have determined that the immune system is also affected by a person's psychological health, or stateof mind. This branch of research is referred to as pscyhoimmunology, or psychoneuroimmunology (the study of the relationship among psychology, neurology,and immunology). A complex network of nerves, hormones, and neuropeptides appear to link the immune system and an individual's psyche. For example, extreme psychological stress has been shown to suppress the immune system and accelerate disease in people with HIV. (Short-term stress is believed to have certain benefits to the body.) Other psychosocial factors--such as a fixation ondying, clinical depression, a lack of purpose in life, inability to be assertive, and lack of a supportive network of friends and family--may also affectthe immune system. Research into pscyhoimmunology focuses on treatments thatcan impact stress levels and other psychological factors.

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 immunological research--the use of recombinant DNA technology, in which specific proteins can be mass produced. This approach has led to new cancer treatments thatcan stimulate the immune system by using synthetic versions of proteins released by interferons.

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