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The Immune Response
The presence of antigens in contact with receptor sites on the surface of a B lymphocyte stimulates the lymphocyte to divide and become a clone (a line of descendant cells), with each cell of the clone specific for the same antigen. Some cells of the clone, called plasma cells, secrete large quantities of antibody; others, called memory cells, enter a resting state, remaining prepared to respond to any later invasions by the same antigen. Antibody secretion by lymphocytes can be stimulated or suppressed by such variables as the concentration of antigens, the way the antigen fits the lymphocyte's receptor regions, the age of the lymphocyte, and the effect of other lymphocytes.
According to the modified clonal selection theory originally postulated by the Australian immunologist Sir Macfarlane Burnet (for which he was awarded the 1960 Nobel Prize for Physiology or Medicine), a lymphocyte is potentially able to secrete one particular, specific humoral, or free-circulating, antibody molecule. It is believed that early in life lymphocytes are formed to recognize thousands of different antigens, including a group of autoimmune lymphocytes, i.e., cells recognizing antigens of the organism's own body. The immune system is self-tolerant; i.e., it does not normally attack molecules and cells of the organism's own body, because those lymphocytes that are autoimmune are inactivated or destroyed early in life, and the cells that remain, the majority, recognize only foreign antigens. Burnet's theory was confirmed with the development of monoclonal antibodies.
The antibodies produced by B cells are a type of globulin protein called immunoglobulins. There are five classes of immunoglobulins designated IgA, IgD, IgE, IgG, and IgM; gamma globulin (IgG) predominates. Antibody molecules are able to chemically recognize surface portions, or epitopes, of large molecules that act as antigens, such as nucleic acids, proteins, and polysaccharides. About 10 amino acid subunits of a protein may compose a single epitope recognizable to a specific antibody. The fit of an epitope to a specific antibody is analogous to the way a key fits a specific lock. The amino acid sequence and configuration of an antibody were determined in the 1960s by the biochemists Gerald Edelman, an American, and R. R. Porter, an Englishman; for this achievement they shared the 1972 Nobel Prize for Physiology or Medicine.
The antibody molecule consists of four polypeptide chains, two identical heavy (i.e., long) chains and two identical light (i.e., short) chains. All antibody molecules are alike except for certain small segments that, varying in amino acid sequence, account for the specificity of the molecules for particular antigens. In order to recognize and neutralize a specific antigen, the body produces millions of antibodies, each differing slightly in the amino acid sequence of the variable regions; some of these molecules will chemically fit the invading antigen.
Antibodies act in several ways. For example, they combine with some antigens, such as bacterial toxins, and neutralize their effect; they remove other substances from circulation in body fluids; and they bind certain bacteria or foreign cells together, a process known as agglutination. Antibodies attached to antigens on the surfaces of invading cells activate a group of at least 11 blood serum proteins called complement, which cause the breakdown of the invading cells in a complex series of enzymatic reactions. Complement proteins are believed to cause swelling and eventual rupture of cells by making holes in the lipid portion of the cell's membrane.
After their production in the bone marrow, some lymphocytes (called T lymphocytes or T cells) travel to the thymus, where they differentiate and mature. The T cells interact with the body's own cells, regulating the immune response and acting against foreign cells that are not susceptible to antibodies in what is termed “cell-mediated immunity.” Three classes of T lymphocytes have been identified: helper T cells, suppressor T cells, and cytotoxic T cells. Each T cell has certain membrane glycoproteins on its surface that determine the cell's function and its specificity for antigens.
One type of function-determining membrane glycoprotein exists in two forms called T4 or T8 (CD4 or CD8 in another system of nomenclature); T4 molecules are on helper T cells, T8 molecules are on suppressor and cytotoxic T cells. Another type of membrane glycoprotein is the receptor that helps the T cell recognize the body's own cells and any foreign antigens on those cells. These receptors are associated with another group of proteins, T3 (CD3), whose function is not clearly understood.01/00 T cells distinguish self from nonself with the help of antigens naturally occurring on the surface of the body's cells. These antigens are, in part, coded by a group of genes called the major histocompatibility complex (MCH). Each person's MCH is as individual as a fingerprint.
When a cytotoxic T lymphocyte recognizes foreign antigens on the surface of a cell, it again differentiates, this time into active cells that attack the infected cells directly or into memory cells that continue to circulate. The active cytotoxic T cells can also release chemicals called lymphokines that draw macrophages. Some (the “killer T cells”) release cell-killing toxins of their own; some release interferon. Helper T cells bind to active macrophages and B lymphocytes and produce proteins called interleukins, which stimulate production of B cells and cytotoxic T cells. Although poorly understood, suppressor T cells appear to help dampen the activity of the immune system when an infection has been controlled.
Active and Passive Immunity
Naturally acquired active immunity occurs when the person is exposed to a live pathogen, develops the disease, and becomes immune as a result of the primary immune response. Artificially acquired active immunity can be induced by a vaccine, a substance that contains the antigen. A vaccine stimulates a primary response against the antigen without causing symptoms of the disease (see vaccination).
Artificially acquired passive immunity is a short-term immunization by the injection of antibodies, such as gamma globulin, that are not produced by the recipient's cells. Naturally acquired passive immunity occurs during pregnancy, in which certain antibodies are passed from the maternal into the fetal bloodstream. Immunologic tolerance for foreign antigens can be induced experimentally by creating conditions of high-zone tolerance, i.e., by injecting large amounts of a foreign antigen into the host organism, or low-zone tolerance, i.e., injecting small amounts of foreign antigen over long periods of time.
Undesirable Immune Responses and Conditions
Immunity has taken on increased medical importance since the mid-20th cent. For instance, the ability of the body to reject foreign matter is the main obstacle to the successful transplantation of certain tissues and organs. In blood transfusions the immune response is the cause of severe cell agglutination or rupture (lysis) when the blood donor and recipient are not matched for immunological compatibility (see blood groups). An immune reaction can also occur between a mother and baby (see Rh factor). Allergy, anaphylaxis, and serum sickness are all manifestations of undesirable immune responses.
Many degenerative disorders of aging, e.g., arthritis, are thought to be disorders of the immune system. In autoimmune diseases, such as rheumatoid arthritis and lupus, individuals produce antibodies against their own proteins and cell components. Combinations of foreign proteins and their antibodies, called immune complexes, circulating through the body may cause glomerulonephritis (see nephritis) and Bright's disease (a kidney disease). Circulating immune complexes following infection by the hepatitis virus may cause arthritis.
At an extreme end of the spectrum of undesirable conditions is the lack of immunity itself. As a childhood condition, this absence can result from a congenital inability to produce antibodies or from severe disorders of the immune system, which leave individuals unprotected from disease. Such children usually die before adulthood. AIDS (Acquired Immune Deficiency Syndrome), which ultimately destroys the immune system, is caused by a retrovirus called the human immunodeficiency virus (HIV), which was identified in 1981. It infects the helper T cells, thereby disabling the immune system and leaving the person subject to a vast number of progressive complications and death.
See I. Cohen et al., ed., Auto-Immunity (1986); S. Sell, Immunology, Immunopathology, and Immunity (1987); R. Langman, The Immune System (1989); E. Sercarz, ed., Antigenic Determinants and Immune Regulation (1989); J. Kreier, Infection, Resistence, and Immunity (1990)
A substance that initiates and mediates the formation of the corresponding immune body, termed antibody. Antigens can also react with formed antibodies. Antigen-antibody reactions serve as host defenses against microorganisms and other foreign bodies, or are used in laboratory tests for detecting the presence of either antigen or antibody. See Antibody, Antigen-antibody reaction
A protein immunogen (any substance capable of inducing an immune response) is usually composed of a large number of antigenic determinants. Thus, immunizing an animal with a protein results in the formation of a number of antibody molecules with different specificities. The antigenicity of a protein is determined by its sequence of amino acids as well as by its conformation. Antigens may be introduced into an animal by ingestion, inhalation, sometimes by contact with skin, or more regularly by injection into the bloodstream, skin, peritoneum, or other body part.
With a few exceptions, such as the autoantigens and the isoantigens of the blood groups, antigens produce antibody only in species other than the ones from which they are derived. All complete proteins are antigenic, as are many bacterial and other polysaccharides, some nucleic acids, and some lipids. Antigenicity may be modified or abolished by chemical treatments, including degradation or enzymatic digestion; it may be notably increased by the incorporation of antigen into oils or other adjuvants. See Isoantigen
Bacteria, viruses, protozoans, and other microorganisms are important sources of antigens. These may be proteins or polysaccharides derived from the outer surfaces of the cell (capsular antigens), from the cell interior (the somatic or O antigens), or from the flagella (the flagellar or H antigens). Other antigens either are excreted by the cell or are released into the medium during cell death and disruption; these include many enzymes and toxins, of which diphtheria, tetanus, and botulinus toxins are important examples. The presence of antibody to one of these constituent antigens in human or animal sera is presumptive evidence of past or present contact with specific microorganisms, and this finds application in clinical diagnosis and epidemiological surveys. See Botulism, Diphtheria, Toxin
Microbial antigens prepared to induce protective antibodies are termed vaccines. They may consist of either attenuated living or killed whole cells, or extracts of these. Since whole microorganisms are complex structures, vaccines may contain 10 or more distinct antigens, of which generally not more than one or two engender a protective antibody. Examples of these are smallpox vaccine, a living attenuated virus; typhoid vaccine, killed bacterial cells; and diphtheria toxoid, detoxified culture fluid. Several independent vaccines may be mixed to give a combined vaccine, and thus reduce the number of injections necessary for immunization, but such mixing can result in a lesser response to each component of the mixture. See Vaccination
Allergens are antigens that induce allergic states in humans or animals. Examples are preparations from poison ivy, cottonseed, or horse dander, or simple chemicals such as formaldehyde or picryl chloride. See Hypersensitivity, Immunology