branch of medicine that studies the response of organisms to foreign substances, e.g.,

), and the influence of genetic, nutritional, and other factors on the immune system. They also study disease-causing organisms to determine how they injure the host and help to develop vaccines (see

).

In addition to studying the normal workings of the immune system, immunologists study unwanted immune responses such as allergiesallergy, hypersensitive reaction of the body tissues of certain individuals to certain substances that, in similar amounts and circumstances, are innocuous to other persons. Allergens, or allergy-causing substances, can be airborne substances (e.g. ..... Click the link for more information. , essentially immunological responses of the body to substances or organisms that, as a rule, do not affect most people, and autoimmune diseasesautoimmune disease, any of a number of abnormal conditions caused when the body produces antibodies to its own substances. In rheumatoid arthritis, a group of antibody molecules called collectively RF, or rheumatoid factor, is complexed to the individual's own gamma globulin ..... Click the link for more information. (e.g., rheumatoid arthritisarthritis, painful inflammation of a joint or joints of the body, usually producing heat and redness. There are many kinds of arthritis. In its various forms, arthritis disables more people than any other chronic disorder. ..... Click the link for more information. and lupus erythematosus) which occur when the body reacts immunologically to some of its own constituents.

Immunologists have developed a large number of procedures have been developed to detect and measure quantities of immunologically active substances such as circulating antibodies and immune globulinsglobulin, any of a large family of proteins of a spherical or globular shape that are widely distributed throughout the plant and animal kingdoms. Many of them have been prepared in pure crystalline form. ..... Click the link for more information. . Immune globulins that can be given intravenously (IVIGs) have been found to be more effective against antibody deficiencies and certain autoimmune diseases than their older intramuscular counterparts; their use in a wide spectrum of bacterial and viral infections is under study. Current research in immunology is also aimed at understanding the role of T lymphocytes (see immunityimmunity, ability of an organism to resist disease by identifying and destroying foreign substances or organisms. Although all animals have some immune capabilities, little is known about nonmammalian immunity. ..... Click the link for more information. ), which play a major part in the body's defenses against infections and neoplasmsneoplasm or tumor, tissue composed of cells that grow in an abnormal way. Normal tissue is growth-limited, i.e., cell reproduction is equal to cell death. Feedback controls limit cell division after a certain number of cells have developed, allowing for tissue repair ..... Click the link for more information. . AIDSAIDS or acquired immunodeficiency syndrome, fatal disease caused by a rapidly mutating retrovirus that attacks the immune system and leaves the victim vulnerable to infections, malignancies, and neurological disorders. It was first recognized as a disease in 1981. ..... Click the link for more information. , for example, is the disease that results when the HIVHIV, human immunodeficiency virus, either of two closely related retroviruses that invade T-helper lymphocytes and are responsible for AIDS. There are two types of HIV: HIV-1 and HIV-2. HIV-1 is responsible for the vast majority of AIDS in the United States. ..... Click the link for more information. virus destroys certain of these T cells.

See studies by R. Desowitz (1988) and R. Gallo (1991).

The division of biological science concerned with the native or acquired response of complex living organisms to the intrusion of other organisms or foreign substances. The immune system allows the host organism to distinguish between self and nonself and to respond to a target (termed an antigen).

It was not until the germ theory of infectious disease was established that the full implication of immunology was realized. First came the recognition that certain bacteria caused corresponding diseases. Second came the recognition that it was a specific resistance to that bacterium or its toxins that prevented recurrence of the same disease. Third came the discovery that after recovery from an infectious disease, protective substances called antibodies could be found in the blood of animals and humans. Antigens, such as bacteria and their products, triggered the production of antibodies and indeed all kinds of chemical and biological molecules. The action of these effector mechanisms, however, has come to be recognized as being not always protective or conferring immunity, but sometimes becoming grossly exaggerated or inappropriate, or capable of turning upon the host in a destructive fashion that causes disease. These responses are classified as allergies. Illnesses associated with a misguided response of the immune system that is directed against the self and results from a breakdown in the normal immunological tolerance of, or unresponsiveness to, self antigens are termed autoimmune. The mechanisms responsible for these disorders are unknown but probably include the intervention of factors such as viruses that either modify or naturally resemble self molecules. Subsequently, the immune response, in seeking out what is foreign, proceeds to attack the self. See Allergy, Autoimmunity

Immunology is also concerned with assaying the immune status of the host through a variety of serological procedures, and in devising methods of increasing host resistance through prophylactic vaccination. There has also been much important investigation of induced resistance and tolerance to transplants of skin and organs, including tumors. See Blood groups, Hypersensitivity, Immunity, Immunoassay, Isoantigen, Phagocytosis, Serology, Transplantation biology, Vaccination

the science concerned with the protective reactions of the body, or those reactions aimed at preserving the bodys structural and functional integrity and its biological individuality. Immunology is a broad and rapidly growing biological discipline which started as a branch of medical microbiology. The theoretical aspects of immunologythe study of the cellular and molecular mechanisms governing the formation of antibodies and their pathogenetic role and the phylogeny and ontogeny of the immune systemare increasingly being described by the term immunobiology.

Immunology originated after it was observed that individuals who had recovered from an infectious disease were usually able to take care of sick persons during an epidemic of that disease without endangering themselves. In 1796, E. Jenner developed a method for artificially immunizing human beings against smallpox by inoculating them with cowpox. L. Pasteurs discovery in 1880 that immunizing chickens with an old cholera culture made them resistant to infection by the highly virulent causative agent of fowl cholera was the beginning of immunology as an independent science. Pasteur formulated the main principle underlying vaccines and produced vaccines against anthrax and rabies. In 1887, E. Metchnikoff discovered the phenomenon of phagocytosis and developed a cellular (phagocytic) theory of immunity. By 1890 the German bacteriologist E. von Behring and his co-workers had shown that protective substances, or antibodies, are formed in the body in response to the introduction of microbes and their toxins. The German scientist P. Ehrlich advanced the humoral theory of immunity (1898, 1900). In 189899 the Belgian scientist J. Bor-det and the Russian scientist N. N. Chistovich discovered that antibodies are formed in response to the injection of foreign erythrocytes and serum proteins. This discovery gave rise to the study of immune responses to agents other than infection. In 1900 the Austrian immunologist K. Landsteiner discovered human blood groups and laid the foundation for the theory of tissue isoantigens. A new direction in immunology (anticipated by the Australian scientist M. Burnet), the theory of immunological tolerance, evolved after this phenomenon was induced experimentally by the English scientist P. Medawar in 1953.

Soviet immunology was initiated by the research of E. Metchnikoff, A. A. Bezredka, G. N. Gabrichevskii, N. F. Gamaleia, and L. A. Tarasevich. In the 1920s and 1930s Soviet immunology not only solved practical problems but engaged in fruitful theoretical research as well (I. L. Krichevskii, V. A. Barykin, V. A. Liubarskii, S. I. Ginzburg-Kalinina). L. A. Zilber, P. F. Zdrodovskii, G. V. Vygodchikov, M. P. Pokrov-skaia, V. I. Ioffe, A. T. Kravchenko, and P. N. Kosiakov made important contributions in the 1940s, 1950s, and 1960s. Immunology continues to progress very rapidly, especially where it joins with chemistry, genetics, physiology, radiobiology, and other branches of biology and medicine. Immunology itself consists of several more or less distinct branches (see Figure 1); these are described below.

Immunomorphology studies the anatomy, histology, and cytology of the bodys immune system. It makes use of histological

Figure 1. Diagram of the development of ideas in immunology and the appearance of the modern branches of the science (after R. V. Petrov, 1968). Nobel Prizes awarded for research in the field of immunology: (1) first, for the theory of immunity (jointly, with P. Ehrlich, 1908); (2) second, for the creation of antitoxic sera (1902); (3) third, for the discovery of isoantigens and blood groups (1930); (4) fourth, for the discovery of tolerance and a theory of immunity (jointly, with M. Burnet, 1960). (a) First vaccine against cholera (A. V. Khavkin, 1892).

and cytological methods of investigation; cultivation of cells outside the body; light, fluorescent, and electron microscopy; and autoradiography. In recent years the entire primary immune response of lymphoid cells has been successfully duplicated in a test tube. It was found that the specific immune response and, in part, the bodys natural resistance are functions of the lymphoid system and of phagocytic cells scattered through all tissues. Neutrophilic and eosinophilic granulocytes, monocytes, and thrombocytes in the blood, histiocytes in connective tissue, microglia in the brain, cells of the sinuses of the liver, spleen, adrenals, bone marrow, and anterior lobe of the pituitary, reticular cells of the spleen, lymph nodes, bone marrow, and thymus, and some circulating lymphocytes are capable of capturing antigen. Most of the antigen introduced into the body is captured, destroyed, and eliminated by these cells. Only a fraction of the antigenic molecules survive long enough to provoke specific immunological reactions. The antigenic molecules that settle on the surface of the reticular cells in the lymph nodes play an especially important part. The immune response is provoked by the interaction of at least two types of small lymphocytes that constantly migrate in the tissues and circulate through the lymphatic and blood vessels (see Figure 2).

One type of cell (the B cell) originates in bone marrow and, on coming into contact with antigen, is converted into an antibody-forming cell (plasma cell). Another type of cell (the T cell) originates in the thymus. It is able to react specifically to antigen molecules and bring about the interaction of the B cells with antigen.

In an immunologically mature (immunocompetent) organism, phagocytic cells and T and B lymphocytes carry out all forms

Figure 2. Diagram of the interaction of the cells of the immune system

of specific response. They form circulating antibodies belonging to various classes of the immunoglobulins (see Figure 2, upper part) and produce immune reactions of the cellular type delayed increased sensitivity, rejection of transplant, and so forth. The organism responds in this way to a number of bacterial and parasitic invasions (tuberculosis, brucellosis, leishmaniasis) and to the transplantation of cells and tissues from another organism. The differentiation and interaction of these cells under the influence of antigen may lead to the development of immunological memory or of specific immunological tolerance.

Comparative immunology studies the immune response in different animal species. The evolutionary interpretation of immunity phenomena is helpful in elucidating their mechanisms. The lymphoid system and the ability to produce specific antibodies appear only in vertebrates. For example, the sea lamprey has a primitive lymphoepithelial thymus, lymphoid islets in the spleen and bone marrow, and circulating lymphocytes. It forms antibodies and immunological memory develops, but the set of antigens to which the lamprey responds is very limited. The lymphoid system is more developed in primitive cartilaginous fish (sharks and rays), which are capable of reacting to a great many antigens. Typical plasma cells appear in cartilaginous, actinopterygian, and teleost fish, all of which manufacture several types of immunoglobulins. Amphibians are the first in the phylogenetic series to develop the system of plasma cells, which synthesize high- and low-molecular immunoglobulins with different antigenic properties. Reptiles have a very similar system. The complement system (which consists of various native serum proteins) is apparently very ancient; it exists in a similar form both in the lower and in the higher vertebrates.

In most mammals immune reactions reach full development only after birth. A system of selective transfer of immunoglobulins from mother to fetus functions during embryonic development, when the embryo is protected against the effect of antigens. However, the human fetus forms M and G immunoglobulins independently by the fourth or fifth month. Birds and mammals, including man, possess an identical spectrum of immunological reactions. The degree of immunoreactivity is age-related, decreasing noticeably as the body ages.

Physiology of immune reactions studies the mechanisms by which the organism finds and removes foreign elements, or substances that are not normal constituents of the bodys own tissues, such as dead and malignantly degenerated cells, the bodys own injured molecules, foreign cells and molecules, bacteria, viruses, protozoans, and helminths and their toxins. The functional expression of the foreignness of an antigen is its ability to induce the formation of specific antibodies and combine with them. The nature of antigenicity, the question of why the organism does not form antibodies to any of the vast number of its own molecules yet forms antibodies to an infinite number of foreign antigens, and the essence of the specific immune response (specifically, the synthesis of antibodies) are the problems that constitute the main elements of the so-called theory of antibody formation. Antibody formation, that is, the biosynthesis of highly specialized protein molecules, is assumed to occur like the synthesis of other blood-plasma proteins.

A general theory of immunological reactions has to explain the physicochemical nature of antigenicity, describe the molecular mechanisms governing the synthesis of antibodies, and elucidate the nature of immunochemical specificity. Such a theory can be developed if three important and interrelated problems of the immune response are successively solved: (1) the genetic basis for the variety of immunoglobulins; (2) the number of antibodies of different specificity that a cell can synthesize, the nature of the intercellular interactions, and the level (cellular or subcellular) at which antigen acts; (3) the mechanism of specific immunological tolerance (the absence of a specific response to antigen). The first attempt to provide a chemical interpretation of immunological reactions was undertaken by P. Ehrlich in 1900. He suggested that every antibody-forming cell has a preformed side chain that by chance corresponds spatially to an antigen. The side chains, separated from the cell-carrier and entering the bloodstream, were identified with antibodies. This hypothesis is strikingly close to modern ideas of protein biosynthesis, in that it postulates the pre-existence (preceding the action of antigen) of a genetic code for each type of antibody. Antigen molecules must only select the preceding structure and intensify its reproduction. The popularity of Ehrlichs selection idea was shaken by K. Landsteiners discovery (1936) that a great many artificial antigens, produced synthetically, can induce the formation of specific antibodies. Accordingly, the American scientists F. Breinl, F. Haurowitz, D. Alexander, and S. Mudd (1930) conjectured that preformed antibodies do not exist. Antigen interferes with the formation of a globulin molecule by disrupting its assembly. The result is the formation of an antibody with a structure specific to the given antigen. The action of the antigen in this case is described as instructive; this readily accounts for the limitless variety of antibodies synthesized by the organism. The American scientist L. Pauling (1940) ascribed to antigen the role of a template where the polypeptide chains of the antibody are formed.

A new stage in the development of immunology was marked by the appearance of the concept of the Australian scientists M. Burnet and F. Fenner (1941), who regarded antibody synthesis as a special case of adaptive protein synthesis, similar to the synthesis of induced enzymes in bacteria. Antigen in the cell was assumed to have an indirect instructive function, inducing a change in the complex of enzymes participating in the synthesis of the antibody molecule. This concept was subsequently supplemented by the hypothesis of the existence of special labels for the bodys own antigens, which would explain the natural tolerance for them. According to the American scientist R. Owen (1957), an antigen, like a mutagen, causes corresponding changes in deoxyribonucleic acid (DNA) that result in the biosynthesis of antibody molecules. The American scientist G. Goldstein (1960) suggested that antigen acts in analogous fashion on messenger ribonucleic acid. In 1950 the German scientist N. K. Jerne advanced a new hypothesis, based on Ehrlichs selection idea, to explain the specific immune response. Jernes natural selection hypothesis was essentially that antibody molecules, differing in specificity, are formed in the thymus during the embryonic period. The complex of antigen and corresponding antibody comes into contact with an antibody-synthesizing cell, which uses the antibody as a template to form similar molecules. Jerne postulated the absence of antibodies to the bodys own antigens and the recognition only of foreign configurations.

The clonal-selection theory of acquired immunity, advanced by M. Burnet (1957), was an elaboration of the selection idea. A clone is a group of cells descended by division from a single precursor cell. According to Burnet, the lymphoid system of an immunologically mature organism contains a great many (at least 104105) clones of cells capable of responding specifically to different antigens. The nature of the genetic diversity of the immunoglobulins is unknown. However, the clonal-selection theory seems to be the most plausible and consistent with modern ideas of protein biosynthesis. Burnet ascribed the absence of a reaction to the organisms own antigens to the elimination of any prohibited clones (that is, clones capable of synthesizing antibodies to ones own) during the embryonic period. According to this theory, an antigen entering the organism selects a cell that is capable of forming the corresponding antibody and stimulates it to multiply and then to synthesize the antibody. Where this selection takes placeat the level of the cell clones (as Burnet believes) or at the level of subcellular unitsdepends on how many antibody molecules of different specificities the cell is capable of synthesizing. It is conceivable that the cell bears genetic information for the synthesis of more than 105 different immunoglobulins. However, because of differentiation, the cells ability to synthesize antibodies is in effect neutralized. Antigen depresses the synthesis of corresponding antibodies, so that antibodies of only a single specificity are synthesized. This notion is the basis of the repression-depression hypothesis advanced by the American scientist L. Szilard, the Australian I. Finch, and the Soviet scientists V. P. Efroimson, A. E. Gurvich, and R. S. Nezlin.

Immune-reactions physiology also studies the factors that regulate the quantitative characteristics of the immune response, including the role of the nervous system (especially of the hypothalamus), hormones, age, nutrition, condition of the organism (specifically, the degree of fatigue), and external influences. It is now known that pituitary and adrenal hormones can alter immunological reactivity and that the placenta secretes a special hormone that to a large degree inhibits the mothers immune reactions to the antigens of the fetus.

Immunopathology studies not only extreme or injurious immune reactions but also diseases accompanied by defects in the immune system: hereditary and acquired agammaglobulinemias and immunoglobulinopathies in tumors of the lymphoreticular tissue, in nephroses, after the use of cytostatic drugs, and after irradiation. Special attention is given to methods of inhibiting and stimulating the immune response. Intensification of the immune response by nonspecific stimulants (so-called adjuvants) or by transplantation of active lymphoid tissues is a promising approach to the treatment of infectious diseases and defects of the immune system. Conversely, inhibition of the immune response is a method of treating diseases with extreme or undesirable activity of the immune system. Inhibition is achieved by injuring lymphoid cells by irradiation, nitrogen mustard, antimetabolites, corticosteroid hormones, and antilymphocytic serum. The immune response can also be suppressed by the passive introduction of antibodiesfor example, by injecting the mothers body with antirhesus antibodies to prevent hemolytic jaundice of the newborn.

The bodys reaction to the cells and macromolecules of individuals of the same or of other species has been studied intensively in recent years. This branch of the science is called noninfection immunology (the study of immune responses to agents other than infection). The proteins and cellular membranes of every multicellular organism possess certain unique and inimitable structural features. The differences between individuals are due to genetic mechanisms. It is for this reason that cells and molecules introduced into the organism from without are recognized as foreign and evoke a complex of immune reactions directed toward eliminating them. Hence, despite the finest surgical technique, transplanted organs and tissues are usually rejected, since they are unable to overcome the barrier of tissue incompatibility. This problem is the concern of transplantation immunology. Another branch of noninfection immunology is the immunology of tumors, which studies tumor antigens and the mechanisms of recognition and elimination of malignantly degenerated cells. The scope of noninfection immunology also includes the development of methods for creating specific immunological tolerance; these methods will eventually make organ transplantation a practicable method of treating all kinds of diseases. The data obtained by immunology are the basis for the development of applied and clinical immunology and their various concerns, such as immunoprophylaxis, immunotherapy, and immunodiagnosis.

Immunological methods of research are widely used for purposes of precise analysis in diverse branches of medicine (hematology, obstetrics, dermatology), and biology (biochemistry, embryology, genetics, and anthropology).

There are more than 50 scientific-research institutes in the USSR dealing with the problems of immunology. The most important of these are the N. F. Gamaleia Institute of Epidemiology and Microbiology of the Academy of Medical Sciences of the USSR (the department of immunology and oncology of this institute is an international center for the study of tumor-specific antigens), the E. Metchnikoff Moscow Institute of Vaccines and Sera, the L. A. Tarasevich State Control Institute of Biomedical Preparations, the Moscow Institute of Epidemiology and Microbiology, and the Leningrad Institute of Experimental Medicine.

Among the foreign organizations doing research in immunology are the Institute of Immunology (Basel) and the Institute of Biochemistry of Lausanne University (Switzerland), the National Institute of Medical Research (Mill Hill, Great Britain), the National Cancer Institute, the National Institute of Health, and the Rockefeller Institute of Medical Research (United States), the Scientific Research Institute of Immunology (Prague, Czechoslovakia), and the L. Pasteur Institute (Paris, France). Since 1963, as part of its program on immunology, the World Health Organization has been developing information centers for immunology and immunoglobulins and sponsoring symposia and conferences on immunopathology, the immunology of parasitic diseases, the immunotherapy of cancer, the typing of antigens of tissue incompatibility, and cellular immunity.

Immunological studies in the USSR are published in a number of medical and biological journals: Zhurnal mikrobiologii, epidemiologii i immunobiologii (since 1924), Patologicheskaia fiziologiia i eksperimentalnaia terapiia (since 1957), Voprosy virusologii (since 1956), Meditsinskaia parazitologiia i parazitar-nye bolezni (since 1923), and Biulleten eksperimentalnoi biologii i meditsiny (since 1936).

The following foreign journals are devoted entirely to immunology: Journal of Immunology (Baltimore, since 1916), Journal of Experimental Medicine (New York, since 1896), Journal of Allergy (St. Louis, since 1929), Immunology (Oxford, since 1958), Clinical and Experimental Immunology (Oxford, since 1966), Immunochemistry (New York, since 1964), Advances in Immunology (New York-London, since 1961), Zeitschrift fur Immunitats- und Allergieforschung (Jena-Stuttgart, since 1909), International Archives of Allergy and Applied Immunology (New York-Basel, since 1950), Revue dImmunologie et de Therapie antimicrobienne (Paris, since 1935).

Many articles on immunology appear in the Russian-language Biulleten Vsemirnoi organizatsiizdravookhraneniia (Bulletin of the World Health Organization), in some issues of the series of WHO technical reports, and in the international Zhurnal gigieny, epidemiologii, mikrobiologii i immunologii, published in Russian in Prague (since 1957).

Practical (including clinical) immunology is concerned with the use of immunological reactions for the diagnosis, prevention, and treatment of a number of diseases. It is closely related to medical and veterinary microbiology, epidemiology, physiology and pathophysiology, biochemistry, and endocrinology. Viral immunology and the immunology of parasitic diseases are independent branches of practical immunology. Immunology studies the antigenic composition of microorganisms, characteristics of the immune processes in various kinds of infections, and nonspecific forms of resistance to the causative agents of infectious diseases. Study of the immunological processes and the immunological reconstruction of the organism caused by noninfectious antigens of exogenous and endogenous origin and the development of methods for controlling allergic diseases are becoming increasingly important. Other branches of clinical immunology are also developing intensively. These include radiation immunology, which studies the disruption of immunological reactivity by irradiation, and immunohematology, which investigates the antigenic composition of blood cells and the causes and mechanism of development of immunological injury to the circulatory system. Immunology is developing methods of immunoprophylaxis, immunotherapy, and immunodiagnosis.

Clinical immunology uses a variety of research techniques. For example, biochemical and physicochemical methods are used to study the nature and properties of antigens and antibodies. Using isotopic indicators and fluorescence microscopy, im-munologists study the fate of antigens in the body and the laws of antibody formation at the cellular level. The mechanisms of development of nonspecific inflammatory and allergic reactions are investigated by biochemical and cytochemical methods.

Immunological methods of research are based on the specificity of the interaction of an antigen (microbe, virus, foreign protein, and so forth) with antibodies. Serology is a branch of immunology that studies the reaction of antigen with serum antibodies. The most widely used immunological methods include the precipitation reaction, the agglutination reaction, lysis, and the neutralization reaction. The interaction of antigen with immune cells is receiving extensive study. Many immunological methods are highly specific and sensitive (for example, the anaphylactic reaction is more sensitive than the methods of analytical chemistry), and they are employed in other disciplines, such as forensic medicine.

Immunology is taught in the USSR and abroad in medical and veterinary schools in departments of pathological physiology, microbiology, and general pathology, as well as in special scientific research institutes. Problems of clinical immunology are discussed at international congresses on microbiology and allergology and in many Soviet and foreign periodicals.

A. KH. KANCHURIN and N. V. MEDUNITSYN

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