autoimmunity(redirected from Auto-immune disease)
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The occurrence in an organism of an immune response to one of its own tissues, that is, a response to a self constituent. Efficient discrimination between self and nonself, the basis of normal immune function, depends upon a function known as immune tolerance (inertness to substances that could be capable of provoking an immune response). Failure of immune tolerance to self constituents results in an autoimmune response which is often, although not invariably, associated with autoimmune disease. Autoimmune disease occurs when the autoimmune response to self constituents has damaging effects of a structural or functional character.
Lymphocytes that participate in immune responses belong to two major groups. One group, which matures in the thymus gland, comprises thymic or T lymphocytes, of which there are several subsets. These subsets have different functions and carry unique surface molecules: (1) helper T lymphocytes, marked by the CD4 molecule, respond to antigens by releasing stimulatory cytokines (intercellular hormones) that can amplify the number and activity of lymphocytes participating in the immune response; (2) cytolytic T lymphocytes, marked by the CD8 molecule, can directly recognize and kill cellular targets, usually virus-infected cells; and (3) suppressor T lymphocytes, which also carry the CD8 molecule, release molecules that reduce the intensity of immune responses, or switch these off altogether. The other major group of lymphocytes, which mature in the bone marrow, are B lymphocytes. After stimulation with antigen molecules, and under the influence of factors released by helper T cells, B lymphocytes proliferate and later secrete the antibody molecules which, when circulating in the blood, provide for humoral immune responses. The normal immune system remains in a state of balance conditioned by positive signals and negative signals. Positive signals are provided by antigen in low dose and the amplifying factors released by activated helper T lymphocytes, while negative signals are provided by antigen present in excess, which causes an overload paralysis, and by suppressor T lymphocytes which are generated preferentially when self antigens are presented. There is still a lack of full understanding of the mechanism by which immune responses to self antigens are suppressed so as to provide for natural tolerance to self. The major processes are (1) permanent deletion, or functional inactivation in early life, of cells capable of responding to self antigens; and (2) regulatory controls, which inhibit the activity of self-reactive lymphocytes that escape the deletion process. The relative contribution of these two mechanisms for specific self antigens appears to differ, and both probably operate to control autoimmunity. There are low background levels of immunologic reactivity to many self antigens in healthy subjects, indicating that suppressor activity over immune responses to autoantigens must be continuously operative. See Immunity
Failure of immune regulation is responsible for autoimmune disease. Inheritance may account for 25–50% of the risk for autoimmune diseases. It is known that autoimmune disease, or at least the tendency to produce autoantibodies, runs in families. There are many genetic determinants, and they are poorly understood. One set is in some way associated with major histocompatibility complex (MHC; called HLA in humans), a gene complex that codes for cell-surface molecules which confer biological uniqueness on cells of an individual. Since products of HLA genes normally function to direct T lymphocytes to cells with which they should interact, it is not surprising that autoimmune diseases are associated with the presence of particular HLA types; examples include B8 (thyrotoxicosis), DR4 (rheumatoid arthritis, type 1 diabetes mellitus), and DR2 (multiple sclerosis). The reason may be that the autoantigen readily associates with the MHC (HLA) molecule on cells which present antigen to helper T lymphocytes. The MHC influences the occurrence of autoimmunity in other ways. Release of cytokines by T lymphocytes may induce aberrant expression of molecules on tissue cells which then can present their own antigens, and these become inducers of an autoimmune response. In addition to the MHC, there are other inherited determinants of autoimmunity, including genes specifying immunoglobulin structure and genes specifying weakness in the down-regulation of immune reactions. There may also be somatic genetic causes of autoimmunity (random mutations in later life) among genes that code for immunoglobulins that function as recognition structures on the surface of B lymphocytes; such a mutation may generate a cell with a receptor structure with exquisite specificity for a self antigen which is resistant to regulation. Environmental causes could include infection with microorganisms that carry antigenic structures closely resembling those of self; these could provoke an uncontrolled response to the related self structures of the body. See Immunogenetics
Any autoimmune response must become self-sustaining, which implies coexisting failure of normal regulatory processes, either by reason of genetic predisposition or by an acquired disruption of immune function. Once self-sustaining, the autoimmune reaction can cause damage or dysfunction in one of several ways. First, autoantibody molecules circulate in the blood and, by attaching to self antigens on cell surfaces, either damage cells or interfere with important cell-surface receptor molecules. Second, antibodies can unite with their autoantigen, which results in the binding of a serum factor, complement, to form immune complexes that are capable of provoking inflammatory responses. Third, there may be generated T lymphocytes with the capacity for cellular destruction, and these may cause the progressive inflammatory damage that characterizes autoimmune reactions in solid organs. Many human diseases can be attributed to autoimmune reactions. Circulating autoantibodies are responsible for diseases in which there is intravascular destruction of elements of the blood, for example, the red blood cells in hemolytic anemia. T lymphocytes may be responsible for some types of thyroid goiter, such as Hashimoto's disease; a stomach mucosal degeneration that results in nonabsorption of vitamin B12 and thus the blood disease pernicious anemia; the insulin-dependent or juvenile type of diabetes mellitus; and one type of chronic hepatitis. Immune complexes cause glomerulonephritis and most of the features of systemic lupus erythematosus, in which autoantibodies are formed to various constituents of cell nuclei. In Sjogren's disease, in which salivary and lacrimal glands are destroyed, damage by T lymphocytes within the glands may be accompanied by damage by immune complexes throughout the body. Some autoimmune diseases are caused by antibodies to cell receptors, which either block neuromuscular transmission, as in myasthenia gravis, or stimulate thyroid cells to overactivity, as in Graves' disease. Some important human diseases may be autoimmune disorders, although demonstration of an autoimmune basis is not yet adequate: these include rheumatoid arthritis, multiple sclerosis, and ulcerative colitis. See Hepatitis
Autoimmune diseases are alleviated by treatment, though these diseases are seldom curable. At the simplest level, replacement of the specific secretions of tissues or organs damaged by autoimmune reactions may help. For multisystem autoimmune disease, such as lupus, there are drugs, particularly cortisone derivatives, that modify the harmful effects of humoral or cellular autoimmune attack on tissues and so allow the body to reestablish immunologic homeostasis. Also used are cytotoxic immunosuppressive drugs, which are given specifically to inhibit the activity of immunologically active cells responsible for autoantibody formation or for cytolytic damage to tissues. See Immunology