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Autoimmunity - in which the immune system recognizes and attacks the self's own tissue is not as simple as it seems. Self recognition appears to be at the heart of health as well as of certain diseases. It is generally assumed that the main job of the immune system is to distinguish between what is "self" and what is "not self". Once the distinction has been made, "self" is preserved and "not self" is destroyed. At the most general level, of course, this is true, and human beings remain alive and healthy only because it is so. Recently it has become clear, however, that at a finer level of detail the distinction between self and other is not absolute. One of the paths to this insight has been provided by the autoimmune disorders, in which the immune system attacks normal, healthy tissue. Autoimmune disease, which may be crippling or fatal, can strike any tissue or organ. Its victims are often in the prime of life, and for unknown reasons they are more frequently women than men. Research work on a form of autoimmune arthritis shows that the basis of autoimmunity may be a resemblance between a specific foreign molecule and a molecule of the self. This finding is consistent with a model of the immune system in which the immune-system receptors that perform the work of recognition can themselves be recognized by other receptors. Such "self-recognition," which was strictly outlawed by older models of the immune system, may form the basis of a network whose equilibrium keeps the body healthy. When it is disrupted, as it is in autoimmunity, disease results. This new picture, in which self and world are no longer absolutely distinct, has already begun to yield practical benefit in the form of vaccines that may ultimately ease the substantial suffering caused by autoimmune diseases. The list of autoimmune diseases is both long and disturbing. It includes multiple sclerosis, in which the tissue attacked is myelin (a substance that sheathes nerves in the central nervous system); myasthenia gravis, in which the target is a receptor molecule for the important neurotransmitter acetylcholine; rheumatoid arthritis, whose target is the peripheral joint; type I (juvenile) diabetes mellitus, in which the cells producing insulin are destroyed, and systemic lupus erythematosis, in which DNA, blood vessels, skin and kidneys are attacked. In contrast to AIDS, which is marked by an inactivation of key cells in the immune system, in all these diseases the immunological response is strong and well focused; it is, however, directed at some essential component of the body. These immunological attacks are detected in clinical laboratory by the measurement of tissue specific and tissue non-specific antibodies. Autoimmune diseases can be separated broadly into two categories. One group is characterized by the presence of autoantibodies which are broadly reactive with nuclear or cytoplasmic antigens and do not demonstrate any tissue specificity. Included in this group are diseases such as rheumatoid arthritis, SLE, mixed connective tissue disease, scleroderma, Sjogren's syndrome, and dermatomyositis/polymyositis. A second group of autoimmune diseases is characterized by autoantibodies which demonstrate tissue specificity. These diseases include thyroiditis, chronic liver diseases (including primary biliary cirrhosis and chronic active Hepatitis). certain cases of pernicious anemia, and myasthenia gravis. The autoantibodies which appear in these disease states demonstrate different degrees of specificity with respect to both tissue and species. Tissue-specific autoantibodies include those which react against erythrocyte stromal antigens, platelets, antihemophilic globulin, thyroid tissue and other tissues, and g-globulin (rheumatoid factor). Autoantibodies without tissue specificity include antinuclear, antinucleoprotien, anti-DNA, and anti-cytoplasmic antibodies. Autoantibodies directed against the formed elements of the blood can undoubtedly induce disease by causing the destruction and removal of these cells from the circulation. However, it is far less certain whether other types of autoantibodies play pathogenic roles. Most studies of autoantibodies in both humans and animals have concentrated on the reactivity of humoral constituents. However, it should be remembered that the cell-mediated immune response is far more efficient in terms of tissue destruction. Since humoral antibodies have been shown, under appropriate circumstances, to prevent cell-mediated tissue damage, it is conceivable that they may have a protective rather than a destructive function. There is presently no indication whether the autoantibodies detected in human disease represent a primary manifestation of the disease itself or a secondary event stimulated by an underlying, but unrelated, abnormality. In either event, the mechanisms which may be responsible for the abrogation of natural immunologic tolerance are worthy of consideration. Four general mechanisms have been proposed in the pathogenesis of autoantibody production: |
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