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One of the central features of the immune system is the capacity to mount an inflammatory response to potentially harmful foreign materials while avoiding damage to self-tissues. Whereas recognition of self plays an important role in shaping the repertoires of immune receptors on both T and B cells and in clearing apoptotic and other tissue debris from sites throughout the body, the development of potentially harmful immune responses to self-antigens is, in general, prohibited. The essential feature of an autoimmune disease is that tissue injury is caused by the immunologic reaction of the organism against its own tissues. Autoimmunity, on the other hand, refers merely to the presence of antibodies or T lymphocytes that react with self-antigens and does not necessarily imply that the self-reactivity has pathogenic consequences. Autoimmunity is present in all individuals and increases with age; however, autoimmune disease occurs only in those individuals in whom the breakdown of one or more of the basic mechanisms regulating immune tolerance results in self-reactivity that can cause tissue damage.

Polyreactive autoantibodies that recognize many host antigens are present throughout life. These antibodies are usually of the IgM heavy chain isotype and are encoded by nonmutated germline immunoglobulin variable region genes. These antibodies are essential, as they remove apoptotic debris through non inflammatory pathways. Expression of these autoantibodies may be increased after some inciting events. When autoimmunity is induced by an inciting event, such as infection or tissue damage from trauma or ischemia, the autoreactivity is in general self-limited. When such autoimmunity does persist, however, pathology may or may not result. Even in the presence of organ pathology, it may be difficult to determine whether the damage is mediated by autoreactivity. After an inciting event, the development of self-reactivity may be the consequence of an ongoing pathologic process, may be nonpathogenic, or may exacerbate tissue inflammation and damage. Individuals with autoimmune disease may have numerous autoantibodies, only some or even none of which may be pathogenic. For example, patients with systemic sclerosis may have a wide array of antinuclear antibodies that are important in disease classification but are not clearly pathogenic; in contrast, patients with pemphigus may also exhibit a wide array of autoantibodies, one of which (antibody to desmoglein 1 and 3) is known to be pathogenic.


Since Ehrlich first postulated the existence of mechanisms to prevent the generation of self-reactivity in the early 1900s, there has been a progressive increase in understanding of this prohibition in parallel with a progressive increase in understanding of the immune system. Burnet’s clonal selection theory included the idea that interaction of lymphoid cells with their specific antigens during fetal or early postnatal life would lead to elimination of such “forbidden clones.” This idea was refuted, however, when it was shown that autoimmune diseases could be induced in experimental animals by simple immunization procedures, that autoantigen-binding cells could be demonstrated easily in ...

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