One of the central features of the immune system is the capacity to mount an inflammatory response to nonself while avoiding harm to self tissues. While recognition of self plays an important role in shaping the repertoires of immune receptors on both T and B cells, and in the clearance of apoptotic debris from tissues throughout the body, the development of potentially harmful immune responses to self-antigens is, in general, precluded. 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; however, autoimmune disease represents the end result of the breakdown of one or more of the basic mechanisms regulating immune tolerance.
Autoimmunity is seen in normal individuals and in higher frequency in normal older people. Polyreactive autoantibodies that recognize many host antigens are present throughout life. Expression of these antibodies may be increased following some inciting events. These are usually of the IgM heavy chain isotype and are encoded by nonmutated germline immunoglobulin variable region genes. 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. Such autoimmunity may, however, be persistent, and then may or may not result in ensuing pathology. Even in the presence of organ pathology, it may be difficult to determine whether the damage is mediated by autoreactivity. Following an inciting event, the development of self-reactivity may be the consequence of an ongoing pathologic process, and be nonpathogenic, or may contribute to tissue inflammation and damage.
Since Ehrlich first postulated the existence of mechanisms to prevent the generation of self-reactivity in 1900, ideas concerning the nature of this inhibition have developed 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 became untenable, 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 the circulation of normal individuals, and that self-limited autoimmune phenomena frequently developed following tissue damage from infection or trauma. These observations indicated that clones of cells capable of responding to autoantigens were present in the repertoire of antigen-reactive cells in normal adults and suggested that mechanisms in addition to clonal deletion were responsible for preventing their activation.
Currently, three general processes are thought to be involved in the maintenance of selective unresponsiveness to autoantigens (Table 318-1): (1) sequestration of self-antigens, rendering them inaccessible to the immune system; (2) specific unresponsiveness (tolerance or anergy) ...