Consequences of autoimmunity

Autoimmunity is defined as an immune response leading to reaction with self antigen, i.e. any molecule that is a normal body constituent of the animal mounting the response. Self reactivity can arise either through the triggering of receptors directly by autoantigen or by virtue of cross-reaction between foreign and self antigens. Topographic similarity of B cell epitopes or sequence homologies of linear T cell epitopes may lead to such cross-reactions and it is highly unlikely that the immune system is able to recognize all foreign antigens specifically without some recognition of self epitopes also occurring.

Techniques such as polyclonal activation of cells with mitogens, and the establishment of lymphocyte clones and hybridomas, have established that self reactive T and B lymphocytes are frequently found in individuals who lack readily detectable autoantibodies in their serum. Indeed, at least some degree of self reactivity appears to be a normal physiological phenomenon during lymphocyte development and perhaps may be necessary in preparing the immune system for its future encounters with foreign antigen. The B-la (CD5+, Mac-1+, CD23", strongly slgM4) subset of B lymphocytes are found mainly in the peritoneal cavity where they are self-renewing and express germ line V genes encoding polyspecific low affinity IgM autoantibodies bearing cross-reactive idiotypes. This B cell subset is elevated in, for example, the autoimmune NZB mouse and in patients with rheumatoid arthritis. Low affinity IgM autoantibodies are probably not pathogenic. Encounter with nonidentical cross-reacting foreign antigen will, in the presence of T cell help, lead to affinity maturation within germinal centers, thereby generating antibodies with high affinity for foreign antigen which simultaneously lose their original self-reactivity. However, as certain self antigens such as idiotypes form key recognition structures for immunological regulation it is crucial that the immune system retains the ability to recognize these particular self components.

The pathogenicity of an autoimmune response is determined not only by the magnitude but also by the nature of the response. For instance, although 10-20% of clinically normal individuals possess low titers of autoantibodies specific for thyroglobulin, and although these antibodies are present at higher titers in about 70% of Hashimoto's disease patients, it is autoantibodies to another thyroid component, thyroid peroxidase, which show a stronger correlation with histopathological lesions. These autoantibodies occur in 95% of patients with Hashimoto's disease and, unlike most thyroglobulin autoantibodies, are complement fixing and therefore potentially cytotoxic to thyroid epithelial cells. Another example underlining the distinction between autoimmunity and disease is seen in patients treated for longer than 1 year with the drug procainamide (used to control cardiac arrhythmia). Over 90% of these patients develop IgM antibodies reactive with a broad spectrum of self histones but it is only in the 10-20% of patients who develop high levels of IgG antibodies specific for the H2A-H2B histone dimer bound to DNA that a lupus-like autoimmune disease arises. In the case of immunoglobulin, different parts of the same molecule can elicit both physiological (idiotypic) and potentially pathogenic (rheumatoid factor) autoantibodies.

Animal models have confirmed the importance of cell-mediated immune responses in the development of autoimmune disease; the adoptive transfer of autoantigen-specific T cell clones is often sufficient to induce disease in normal recipients. Most autoimmune diseases probably have both T and B cell components and in some situations other mechanisms involving natural killer (NK) cells or antibody-dependent cellular cytotoxicity may play a role in the pathogenic process.

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