The superantigens (SAgs) are a relatively newly described group of proteins produced by mycoplasmas, bacteria and retrovirus that interact with the cells of the immune system in a unique manner and which exert profound effects upon the immune system in vivo. It has been postulated that SAgs may restrict the function of the immune system and also promote changes that result in autoimmune disease. M. arthritides which cause a chronic arthritis of rodents produces a SAgs MAM which activates a subset of TCR-bearing T cells that contributes to experimental collagen-induced arthritis and which are also found to be enriched in the synovium of patients with rheumatoid arthritis. MAM has been shown to trigger collagen arthritis and to induce B cell activation in vitro and in vivo, thus providing a mechanism by which it might contribute to autoimmune disease. The applicant proposes to 1) Through the use of characterized recombinant MAM, determine the structure of MAM and compare this with that of other superantigens in order to predict active sites on the molecule that interact with MHC molecules. 2) Identify the active sites on MAM that enable it to bind to MHC Class II molecules and to determine the sites on MHC molecule to which MAM binds. These studies will shed light on the MHC predisposition to susceptibility to development of autoimmune disease and also provide information on epitopes or peptides that might be used as therapeutic agents. 3) Determine the effect of MAM in vivo on immune functions and to identify the ability of MAM to induce autoantibodies. 4) To test for evidence that superantigens might play a role in the induction of human autoimmune disease by screening for antibodies to SAgs and detecting changes in immune function which might be brought about by the action of specific SAgs. The applicant's long term goal is to elucidate the etiology of the human rheumatic diseases and to design new therapeutic approaches applicable to these diseases.
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