The long-term objective of the proposed research is to define the mechanisms by which antilymphocyte autoantibodies contribute to the pathogenesis of SLE, a prototype systemic autoimmune disorder. Of special interest in this regard is our recent discovery that IgM autoantibodies in SLE are directed against different isoforms of CD45, the major protein tyrosine phosphatase on the surface of hemopoietic cells. CD45 recently has been implicated in the regulation of lymphocyte functional activity, including cytotoxicity, proliferation, and differentiation via interaction of its variable extracellular domains with as yet undefined ligands and through its phosphatase action on intracellular tyrosine kinases and other substrates. The identification of different isoforms of CD45 as specific antilymphocyte autoantibody targets should permit a more precise understanding of the mechanisms by which such autoantibodies influence lymphocyte behavior. We hypothesize, therefore, that anti-CD45 autoantibodies contribute to abnormal lymphocyte function in SLE and, possibly, other autoimmune disorders. Experiments in aim 1 will focus on characterizing the nature of CD45 autoreactivity in SLE, especially with respect to delineation of carbohydrate versus polypeptide reactivity. With this information, anti-CD45 autoantibodies will be isolated from SLE serum for functional experiments by affinity chromatographic procedures using CD45 fusion proteins or CD45 purified biochemically from bulk cell preparations. Emphasis in aim 2 will be on the capacity of purified anti- CD45 autoantibodies to influence proximal signal transduction and late activation events in T cells and other types of cells following defined stimulations in vitro.
Aim 3 will involve longitudinal studies of clinically and immunologically defined patients, with special reference to the relationship of anti-CD45 autoantibodies with disease activity status and immunologic function. A cross-sectional survey of anti-CD45 autoantibodies in other rheumatic and autoimmune disease sera also will be performed to define the specificity of this autoantibody system for SLE and to determine the prevalence of anti-CD45 autoantibodies in other disorders. Because CD45 is not the only antilymphocyte autoantibody specificity in SLE, efforts to identify and to determine the significance of other targets will be pursued in aim 4 as well.
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