Autoimmunity has been viewed to play a major role in the pathogenesis of rheumatoid arthritis (RA). Although rheumatoid factor is the hallmark of autoimmune expression in this disorder, other autoantibodies against diverse antigens have been found. Antibodies to Ro and La have been identified in sera from some patients with RA and are especially prominent in a subset with associated Sjogren's syndrome. To assess mechanisms of autoimmunity, we propose to evaluated the clinical significance, antigen-binding specificities, and the genetic regulation of anti- Ro and anti-La responses in RA and Sjogren's syndrome. Anti-Ro and anti-La antibodies will be detected using an enzyme-linked immunosorbent assay which incorporates molecularly cloned Ro and La fragments as antigens. In a prospective study, we will quantitate anti-Ro and anti-La responses in sera and determine their relationship with rheumatoid factor levels and clinical manifestations of disease. By taking advantage of recombinant DNA strategies, we will assess whether an individual's autoimmune response to different portions of the Ro and La antigens varies during the course of disease. Monoclonal antibodies selected for their reactivity to Ro and La will be produced using Epstein-Barr virus transformation of peripheral blood lymphocytes and hybridoma technology. With these monoclonals, we will address issues of anti-Ro and anti-La polyspecificity. It is possible that anti-Ro and anti-La antibodies bind to repeating epitopes on Ro and La, as represented by the molecularly cloned fragments, or cross-react with antigenic determinants located on immunoglobulin G or other relevant autoantigens. Anti-idiotypic antisera will be developed to probe immunoregulatory disturbances at the genetic level. In sequential sera, idiotype expression over the course of disease will be measured and correlated with manifestations of RA activity. Since the focus of rheumatoid inflammation resides in the joint, we will examine whether anti-Ro and anti-La antibodies are preferentially synthesized by synovial B cells. Importantly, the results of this research will provide valuable insights into the characteristics and regulation of autoantibody production in RA.
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