(Verbatim) - About 10 percent of patients with Lyme arthritis have persistent knee swelling for months or even several years after oral and intravenous antibiotic therapy. After treatment, such patients, in our experience, have no remaining spirochetal DNA in synovial tissue or joint fluid, suggesting that live spirochetes have been eliminated from the joint. During the past grant cycle, we identified a possible autoimmune mechanism that may partially explain the persistence of Lyme arthritis after antibiotic therapy. The mechanism in DRB1*0401-positive individuals involves molecular mimicry between the dominant T cell epitope of B. burgdorferi outer-surface protein A (OspA165-173) and a homologous sequence of human lymphocyte function associated antigen-1 (hLFA-1alpha332-340). In this proposal, we test the hypothesis that synovial inflammation may persist in treatment-resistant arthritis patients with a range of MHC alleles because of molecular mimicry between this dominant T cell epitope of OspA and hLFA-1. Our plan is to determine the frequencies of various MHC alleles in patients with treatment-resistant arthritis compared with those in treatment-responsive patients and those in a control population. PBL and synovial fluid lymphocytes (SFL) from treatment-responsive and treatment-resistant patients will be screened for reactivity with OspA165-173 and LFA-1alpha332-340, and cloned OspA165-173-reactive T cells from selected patients with a range of MHC alleles will be tested for reactivity with hLFA-1alpha332-340. Using an in vitro peptide binding assay, DR or DQ molecules obtained from selected patients' EBV-transformed B cells will be tested for their ability to bind the OspA and hLFA-1 peptides. Finally, after appropriate antibiotic treatment, the efficacy and safety of DMARD therapy will be observed in treatment-resistant patients. Lyme arthritis is the only human form of chronic inflammatory arthritis in which the triggering agent, immunogenetic susceptibility, and a candidate autoantigen are known. Thus, it is currently the only human system in which it is possible to explore specific infectious and autoimmune mechanisms that may lead to chronic inflammatory arthritis.
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