B lymphocytes may act as antigen-presenting cells (APCs). Germane to autoimmune disease, B cells expressing surface autoantibodies may capture self-antigens and potentially induce and/or stimulate self-reactive cellular immunity. Alternatively, self-reactive B cells may serve a homeostatic role, protecting against the development of autoimmunity by inducing T cell anergy to processed self antigens. Relevant to this are B-1 B cells (formerly called CD5 B cells). In contrast to conventional (or B-2) B cells, these cells are long-lived, apparently develop during early B cell ontogeny and are enriched for B cells that express CD5 and/or polyspecific IgM autoantibodies. Patients with rheumatoid arthritis (RA) generally are found to have higher circulating levels of these B cells than non-affected aged matched controls. However, family studies suggest that these higher levels may be under genetic control and thus precede the development of autoimmune disease. We hypothesize that higher levels of B-1 B cells may act as a risk factor for RA by increasing the probability for chance somatic changes in the B-1 B cell population that enhance the capacity of these cells to act as APCs of self-antigen. Accordingly, we will compare normal or neoplastic B-1 B cells with the B-1 B cells of RA patients in their relative: 1) expression of surface accessory molecules involved in T-B or B-B cell interactions or B cell activation; 2) production of immuno-modulatory cytokines: TGF-beta, IL-1, or IL-10; 3) expression frequencies of cross-reactive idiotypes (CRIs) associated with IgM autoantibodies; 4) ability to stimulate allogeneic T lymphocytes; and 5) efficiency in presenting antigen to autologous T cell lines. Furthermore, we will evaluate Ig V gene expression by B-1 B cells in a limited number of RA patients to examine for Ig V gene somatic mutation and clonal longevity. To examine for novel treatment modalities for autoimmune disease, we will test reagents that interfere with CD28-B7/BB-1 T-B cell interaction for their ability to inhibit B-1 B cell antigen presentation to autologous or allogeneic T cells. Through these studies we may appreciate whether somatic changes in the population of B-1 B cells contributes to the etiopathogenesis (or maintenance) of autoimmunity and address potential novel treatment modalities for RA.
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