During an immune response, rare antibody species are amplified to abundance via specific B cell proliferation and differentiation. New structure are also generated by somatic mutagenesis of antibody variable (V genes. Studies from the applicant's laboratory have shown that peptides derived from physiologically-generated antibody V regions are potentially antigenic to the T cell repertoire in the context of class II MHC structures. This creates a dangerous challenge to the immune system, because T cell recognition of antibody V regions that are self-presented by B cell could potentially lead to a chronic state of autoantibody production. Alternatively, the T cell repertoire may attain a state of tolerance to antibody V region-derived peptides, and results obtained by the applicant during the initial funding period indicate that such tolerance does occur in some cases. In this application, if it proposed to study the cellular basis of tolerance to antibody V regions using the anti-Arsonate antibody response of A/J mice, which is highly defined at the molecular level. Germline-encoded V region epitopes to which tolerance is normally achieved will be identified. The type and location of the cells that process and present natural antibody V region peptides will be identified. The applicant will test the hypothesis that B cells induce tolerance by self- presentation of antibody to T cells. In addition, a study will be initiated to investigate tolerance to V regions of autoantibodies from lupusprone mice. Results of this study are expected to shed light on the molecular basis of systemic autoimmunity, where tolerance of antibody V regions may be incomplete.
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