B CELL HYPERACTIVITY IN AUTOIMMUNITY

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DESCRIPTION: (Adapted from the Investigator's abstract): Rheumatoid factors autologous IgG present in the synovial fluid of patients with rheumatoid arthritis. High levels of RF-containing immune complexes and/or cryoglobulins have also been found in patients with microbial infections such as infectious endocarditis, in individuals presenting with hepatitis C-related essential mixed cryogloblulinemia, and in Fas/FasL-deficient (lpr/gld) mice. These immune complexes can deposit in blood vessel walls, fix complement, and thereby promote the vasculitis and glomerulonephritis associated with these diseases. Thus the contribution of RF to the effector arm of systemic autoimmune disease is well documented. Nevertheless, exactly how RF+ B cells become activated, why RF so frequently present as monoclonal gammopathies, and what role RF+ B cells might play in the initiation and propagation of the autoimmune cascade are questions that remain unresolved. The intent of the current application is to address these questions by using an RF+ B cell receptor transgenic mouse line, developed from a prototypic MRL/lpr-derived autoantibody, to evaluate the role RF+ B cells might play in the presentation of autoantigens. Specifically, the project will be organized to: (1) determine the ability of monomeric IgG2a and different types of IgG2a-containing immune complexes to activate RF+ B cells and evaluate the ability of activated and non-activated RF+ B cells to process and present autoantigenic epitopes; (2) evaluate the ability of RF+ B cells to stimulate autoreactive T cells in vitro and determine the specificity of the RF-activated ART; and (3) assess the ability of RF+ B cells and/or RF -activated ART to trigger and propagate systemic autoimmune disease. While dealing with RF in particular, the results of these experiments should be applicable to a more general understanding of the principles governing self/nonself recognition and tolerance induction. Moreover, this experimental strategy should also have direct relevance to human clinical syndromes associated with excessive RF production.