Systemic lupus erythematosus is a systemic autoimmune disease in humans and genetically predisposed mice. Antibodies to a variety of cellular antigens, mostly nuclear in origin, have been detected in lupus sera from mice and humans; however, the autoantibody for which there is the most compelling evidence for pathological relevance is antibody to DNA. Anti-DNA antibodies deposit in kidneys either as immune complexes or by binding directly to glomerular structures and initiate glomerulonephritis. The immunological basis for the generation of anti-DNA autoantibody in mice and humans has been difficult to elucidate. The goal of the applicant's research on """"""""Antigen Driven Selection and Tolerance in Autoimmunity to DNA"""""""" continues to be directed toward understanding how autoimmunity to DNA is initiated and sustained at the level of individual DNA-specific B cells in autoimmune (NZB x NZW) F1 mice. The applicant's research efforts since the last competitive review of this project have continued to support the hypothesis that autoimmunity to DNA is both initiated and sustained as a clonally selective, antigenic-specific immune response to DNA most likely in the form of DNA-protein complexes. The research has continued to focus on experiments to understand how the specificity and specificity maturation of the autoimmune anti-DNA antibody response within individual (NZB x NZW) F1 mice and the DNA-peptide induced immune anti-DNA antibody response in normal mice proceed. The results have provided new information about B cell selection in the autoimmune response to DNA and the V region structures necessary for that selection to occur. In the applicant's continuing research efforts to understand how autoimmunity to DNA is initiated, they will test the hypothesis that autoimmunity to DNA is initiated by antigen-specific B cell stimulation in the absence of peripheral B cell tolerance induced by extracellular DNA or nucleosomes. The specific experimental aims to be pursued in the research proposed will be to determine what role, if any, germinal centers play in the specificity maturation that generates high avidity autoantibodies to native DNA. Proposed experiments will also determine the role of soluble DNA or nucleosomes in maintaining immunological tolerance to DNA. The experimental systems designed to complete the proposed research will include the use of (NZB x NZW) F1 mice transgenic for expression of anti-DNA antibodies. These mice have an interesting autoimmune phenotype that make them highly suited for experiments to test the hypothesis that autoimmunity to DNA in (NZB x NZW) F1 mice derives from antigen-selective B cell stimulation in the absence of effective peripheral tolerance.
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