Systemic lupus erythematosus is a systemic autoimmune disease in humans and genetically predisposed mice that results from the deposition of immune complexes in various tissues of the body, most notably along the glomerular basement membrane of the kidneys. This immune complex deposition and the resulting inflammation eventually lead to tissue destruction and failure of kidney function. 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. The immunological basis for the generation of anti-DNA autoantibody in mice and humans has been difficult to elucidate. Previous attempts to stimulate antibody with the same specificity for binding to DNA as anti- DNA antibody in lupus have been unsuccessful. This fact coupled with the presence of a generalized abnormality in lymphoid cell development in mouse models for lupus has led to the proposal that lupus autoantibodies arise by antigen independent, polyclonal B cell activation. However, recent results form our molecular structural analyses on the structure and ontogeny of autoimmune anti-DNA antibodies have indicated that autoimmunity to DNA is both initiated and sustained as a clonally selected, specific immune response to DNA or DNA complexes. Therefore, understanding the structural basis for specific immunity to DNA could provide useful insight as to the nature of the autoantigen that initiates autoimmunity to DNA in autoimmune disease. We have recently established an experimental immunization model for the induction of antibody to DNA in mice not genetically predisposed to autoimmune disease. The induced anti- DNA antibody has structural and specificity characteristics identical to those of autoimmune anti-DNA antibody in lupus. Moreover, mice producing this antibody develop symptoms of early stage lupus-nephritis. Our research for the continuation of this project, studies on the structure and ontogeny of autoimmune anti-DNA antibodies, will exploit this new and unique experimental system to study the structural and genetic basis for anti-DNA antibody production. The experiments will also seek to establish the structural basis for pathogenicity of induced and autoimmune anti-DNA antibodies in lupus-nephritis.
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