MOLECULAR GENETICS OF INDUCED ANTIDNA PRODUCTION

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THIS IS A SHANNON AWARD PROVIDING PARTIAL SUPPORT FOR THE RESEARCH PROJECTS THAT FALL SHORT OF THE ASSIGNED INSTITUTE'S FUNDING RANGE BUT ARE IN THE MARGIN OF EXCELLENCE. THE SHANNON AWARD IS INTENDED TO PROVIDE SUPPORT TO TEST THE FEASIBILITY OF THE APPROACH; DEVELOP FURTHER TESTS AND REFINE RESEARCH TECHNIQUES; PERFORM SECONDARY ANALYSIS OF AVAILABLE DATA SETS; OR CONDUCT DISCRETE PROJECTS THAT CAN DEMONSTRATE THE PI'S RESEARCH CAPABILITIES OR LEAD ADDITIONAL WEIGHT TO AN ALREADY MERITORIOUS APPLICATION. THE APPLICATION BELOW IS TAKEN FROM THE ORIGINAL DOCUMENT SUBMITTED BY THE PRINCIPAL INVESTIGATOR. The goal of these experiments is to elucidate immune recognition of DNA by studying the effects of immunization of normal and autoimmune mice with bacterial DNA. Previous studies from our laboratories have demonstrated that bacterial dsDNA is immunologically active, and can induce in normal mice the production of antibodies to non-conserved sites on bacterial DNA. In contrast, preautoimmune NZB/NZW mice when similarly immunized produce crossreactive anti-DNA that resemble lupus anti-DNA in their specificity for conserved DNA sites. Despite the production of these autoantibodies, immunized NZB/NZW mice show attenuated renal disease and prolonged survival, pointing to divergent consequences of bacterial DNA immunization. The renal protection may be related to other effects of bacterial DNA or murine immune cells, including induction of immunomodulating cytokines. To analyze further the immunological properties of bacterial DNA, three specific aims are proposed: 1) To elucidate the basis of antibody production to bacterial DNA in normal and autoimmune mice immunized with DNA varying in sequence and pattern of base methylation. The influence of the protein carrier will also be tested; 2) To assess the effects of bacterial DNA immunization on renal disease in various lupus models as well as its ability to modify B and T cellular subsets and cytokine production in autoimmune and normal mice; 3) To characterize the molecular properties of anti-dsDNA induced in autoimmune mice by bacterial DNA immunization and their relationship to spontaneous anti-dsDNA and anti-DNA induced in normal mice. Together, these studies will clarify the immunological properties of DNA and provide further insight into the mechanisms by which DNA can drive specific Anti-DNA production in SLE and modify immune cell function in both normal and aberrant immune states.