Delineation of genetic pathways to lupus pathogenesis

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DESCRIPTION (provided by the applicant): Systemic lupus erythematosus (SLE) is characterized by the presence of anti-nuclear antibodies (ANA) directed against naked DNA and entire nucleosomes. Development of congenic mouse models carrying lupus susceptibility gene intervals has provided powerful tools for studying the mechanism of lupus pathogenesis. Sle1 mediates the loss of tolerance to nuclear antigens and the initiation of autoimmunity. Our recent study demonstrated that Sle1 mediates the abnormal expression of several genes, including the c-myc protooncogene, that control B-cell activation and proliferation. We hypothesize that autoreactive B-cells are generated from B-cell populations that have aberrant c-myc expression. We propose to identify the mechanisms leading to the aberrant c-myc expression and to characterize the B-cell populations that have aberrant c-myc expression in B6.Sle1 mice. We also propose to use powerful, microarray-based approaches to identify the molecular mechanisms by which Sle1 and S1e3 interact to cause lupus. Furthermore, we propose to identify lupus susceptibility gene(s) in the S1e3 interval using fine mapping in combination with functional genomics. By identifying the lupus susceptibility genes and the molecules involved in the pathogenesis, we can select candidate therapeutic targets for curing lupus.