Defining genetic pathways to severe systemic autoimmunity

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We propose to identify and characterize the genetic and immunologic mechanisms that mediate the transition from benign autoimmunity into pathogenic autoimmunity in our B6-congenic models of murine lupus. We previously demonstrated that Sle1mediates a breach in immunologic tolerance that causesa relatively benign autoimmune phenotype characterized by the production of anti-nuclear autoantibodies with little or no kidney disease. The introgression of either S/e3 or Sle5 onto BQ.SIel (to produce BQ.SIe1Sle3 or B6.S/e7S/e5 bi-congenics) will drive the development of severe systemic autoimmunity and fatal glomerulonephritis. The overall goal of this project will be to identify the gene or genes responsible for the S/e3 and S/e5 phenotypes and to characterizetheir functional roles in the conversion of "benign" autoimmunity into pathogenic autoimmunity. We have two specific aims. Aim 1 will fine map and identify the causative alleles for three phenotypes associated with the S/e3 congenic interval. The S/e3 phenotypes are: 1) in vivo transition to fatal lupus nephritis with severe IgG humoral autoimmunity in combination with Sle1; 2) variations in cytokine and gene expression profiles of B6 versus B6.S/e3 bone-marrow derived macrophage and dendritic cell cultures; and 3) increased susceptibility of B6.S/e3 mice to kidney glomerulonephritis induced by rabbit anti-mouse glomerulus antiserum. This analysis will identify the causative alleles for each of these phenotypes and assess their role in autoimmune pathogenesis. The second specific aim will be to identify the causative allele or alleles in the S/e5 congenic interval that are responsible for two phenotypes. These phenotypes are:1) in vivo transition to fatal disease in combination with Sle1; and 2) B cell functional polymorphisms leading to B cell expansions in vivo and increased production of IgM autoantibodies recognizing a variety of autoantigens. We have produced a series of truncated congenic strains across the S/e3 and S/e5 congenic intervals that will facilitate the fine mapping of the loci that control these phenotypes and have developed an integrated strategy employing genomic analysis and high resolution meiotic recombination to identify specific disease genes. These studies will provide important new insights into the genetic mechanisms that mediate the transition of benign autoimmunity into severe disease.