Systemic lupus erythematosus (SLE) is an autoimmune disorder affecting multiple organs with considerable morbidity and mortality. The disorder is characterized by multiple autoantibody production including antinuclear antibodies (ANA and anti-dsDNA antibodies with immune complex formation leading to intense inflammation and end organ damage. Immune complex-mediated glomerulonephritis (GN) is a major manifestation of this disorder. Both genetic and environmental factors play important roles in its pathogenesis. Our laboratory has focused on the origin(s) of the autoantibodies detected in SLE and the genetic factors important in the generation of ANA and anti-dsDNA antibodies and lupus nephritis. Recently, a new model of SLE NZM2328 has been characterized. In this strain, there is female bias for ANA and chronic GN. In a backcross (NZM2328 X C57L/J F1) X NZM2328 analysis, a genetic interval has been identified on chromosome 1 in NZM2328 to control the development of chronic GN. An interval on chromosome 4 was shown to be linked to the production of ANA and anti-dsDNA antibodies. By a marker assisted method, two congenics NZM2328.C57Lc1 and NZM2328.C57L.c4 were generated by moving the genetic segments of interest from chromosomes 1 and 4 respectively from C57L/J to NZM2328. In NZM2328.C57Lc1 little ANA, anti-dsDNA or chronic GN were seen. In contrast in NZM2328.C57Lc4, chronic GN was detected despite marked reductions in ANA and anti dsDNA, dissociating ANA and anti-dsDNA production from lupus nephritis. It appeared that the genetic segment on chromosome 1 controls lupus nephritis and regulates ANA and anti-dsDNA production. These genetic loci have been named Lnc 1, the lupus nephritis controlling gene 1 and Adn1, the anti-dsDNA and ANA production gene 1. For this proposal, Lnc 1 is assumed to be different from Adn1. This application is focused on the elucidation of the cellular and immunochemical basis for autoantibody production and the generation of GN and to identify the genes, Lnc 1 and Adn1.
Four specific aims proposed are (1) to characterize further NZM2328 and its two congenic lines NZM2328.C57Lc1 an NZM2328.C57Lc4; (2) to determine the specificities of immunoglobulins eluted from diseased kidneys from NZM2328.Lc4, clarifying the basis for the dissociation of anti-dsDNA antibody and ANA production from sever proteinuria and chronic GN; (3) to determine the cellular basis of severe proteinuria, chronic GN, and autoantibody production by adoptive cell transfer analysis; and (4) to generate intra c1 congenic recombinant strains from the parental strain NZM2328.C57Lc1, which contain smaller genetic intervals of chromosome 1 derived from C57LIJ to determine the minimal C57L/J genetic segment(s) to suppress anti-dsDNA antibody and ANA production, and/or severe proteinuria an chronic GN. Thus, we will refine the genetics for this interval so that we may identify the genes, Lnc 1 and Adn1, relevant to the phenotypic expression by positional cloning. The results from these experiments will provide us further understanding of the pathogenesis of SLE. This information should lead to orthologous gene(s) identification in the SLE patients and provide us potential targets for more specific and novel therapeutic interventions.
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