Autoimmunity is the antecedent to most glomerulonephritis, the most common cause of end stage renal disease worldwide. Yet rudimentary understanding of etiology compels reliance on non-specific toxic immunosuppressive therapy. We developed Ig transgenic (Tg) mice bearing B cells reactive with nephritogenic antigens (Ag) as tools to dissect mechanisms controlling humoral autoimmunity that destroys kidney. We postulate that: a) B cells reactive with structurally diverse self-Ag relevant to renal injury are regulated by diverse mechanisms; b) There are differences in molecular pathways maintaining B cell tolerance to nephritogenic Ag in autoimmune vs nonautoimmune individuals, and between individuals bearing different constellations of susceptibility genes; and, c) There are fundamental differences in regulation of B cells that promote nephritis in systemic versus organ-restricted disease. This predicts that different regulatory mechanisms are breached in different autoimmune nephritides. We will use Ig Tg models to pursue the following Specific Aims: 1) Determine the role of deletion and anergy in regulating B cells reactive with basement membrane, the only confirmed target in human autoimmune nephritis. Inactivated Rag or endogenous Ig genes will link cell fate to Ag specificity using anti-laminin LamH/LamL and duat specific LamH/VSR """"""""monoclonal"""""""" H+L Ig Tg mice in which collateral regulatory influences are eliminated. 2) Dissect the molecular basis of genetic modification of B cell tolerance. Microarray will be used to monitor and analyze transcriptional profiles in receptor-stimulated tolerant Tg cells from autoimmune MRL and nonsusceptible B6 mice to reveal central regulatory pathways. The LamH Tg, with a well defined tolerance phenotype, will also be established on nephritis-prone (NZBxNZW)F1 and BXSB strains to determine if a single Ag-receptor interaction is differentially tolerogenic in genetically disparate disease-susceptible hosts. 3) Determine and compare the fate of kidney-reactive 238H Ig and anti-alpha3(IV) NC1 collagen Tg B cells associated with nephritis in systemic versus renal-limited autoimmunity, respectively. This will assess contributions of nucleic acid crossreactivity and Ag sequestration, factors known to impact immune deposition, to regulation of nephritogenic B cells. Collectively these studies will identify regulatory pathways to be targeted for tailored pharmacologic intervention in immunologic renal disease.
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