Functional dissection of lupus pathogenesis using B6 congenic strains, bearing NZM2410-derived lupus susceptibility intervals (Sle1, Sle2 and Sle3) have collectively added fresh insights to our understanding of this disease, In effect these efforts have collapsed the problem of understanding a polygenic (and hence, multi-factorial) disease into a series of monogenic (and hopefully, unifactorial models) These studies allude to the existence of 3 distinct genetically-programmed pathogenic steps: Initial breach in tolerance to chromatin, """"""""pathogenic maturation"""""""" of the initial response., and finally, end-organ damage. Sle1 appears to trigger the first process, since it apparently leads to anti-chromatin autoimmunity, in a surprisingly, antigen-specific manner. In contrast, Sl32 and Sl32 appear to impact the immune system in a generalized fashion (leading to B-cell hyperactivity, and -cell aberrations, respectively), in effect, promoting the """"""""pathogenic maturation"""""""" of anti- nuclear autoantibodies. Finally, how the Sle loci might facilitate end- organ damage remains unknown. In addition, what role(s) T-cells play in these 3 events is also not clear. This proposal aims to address these knowledge gaps, with the following specific aims. (1) To determine the role of T-cells in mediating the genetically dictated pathogenic processes leading to lupus nephritis. We will test this hypothesis by breeding the TCR -/- mutation onto selected B6.SLE congenics. (2) To gauge the complexity versus clonality of the T-cell repertoire mediating the genetically dictated pathogenic processes leading to lupus nephritis. This will be tested by analyzing the TCR repertoire by FACS analysis and TCR V CDR3 spectratyping in lymphoid and intrarenal T- cells isolated from selected B6. Sle congenics. (3) To define the role of B-cells and autoantibodies in mediating renal pathology in the B6.Sle polycongenic model. This will be verified by breeding either the Igh-/- (lacking B-cells and Ig), or the slgM-/- (lacking Ig but not B-cells) onto selected B6.Sle congenics. (4) To determine if the Sle loci confer intrinsic renal susceptibility to nephrophilic autoantibody-mediated damage. This will be tested by exposing and studying kidneys bearing different genotypes to potentially pathogenic autoantibodies.
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