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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI039824-08
Application #
6654532
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2002-09-01
Project End
2003-06-30
Budget Start
Budget End
Support Year
8
Fiscal Year
2002
Total Cost
Indirect Cost
City
Dallas
State
TX
Country
United States
Zip Code
75390
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