Anti-nuclear autoantibodies (ANA) represent the hallmark of murine and human lupus. The precise cellular and molecular steps leading to the formation of pathogenic ANAs remain poorly understood. We plan to study this by taking advantage of studies that have recently mapped lupus susceptibility loci in the NZM2410 murine model. When the NZM210-derived chromosome 1 interval, l3l is introgressed onto the B6 background, these mice (B6.NZMc1) produce high titres of IgG anti-H2A/H2B/DNA subnucleosome-specific ANAs, that show little reactivity to other chromatin epitopes, and have no avidity for glomerular antigens. In contrast, when the NZM2410-derived chromosome 7 interval, Sle3 (which by itself leads to increased T-cell activation, and reduced activation-induced T-cell death), in introgressed onto the B6.NZMc1 background, these (B6.NZMc1/c7) bicongenic mice develop high titres of ANAs that react strongly with all chromatin epitopes, bind glomerular antigens (i.e., they are """"""""glomerulotrophic"""""""" or """"""""necrophilic""""""""), and precipitate nephritis. This proposal aims to: (1) To define the relative molecular contributions of Sle1 and Sle3 to the generation of necrophilic ANAs, by analyzing monoclonal nuclear- antigen specific -cell hybridomas rescued from B6NZMc7, and B6.NZMc1/c7 congenic strains. The molecular structures, fine-specifications, and necrophilic and pathogenic potential of these mAbs will be analyzed. (2) To define precisely how Sle3 impacts T-cell activation, expansion and tolerance, using a TCR Tg model. (3) To determine if other molecules that modulate T-cell activation, expansion and tolerance, using a TCR Tg model. (3) To determine if other molecules that modulate T-cell activation/tolerance can also collaborate with Sle1, to generate nephrophilic ANAs, by analyzing B6.NZMc1 mice that also bear the CD43++ knockout, or the lpr allele, for serological and clinical evidence of component lupus phenotypes.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Immunological Sciences Study Section (IMS)
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Collier, Elaine S
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University of Texas Sw Medical Center Dallas
Internal Medicine/Medicine
Schools of Medicine
United States
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