Genetic dissection of Sle1c (130.16)

Abstract

Abstract The Sle1c locus, derived from the NZW mouse strain, is a ~6.5Mb interval located at the telomeric end of chromosome 1. Previous work has shown that when Sle1c is congenically bred onto a B6 background to yield B6. Sle1cw, a mild lupus-like disease occurs in aged mice (>8mo.), indicated by low to moderate levels of anti-nuclear antibodies (ANA) and low incidence of glomerulonephritis (GN). Further phenotypic analyses of this strain reveal decreased T-dependant (TD) immune responses, abnormal germinal centers (GC), increased T cell activation and proliferation, amplification of chronic graft-versus-host disease (cGVHD), and decreased number of regulatory T cells (Tregs). Cr2 is located on the telomeric end of Sle1c. It encodes Complement receptor 1 (CR1) and 2 (CR2) thorough alternative splicing has previously been described as a candidate gene for Sle1c. It was shown with subcongenic strains of Sle1c that cr2w results in the abnormal GC and decreased TD immune response phenotypes. However, cr2w does not account for the other phenotypes. We have created a series of subcongenic strains on the centromeric end of Sle1c that map the T cell activation phenotype to <1Mb. Screening is ongoing for the enhanced cGVHD. This should lead to the identification of the corresponding gene(s). This research is supported by NIH R01 AI1045050