Congenic Dissection of Swr Lupus Susceptibility Genes

Swrl-1 is a SWR derived lupus susceptibility locus on distal chromosome 1 mapped in NZB/SWR crosses (2001 J Immunol 167: 7141). This locus was linked to IgG antinuclear autoantibodies in the original cross. The Swrl-1 locus (from 75 Mb to 179 Mb on chromosome 1) has been bred from SWR mice onto the non-autoimmune B6 background, as a congenic interval, using marker assisted selection. B6.Swrl1 congenic mice and B6 controls were aged till 9–12 months, and phenotyped for evidence of lupus. Compared to the B6 controls, B6.Swrl1 female mice had increased levels of serum IgG anti-dsDNA antibodies (OD 0.242 vs 0.116, P < 0.05; N=5 mice per group), IgG anti-histone/DNA antibodies ( OD 0.984 vs 0.386, P<0.001), with the differences being less pronounced among males. When spleens were examined, B6.Swrl1 mice exhibited increased spleen weights (92 vs 72 mg, N =6 ) with total cell numbers. This increase was contributed in part from increased numbers of CD4+ (P<0.05) and CD8+ T-cells (P<0.01), particularly activated T-cells. Finally, when examined for evidence of renal disease, B6.Swrl1 mice exhibited higher urine protein and mild GN without crescents or azotemia. Collectively, these studies indicate the presence of a potent SWR-derived lupus susceptibility locus on distal chromosome 1 that influences autoantibody production, T-cell activation and renal disease.