Genetic dissection of lupus pathogenesis: a recipe for nephrophilic autoantibodies

Sle1 and Sle3 are 2 loci that confer susceptibility to lupus nephritis in t he NZM2410 strain of mice. Our previous work has shown that B6.NZMc1 mice, congenic for Sle1, exhibit loss of tolerance to chromatin but do not develo p any pathogenic autoantibodies or disease. B6.NZMc7 mice, congenic for Sle 3, exhibit low-grade polyclonal B- and T-cell activation, elevated CD4/CD8 ratios, and mildly penetrant glomerulonephritis. In contrast to these monoc ongenics, the present study reveals that B6.NZMc1 \ c7 mice, bicongenic for Sle1 and Sle3, exhibit splenomegaly, significantly expanded populations of activated B and CD4(+) T cells, and a robust, variegated IgG autoantibody response targeting multiple components of chromatin (including double-stran ded DNA), intact glomeruli, and basement membrane matrix antigens. As one m ight predict, these mice, particularly the females, exhibit highly penetran t glomerulonephritis. These findings lend strong support to a two-step epistatic model for the fo rmation of pathogenic, nephrophilic autoantibodies in lupus. Whereas loci s uch as Sle1 may serve to breach tolerance to chromatin, full-blown pathogen ic maturation of the autoantibody response appears to require additional in put from other loci (such as Sle3) and gender-based factors.