TY - JOUR
T1 - Genetic dissection of lupus pathogenesis
T2 - A recipe for nephrophilic autoantibodies
AU - Mohan, Chandra
AU - Morel, Laurence
AU - Yang, Ping
AU - Watanabe, Hiroshi
AU - Croker, Byron
AU - Gilkeson, Gary
AU - Wakeland, Edward K.
PY - 1999/6
Y1 - 1999/6
N2 - Sle1 and Sle3 are 2 loci that confer susceptibility to lupus nephritis in the 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 develop any pathogenic autoantibodies or disease. B6.NZMc7 mice, congenic for Sle3, exhibit low-grade polyclonal B- and T-cell activation, elevated CD4/CD8 ratios, and mildly penetrant glomerulonephritis. In contrast to these monocongenics, 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- stranded DNA), intact glomeruli, and basement membrane matrix antigens. As one might predict, these mice, particularly the females, exhibit highly penetrant glomerulonephritis. These findings lend strong support to a two- step epistatic model for the formation of pathogenic, nephrophilic autoantibodies in lupus. Whereas loci such as Sle1 may serve to breach tolerance to chromatin, full-blown pathogenic maturation of the autoantibody response appears to require additional input from other loci (such as Sle3) and gender-based factors.
AB - Sle1 and Sle3 are 2 loci that confer susceptibility to lupus nephritis in the 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 develop any pathogenic autoantibodies or disease. B6.NZMc7 mice, congenic for Sle3, exhibit low-grade polyclonal B- and T-cell activation, elevated CD4/CD8 ratios, and mildly penetrant glomerulonephritis. In contrast to these monocongenics, 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- stranded DNA), intact glomeruli, and basement membrane matrix antigens. As one might predict, these mice, particularly the females, exhibit highly penetrant glomerulonephritis. These findings lend strong support to a two- step epistatic model for the formation of pathogenic, nephrophilic autoantibodies in lupus. Whereas loci such as Sle1 may serve to breach tolerance to chromatin, full-blown pathogenic maturation of the autoantibody response appears to require additional input from other loci (such as Sle3) and gender-based factors.
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U2 - 10.1172/JCI5827
DO - 10.1172/JCI5827
M3 - Article
C2 - 10377175
AN - SCOPUS:0032743793
SN - 0021-9738
VL - 103
SP - 1685
EP - 1695
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 12
ER -