Genetic dissection of lupus pathogenesis

A recipe for nephrophilic autoantibodies

Chandra Mohan, Laurence Morel, Ping Yang, Hiroshi Watanabe, Byron Croker, Gary Gilkeson, Edward K. Wakeland

Research output: Contribution to journalArticle

146 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1685-1695
Number of pages11
JournalJournal of Clinical Investigation
Volume103
Issue number12
StatePublished - Jun 1999

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Autoantibodies
Dissection
Congenic Mice
Chromatin
Glomerulonephritis
T-Lymphocytes
CD4-CD8 Ratio
Lupus Nephritis
Splenomegaly
Basement Membrane
Immunoglobulin G
Antigens
DNA
Population

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Mohan, C., Morel, L., Yang, P., Watanabe, H., Croker, B., Gilkeson, G., & Wakeland, E. K. (1999). Genetic dissection of lupus pathogenesis: A recipe for nephrophilic autoantibodies. Journal of Clinical Investigation, 103(12), 1685-1695.

Genetic dissection of lupus pathogenesis : A recipe for nephrophilic autoantibodies. / Mohan, Chandra; Morel, Laurence; Yang, Ping; Watanabe, Hiroshi; Croker, Byron; Gilkeson, Gary; Wakeland, Edward K.

In: Journal of Clinical Investigation, Vol. 103, No. 12, 06.1999, p. 1685-1695.

Research output: Contribution to journalArticle

Mohan, C, Morel, L, Yang, P, Watanabe, H, Croker, B, Gilkeson, G & Wakeland, EK 1999, 'Genetic dissection of lupus pathogenesis: A recipe for nephrophilic autoantibodies', Journal of Clinical Investigation, vol. 103, no. 12, pp. 1685-1695.
Mohan C, Morel L, Yang P, Watanabe H, Croker B, Gilkeson G et al. Genetic dissection of lupus pathogenesis: A recipe for nephrophilic autoantibodies. Journal of Clinical Investigation. 1999 Jun;103(12):1685-1695.
Mohan, Chandra ; Morel, Laurence ; Yang, Ping ; Watanabe, Hiroshi ; Croker, Byron ; Gilkeson, Gary ; Wakeland, Edward K. / Genetic dissection of lupus pathogenesis : A recipe for nephrophilic autoantibodies. In: Journal of Clinical Investigation. 1999 ; Vol. 103, No. 12. pp. 1685-1695.
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