Genetic dissection of SLE: Sle1 and FAS impact alternate pathways leading to lymphoproliferative autoimmunity

Xiaoyan Shi, Chun Xie, Desi Kreska, James A. Richardson, Chandra Mohan

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

Genetic dissection of lupus pathogenesis in the NZM2410 strain has recently revealed that Sle1 is a potent locus that triggers the formation of IgG anti-histone/DNA antibodies, when expressed on the B6 background as a congenic interval. B6.lpr mice, in contrast, exhibit distinctly different cellular and serological phenotypes. Both strains, however, do not usually exhibit pathogenic autoantibodies, or succumb to lupus nephritis. In this study, we show that the epistatic interaction of Sle1 (in particular, Sle1/Sle1) with FASlpr leads to massive lymphosplenomegaly (with elevated numbers of activated CD4 T cells, CD4-CD8- double negative (DN) T cells, and B1a cells), high levels of IgG and IgM antinuclear (including anti-ssDNA, anti-dsDNA, and anti-histone/DNA), and antiglomerular autoantibodies, histological, and clinical evidence of glomerulonephritis, and >80% mortality by 5-6 mo of age. Whereas FASlpr functions as a recessive gene, Sle1 exhibits a gene dosage effect. These studies indicate that Sle1 and FASlpr must be impacting alternate pathways leading to lymphoproliferative autoimmunity.

Original languageEnglish (US)
Pages (from-to)281-292
Number of pages12
JournalJournal of Experimental Medicine
Volume196
Issue number3
DOIs
StatePublished - Aug 5 2002

Keywords

  • ALPS
  • Anti-DNA
  • Apoptosis
  • Genetics
  • Lupus

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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