The Journal of Experimental Medicine
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Published 5 August 2002. doi:10.1084/jem.20010955
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© Rockefeller University Press, 0022-1007/2002/8/281/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 3, August 5, 2002 281-292

Genetic Dissection of SLE : SLE1 and FAS Impact Alternate Pathways Leading to Lymphoproliferative Autoimmunity



Xiaoyan Shi1, Chun Xie1, Desi Kreska1, James A. Richardson2 and Chandra Mohan1

1 Simmon's Arthritis Research Center and the Center for Immunology, University of Texas Southwestern Medical School, Dallas, TX 75235
2 Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX 75235

Address for correspondence to Chandra Mohan, Simmons Arthritis Research Center, Dept. of Internal Medicine/Rheumatology, UT Southwestern Medical Center Mail Code 8884, Y8.204 5323 Harry Hines Boulevard, Dallas, TX 75390-8884. Phone: 214-648-9675; Fax: 214-648-7995; E-mail: Chandra.mohan{at}utsouthwestern.edu

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.

Key Words: lupus • genetics • apoptosis • ALPS • anti-DNA


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