Genetic dissection of SLE: SLE1 and FAS impact alternate pathways leading to lymphoproliferative autoimmunity.
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 FAS(lpr) 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 FAS(lpr) functions as a recessive gene, Sle1 exhibits a gene dosage effect. These studies indicate that Sle1 and FAS(lpr) must be impacting alternate pathways leading to lymphoproliferative autoimmunity.
Shi
Xiaoyan
X
Simmon's Arthritis Research Center and the Center for Immunology, University of Texas Southwestern Medical School, Dallas 75235, USA.
Xie
Chun
C
Kreska
Desi
D
Richardson
James A
JA
Mohan
Chandra
C
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D001323:Autoantibodies / Q000097:blood; D001327:Autoimmune Diseases / Q000209:etiology*; D016516:CD4-CD8 Ratio; D002478:Cells, Cultured; D002874:Chromosome Mapping; D018628:Gene Dosage; D005921:Glomerulonephritis / Q000209:etiology; D007074:Immunoglobulin G / Q000096:biosynthesis; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008232:Lymphoproliferative Disorders / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D013163:Splenomegaly / Q000209:etiology
D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D007074:Immunoglobulin G