TY - JOUR
T1 - Genetic dissection of SLE
T2 - Sle1 and FAS impact alternate pathways leading to lymphoproliferative autoimmunity
AU - Shi, Xiaoyan
AU - Xie, Chun
AU - Kreska, Desi
AU - Richardson, James A.
AU - Mohan, Chandra
PY - 2002/8/5
Y1 - 2002/8/5
N2 - 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.
AB - 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.
KW - ALPS
KW - Anti-DNA
KW - Apoptosis
KW - Genetics
KW - Lupus
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U2 - 10.1084/jem.20010955
DO - 10.1084/jem.20010955
M3 - Article
C2 - 12163557
AN - SCOPUS:0037025942
SN - 0022-1007
VL - 196
SP - 281
EP - 292
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 3
ER -