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

63 Citations (Scopus)

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

Fingerprint

Autoimmunity
Autoantibodies
Histones
Dissection
Immunoglobulin G
T-Lymphocytes
Recessive Genes
Lupus Nephritis
Gene Dosage
Antinuclear Antibodies
Glomerulonephritis
Immunoglobulin M
Phenotype
Mortality
DNA

Keywords

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

ASJC Scopus subject areas

  • Immunology

Cite this

Genetic dissection of SLE : Sle1 and FAS impact alternate pathways leading to lymphoproliferative autoimmunity. / Shi, Xiaoyan; Xie, Chun; Kreska, Desi; Richardson, James A.; Mohan, Chandra.

In: Journal of Experimental Medicine, Vol. 196, No. 3, 05.08.2002, p. 281-292.

Research output: Contribution to journalArticle

@article{18f04528423149368b6fc0847d3ddec6,
title = "Genetic dissection of SLE: Sle1 and FAS impact alternate pathways leading to lymphoproliferative autoimmunity",
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.",
keywords = "ALPS, Anti-DNA, Apoptosis, Genetics, Lupus",
author = "Xiaoyan Shi and Chun Xie and Desi Kreska and Richardson, {James A.} and Chandra Mohan",
year = "2002",
month = "8",
day = "5",
doi = "10.1084/jem.20010955",
language = "English (US)",
volume = "196",
pages = "281--292",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "3",

}

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

UR - http://www.scopus.com/inward/record.url?scp=0037025942&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037025942&partnerID=8YFLogxK

U2 - 10.1084/jem.20010955

DO - 10.1084/jem.20010955

M3 - Article

VL - 196

SP - 281

EP - 292

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 3

ER -