Genetic dissection of Sle pathogenesis: Sle3 on murine chromosome 7 impacts T cell activation, differentiation, and cell death

Chandra Mohan, Ying Yu, Laurence Morel, Ping Yang, Edward K. Wakeland

Research output: Contribution to journalArticle

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Abstract

Polyclonal, generalized T cell defects, as well as Ag-specific Th clones, are likely to contribute to pathology in murine lupus, but the genetic bases for these mechanisms remain unknown. Mapping studies indicate that loci on chromosomes 1 (Sle1), 4 (Sle2), 7 (Sle3), and 17 (Sle4) confer disease susceptibility in the NZM2410 lupus strain. B6.NZMc7 mice are C57BL/6 (B6) mice congenic for the NZM2410-derived chromosome 7 susceptibility interval, bearing Sle3. Compared with B6 controls, B6.NZMc7 mice exhibit elevated CD4:CD8 ratios (2.0 vs 1.34 in 1- to 3-mo-old spleens); an age- dependent accumulation of activated CD4+ T cells (33.4% vs 21.9% in 9- to 12-mo-old spleens); a more diffuse splenic architecture; and a stronger immune response to T-dependent, but not T-independent, Ags. In vitro, Sle3- bearing T cells show stronger proliferation, increased expansion of CD4+ T cells, and reduced apoptosis (with or without anti-Fas) following stimulation with anti-CD3. With age, the B cells in this strain acquire an activated phenotype. Thus, the NZM2410 allele of Sle3 appears to impact generalized T cell activation, and this may be causally related to the low grade, polyclonal serum autoantibodies seen in this strain. Epistatic interactions with other loci may be required to transform this relatively benign phenotype into overt autoimmunity, as seen in the NZM2410 strain.

Original languageEnglish (US)
Pages (from-to)6492-6502
Number of pages11
JournalJournal of Immunology
Volume162
Issue number11
StatePublished - Jun 1 1999

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Chromosomes, Human, Pair 7
Dissection
Cell Differentiation
Cell Death
T-Lymphocytes
Spleen
Congenic Mice
Phenotype
CD4-CD8 Ratio
Chromosomes, Human, Pair 1
Disease Susceptibility
Autoimmunity
Inbred C57BL Mouse
Autoantibodies
B-Lymphocytes
Clone Cells
Alleles
Apoptosis
Pathology
Serum

ASJC Scopus subject areas

  • Immunology

Cite this

Genetic dissection of Sle pathogenesis : Sle3 on murine chromosome 7 impacts T cell activation, differentiation, and cell death. / Mohan, Chandra; Yu, Ying; Morel, Laurence; Yang, Ping; Wakeland, Edward K.

In: Journal of Immunology, Vol. 162, No. 11, 01.06.1999, p. 6492-6502.

Research output: Contribution to journalArticle

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abstract = "Polyclonal, generalized T cell defects, as well as Ag-specific Th clones, are likely to contribute to pathology in murine lupus, but the genetic bases for these mechanisms remain unknown. Mapping studies indicate that loci on chromosomes 1 (Sle1), 4 (Sle2), 7 (Sle3), and 17 (Sle4) confer disease susceptibility in the NZM2410 lupus strain. B6.NZMc7 mice are C57BL/6 (B6) mice congenic for the NZM2410-derived chromosome 7 susceptibility interval, bearing Sle3. Compared with B6 controls, B6.NZMc7 mice exhibit elevated CD4:CD8 ratios (2.0 vs 1.34 in 1- to 3-mo-old spleens); an age- dependent accumulation of activated CD4+ T cells (33.4{\%} vs 21.9{\%} in 9- to 12-mo-old spleens); a more diffuse splenic architecture; and a stronger immune response to T-dependent, but not T-independent, Ags. In vitro, Sle3- bearing T cells show stronger proliferation, increased expansion of CD4+ T cells, and reduced apoptosis (with or without anti-Fas) following stimulation with anti-CD3. With age, the B cells in this strain acquire an activated phenotype. Thus, the NZM2410 allele of Sle3 appears to impact generalized T cell activation, and this may be causally related to the low grade, polyclonal serum autoantibodies seen in this strain. Epistatic interactions with other loci may be required to transform this relatively benign phenotype into overt autoimmunity, as seen in the NZM2410 strain.",
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