Genetic Dissection of Systemic Lupus Erythematosu Pathogenesis

Sle2 on Murine Chromosome 4 Leads to B Cell Hyperactivity

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

Research output: Contribution to journalArticle

188 Citations (Scopus)

Abstract

Susceptibility to systemic lupus erythematosus in the NZM2410 murine model maps to Sle1, Sle2, Sle3, and the H2 loci. To unravel how these loci contribute to the pathogenesis of lupus, individual NZM2410-derived genomic intervals bearing these loci have been successfully backcrossed onto the resistant C57BL/6 (B6) background. The focus of this study was to understand how Sle2 on murine chromosome 4 impacts the immune system. Compared with C57BL/6 (B6) mice, B6 mice congenic for Sle2 exhibit a variety of immunophenotypes affecting their B cells. They have an early, but transient, expansion of splenic, CD23low B cells. Thereafter, their B cells appear activated by surface phenotype and functional criteria, paralleled by elevated serum levels of polyreactive/polyclonal IgM. Importantly, Sle2 leads to a heightened B cell responsiveness to in vitro stimuli and to in vivo antigenic challenge. Finally, they exhibit increased levels of peritoneal and splenic B1 cells. Thus, Sle2 harbors a gene that leads to B cell hyperactivity and elevated B1 cell formation. However, Sle2 by itself on the normal B6 background is insufficient to generate IgG antinuclear Abs (ANA) or nephritis. By reducing the B cell signaling threshold, Sle2 might serve to amplify an ongoing autolmmune response.

Original languageEnglish (US)
Pages (from-to)454-465
Number of pages12
JournalJournal of Immunology
Volume159
Issue number1
StatePublished - 1997

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Chromosomes, Human, Pair 4
Dissection
B-Lymphocytes
Congenic Mice
Nephritis
Systemic Lupus Erythematosus
Immunoglobulin M
Immune System
Immunoglobulin G
Phenotype
Serum
Genes

ASJC Scopus subject areas

  • Immunology

Cite this

Genetic Dissection of Systemic Lupus Erythematosu Pathogenesis : Sle2 on Murine Chromosome 4 Leads to B Cell Hyperactivity. / Mohan, Chandra; Morel, Laurence; Yang, Ping; Wakeland, Edward K.

In: Journal of Immunology, Vol. 159, No. 1, 1997, p. 454-465.

Research output: Contribution to journalArticle

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abstract = "Susceptibility to systemic lupus erythematosus in the NZM2410 murine model maps to Sle1, Sle2, Sle3, and the H2 loci. To unravel how these loci contribute to the pathogenesis of lupus, individual NZM2410-derived genomic intervals bearing these loci have been successfully backcrossed onto the resistant C57BL/6 (B6) background. The focus of this study was to understand how Sle2 on murine chromosome 4 impacts the immune system. Compared with C57BL/6 (B6) mice, B6 mice congenic for Sle2 exhibit a variety of immunophenotypes affecting their B cells. They have an early, but transient, expansion of splenic, CD23low B cells. Thereafter, their B cells appear activated by surface phenotype and functional criteria, paralleled by elevated serum levels of polyreactive/polyclonal IgM. Importantly, Sle2 leads to a heightened B cell responsiveness to in vitro stimuli and to in vivo antigenic challenge. Finally, they exhibit increased levels of peritoneal and splenic B1 cells. Thus, Sle2 harbors a gene that leads to B cell hyperactivity and elevated B1 cell formation. However, Sle2 by itself on the normal B6 background is insufficient to generate IgG antinuclear Abs (ANA) or nephritis. By reducing the B cell signaling threshold, Sle2 might serve to amplify an ongoing autolmmune response.",
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