Cyclin-dependent kinase inhibitor Cdkn2c regulates B cell homeostasis and function in the NZM2410-derived murine lupus susceptibility locus Sle2c1

Zhiwei Xu, Hari Hara S K Potula, Anusha Vallurupalli, Daniel Perry, Henry Baker, Byron P. Croker, Igor Dozmorov, Laurence Morel

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Abstract

Sle2c1 is an NZM2410- and NZB-derived lupus susceptibility locus that induces an expansion of the B1a cell compartment. B1a cells have a repertoire enriched for autoreactivity, and an expansion of this B cell subset occurs in several mouse models of lupus. A combination of genetic mapping and candidate gene analysis presents Cdkn2c, a gene encoding for cyclin-dependent kinase inhibitor p18INK4c (p18), as the top candidate gene for inducing the Slec2c1-associated expansion of B1a cells. A novel single nucleotide polymorphism in the NZB allele of the Cdkn2c promoter is associated with a significantly reduced Cdkn2c expression in the splenic B cells and peritoneal cavity B1a cells from Sle2c1-carrying mice, which leads to a defective G1 cell cycle arrest in splenic B cells and increased proliferation of peritoneal cavity B1a cells. As the cell cycle is differentially regulated in B1a and B2 cells, these results suggest that Cdkn2c plays a critical role in B1a cell self-renewal and that its impaired expression leads to an accumulation of these cells with high autoreactive potential.

Original languageEnglish (US)
Pages (from-to)6673-6682
Number of pages10
JournalJournal of Immunology
Volume186
Issue number12
DOIs
StatePublished - Jun 15 2011

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Cyclin-Dependent Kinases
Homeostasis
B-Lymphocytes
Peritoneal Cavity
G1 Phase Cell Cycle Checkpoints
B-Lymphocyte Subsets
Genetic Association Studies
Genes
Single Nucleotide Polymorphism
Cell Cycle
Alleles
Cell Proliferation

ASJC Scopus subject areas

  • Immunology

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Cyclin-dependent kinase inhibitor Cdkn2c regulates B cell homeostasis and function in the NZM2410-derived murine lupus susceptibility locus Sle2c1. / Xu, Zhiwei; Potula, Hari Hara S K; Vallurupalli, Anusha; Perry, Daniel; Baker, Henry; Croker, Byron P.; Dozmorov, Igor; Morel, Laurence.

In: Journal of Immunology, Vol. 186, No. 12, 15.06.2011, p. 6673-6682.

Research output: Contribution to journalArticle

Xu, Zhiwei ; Potula, Hari Hara S K ; Vallurupalli, Anusha ; Perry, Daniel ; Baker, Henry ; Croker, Byron P. ; Dozmorov, Igor ; Morel, Laurence. / Cyclin-dependent kinase inhibitor Cdkn2c regulates B cell homeostasis and function in the NZM2410-derived murine lupus susceptibility locus Sle2c1. In: Journal of Immunology. 2011 ; Vol. 186, No. 12. pp. 6673-6682.
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