Cyclin-dependent kinase inhibitor Cdkn2c regulates B cell homeostasis and function in the NZM2410-derived murine lupus susceptibility locus Sle2c1.
J Immunol, 2011/6/15;186(12):6673-82.
Xu Z[1], Potula HH, Vallurupalli A, Perry D, Baker H, Croker BP, Dozmorov I, Morel L
Affiliations
PMID: 21543644DOI: 10.4049/jimmunol.1002544
Impact factor: 5.426
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 p18(INK4c) (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.
MeSH terms
Animals; Autoimmunity; B-Lymphocyte Subsets; B-Lymphocytes; Cell Cycle; Cell Proliferation; Chromosome Mapping; Cyclin-Dependent Kinase Inhibitor p18; Disease Models, Animal; Genetic Loci; Genetic Predisposition to Disease; Homeostasis; Lupus Erythematosus, Systemic; Lymphocyte Count; Mice; Polymorphism, Single Nucleotide
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