Cyclin-dependent kinase inhibitor Cdkn2c deficiency promotes B1a cell expansion and autoimmunity in a mouse model of lupus.

Hari-Hara S K Potula, Zhiwei Xu, Leilani Zeumer, Allison Sang, Byron P Croker, Laurence Morel

Journal of immunology (Baltimore, Md. : 1950) 2012 Sep 15

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The lupus-prone NZM2410 mice present an expanded B1a cell population that we have mapped to the Sle2c1 lupus susceptibility locus. The expression of Cdkn2c, a gene encoding for cyclin-dependent kinase inhibitor p18(Ink4c) and located within Sle2c1, is significantly lower in B6.Sle2c1 B cells than in B6 B cells. To test the hypothesis that the B1a cell expansion in B6.Sle2c1 mice was due to a defective p18 expression, we analyzed the B1a cell phenotypes of p18-deficient C57BL/6 mice. We found a dose-dependent negative correlation between the number of B1a cells and p18 expression in B cells, with p18-deficient mice showing an early expansion of the peritoneal B1a cell pool. p18 deficiency enhanced the homeostatic expansion of B1a cells but not of splenic conventional B cells, and the elevated number of B6.Sle2c1 B1a cells was normalized by cyclin D2 deficiency. These data demonstrated that p18 is a key regulator of the size of the B1a cell pool. B6.p18(-/-) mice produced significant amounts of anti-DNA IgM and IgG, indicating that p18 deficiency contributes to humoral autoimmunity. Finally, we have shown that Sle2c1 increases lpr-associated lymphadenopathy and T cell-mediated pathology. B6.p18(-/-).lpr mice showed a greater lymphadenopathy than B6.Sle2c1.lpr mice, but their renal pathology was intermediate between that of B6.lpr and B6.Sle2c1.lpr mice. This indicated that p18-deficiency synergizes, at least partially, with lpr-mediated pathology. These results show that Cdkn2c contributes to lupus susceptibility by regulating the size of the B1a cell compartment and hence their contribution to autoimmunity.

Citation

Hari-Hara S K Potula, Zhiwei Xu, Leilani Zeumer, Allison Sang, Byron P Croker, Laurence Morel. Cyclin-dependent kinase inhibitor Cdkn2c deficiency promotes B1a cell expansion and autoimmunity in a mouse model of lupus. Journal of immunology (Baltimore, Md. : 1950). 2012 Sep 15;189(6):2931-40