Circadian clock cryptochrome proteins regulate autoimmunity

Abstract

The circadian system regulates numerous physiological processes including immune responses. Here, we show that mice deficient of the circadian clock genes <i>Cry1</i> and <i>Cry2</i> [<i>Cry</i> double knockout (DKO)] develop an autoimmune phenotype including high serum IgG concentrations, serum antinuclear antibodies, and precipitation of IgG, IgM, and complement 3 in glomeruli and massive infiltration of leukocytes into the lungs and kidneys. Flow cytometry of lymphoid organs revealed decreased pre-B cell numbers and a higher percentage of mature recirculating B cells in the bone marrow, as well as increased numbers of B2 B cells in the peritoneal cavity of <i>Cry</i> DKO mice. The B cell receptor (BCR) proximal signaling pathway plays a critical role in autoimmunity regulation. Activation of <i>Cry</i> DKO splenic B cells elicited markedly enhanced tyrosine phosphorylation of cellular proteins compared with cells from control mice, suggesting that overactivation of the BCR-signaling pathway may contribute to the autoimmunity phenotype in the <i>Cry</i> DKO mice. In addition, the expression of <i>C1q</i>, the deficiency of which contributes to the pathogenesis of systemic lupus erythematosus, was significantly down-regulated in <i>Cry</i> DKO B cells. Our results suggest that B cell development, the BCR-signaling pathway, and <i>C1q</i> expression are regulated by circadian clock CRY proteins and that their dysregulation through loss of CRY contributes to autoimmunity.