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 and [ 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 DKO mice. The B cell receptor (BCR) proximal signaling pathway plays a critical role in autoimmunity regulation. Activation of 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 DKO mice. In addition, the expression of, the deficiency of which contributes to the pathogenesis of systemic lupus erythematosus, was significantly down-regulated in DKO B cells. Our results suggest that B cell development, the BCR-signaling pathway, and expression are regulated by circadian clock CRY proteins and that their dysregulation through loss of CRY contributes to autoimmunity.

Time-of-Day-Dependent Trafficking and Function of Leukocyte Subsets

“…Cry1 À/À Cry2 À/À double-knockout mice spontaneously develop an autoimmune-like phenotype comprising serum autoantibodies and infiltration of leukocytes into lungs and kidneys [80]. Furthermore, B cell development and maturation are highly impaired in these mice, resulting in the expansion of overactivated B cells in the BM [80].…”

“…Cry1 À/À Cry2 À/À double-knockout mice spontaneously develop an autoimmune-like phenotype comprising serum autoantibodies and infiltration of leukocytes into lungs and kidneys [80]. Furthermore, B cell development and maturation are highly impaired in these mice, resulting in the expansion of overactivated B cells in the BM [80]. In addition, immunization of mice with nitrophenyl-gamma globulin (chicken) yields higher IgG and IgM titers at night than during the day; this indicates that time-specific induction of humoral immune responses can generate higher antibody titers in the host [69].…”

Epigenetic Regulation of Circadian Rhythm and Its Possible Role in Diabetes Mellitus

“…There is evidence that dysregulations of molecular clocks are connected with the emergence of autoimmune diseases. In these cases, simply balancing the circadian rhythm cannot solve the consequences of those diseases [74,131,132].…”

Epigenetic Modulation of Circadian Rhythms: Bmal1 Gene Regulation

“…Circadian rhythms are also associated with diseases other than cancer through effects on the cardiovascular, renal, immune, endocrine, neuropsychiatric and metabolic systems [5,[62][63][64][65][66][67]. Many physiological processes cannot be harmonised when the intrinsic rhythm is aberrant and such dyssynchrony leads to many diseases.…”