Circadian clock cryptochrome proteins regulate autoimmunity

Proc Natl Acad Sci U S A. 2017 Nov 21;114(47):12548-12553. doi: 10.1073/pnas.1619119114. Epub 2017 Nov 6.


The circadian system regulates numerous physiological processes including immune responses. Here, we show that mice deficient of the circadian clock genes Cry1 and Cry2 [Cry 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 Cry DKO mice. The B cell receptor (BCR) proximal signaling pathway plays a critical role in autoimmunity regulation. Activation of Cry 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 Cry DKO mice. In addition, the expression of C1q, the deficiency of which contributes to the pathogenesis of systemic lupus erythematosus, was significantly down-regulated in Cry DKO B cells. Our results suggest that B cell development, the BCR-signaling pathway, and C1q expression are regulated by circadian clock CRY proteins and that their dysregulation through loss of CRY contributes to autoimmunity.

Keywords: B cell receptor; autoimmune; cryptochrome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Antinuclear / biosynthesis
  • Autoimmune Diseases / genetics
  • Autoimmune Diseases / immunology*
  • Autoimmune Diseases / metabolism
  • Autoimmune Diseases / pathology
  • Autoimmunity / genetics*
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology
  • Circadian Clocks / genetics
  • Circadian Clocks / immunology*
  • Complement C1q / genetics
  • Cryptochromes / deficiency
  • Cryptochromes / genetics
  • Cryptochromes / immunology*
  • Gene Expression Profiling
  • Gene Expression Regulation / immunology
  • Kidney / immunology
  • Kidney / pathology
  • Lung / immunology
  • Lung / pathology
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Antigen, B-Cell / genetics
  • Receptors, Antigen, B-Cell / immunology
  • Signal Transduction
  • Spleen / immunology
  • Spleen / metabolism
  • Spleen / pathology


  • Antibodies, Antinuclear
  • Cry1 protein, mouse
  • Cry2 protein, mouse
  • Cryptochromes
  • Receptors, Antigen, B-Cell
  • Complement C1q