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

Circadian clock cryptochrome proteins regulate autoimmunity.

Author information

1
Department of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048; caodapi@gmail.com downes@salk.edu evans@salk.edu.
2
Department of Pathology and Laboratory Medicine, LAC+USC Medical Center, Los Angeles, CA 90033.
3
Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037.
4
Department of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
5
Department of Oncology, Xiang An Hospital of Xiamen University, Xiamen 361102, China.
6
Department of Endocrinology, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
7
Department of Systems Biology, Beckman Research Institute, City of Hope National Medical Center, Pasadena, CA 91016.
8
Nomis Foundation Laboratories for Immunobiology and Microbial Pathogenesis, The Salk Institute for Biological Studies, La Jolla, CA 92037.
9
Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599.
10
Sanford Burnham Preybs Medical Discovery Institute, La Jolla, CA 92037.
11
Department of Immunology, Microarray Core Facility, University of Texas Southwestern Medical Center, Dallas, TX 75390.
12
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.
13
Storr Liver Centre, Westmead Institute for Medical Research and Sydney Medical School, University of Sydney, Westmead Hospital, Westmead, NSW 2145, Australia.
14
Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
15
Department of Pathology and Laboratory Medicine, University of California, Los Angeles Medical Center, Los Angeles, CA 90095.
16
Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037; caodapi@gmail.com downes@salk.edu evans@salk.edu.
17
Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037.

Abstract

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

PMID:
29109286
PMCID:
PMC5703267
DOI:
10.1073/pnas.1619119114
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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