@article{42d046f1e6df44f9bab658744e35812e,
title = "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 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 = "Autoimmune, B cell receptor, Cryptochrome",
author = "Qi Cao and Xuan Zhao and Jingwen Bai and Sigal Gery and Haibo Sun and Lin, {De Chen} and Qi Chen and Zhengshan Chen and Lauren Mack and Henry Yang and Ruishu Deng and Xianping Shi and Chong, {Ling Wa} and Han Cho and Jianjun Xie and Li, {Quan Zhen} and Markus M{\"u}schen and Atkins, {Annette R.} and Christopher Liddle and Yu, {Ruth T.} and Serhan Alkan and Said, {Jonathan W.} and Ye Zheng and Michael Downes and Evans, {Ronald M.} and Koeffler, {H. Phillip}",
note = "Funding Information: ACKNOWLEDGMENTS. This research is supported by the National Research Foundation Singapore under its Singapore Translational Research Investigator Award (NMRC/STaR/0021/2014) and administered by the Singapore Ministry of Health{\textquoteright}s National Medical Research Council (NMRC); by the NMRC Centre Grant awarded to the National University Cancer Institute of Singapore; by the National Research Foundation Singapore; by the Singapore Ministry of Education under its Research Centres of Excellence initiatives; by the Leukemia-Lymphoma Society; and by the generous support of the Melamed Family LLS and Reuben Yeroushlami (Yeroushlami & Associates). R.M.E. was funded by the NIH (Grants DK057978, HL105278, HL088093, ES010337, and CA014195) as well as by the Helmsley Charitable Trust, Leducq Foundation, and Ipsen/Biomeasure. R.M.E is an investigator of the Howard Hughes Medical Institute and March of Dimes Chair in Molecular and Developmental Biology at the Salk Institute. Publisher Copyright: {\textcopyright} 2017, National Academy of Sciences. All rights reserved.",
year = "2017",
month = nov,
day = "21",
doi = "10.1073/pnas.1619119114",
language = "English (US)",
volume = "114",
pages = "12548--12553",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "47",
}