Circadian clock cryptochrome proteins regulate autoimmunity
| Autor: | Lauren A. Mack, Christopher Liddle, Sigal Gery, Zhengshan Chen, Qi Cao, Henry Yang, Xianping Shi, Xuan Zhao, Haibo Sun, De-Chen Lin, Qi Chen, Jonathan W. Said, Serhan Alkan, Jing-Wen Bai, Ruishu Deng, Ling Wa Chong, Markus Müschen, Michael Downes, Ronald M. Evans, Jian-Jun Xie, Han Cho, Ruth T. Yu, Annette R. Atkins, Ye Zheng, Quan Zhen Li, H. Phillip Koeffler |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Cell Circadian clock Autoimmunity medicine.disease_cause Kidney Inbred C57BL Lymphocyte Activation chemistry.chemical_compound Mice Antinuclear Receptors 2.1 Biological and endogenous factors Aetiology Lung Mice Knockout B-Lymphocytes Multidisciplinary Biological Sciences Cell biology medicine.anatomical_structure Antibodies Antinuclear Antigen cryptochrome Signal transduction Sleep Research Signal Transduction endocrine system Knockout 1.1 Normal biological development and functioning B-cell receptor Receptors Antigen B-Cell Lupus Biology Autoimmune Disease Antibodies Autoimmune Diseases Vaccine Related 03 medical and health sciences Immune system Underpinning research Circadian Clocks Biodefense medicine Animals B cell B cell receptor Gene Expression Profiling Complement C1q Prevention Inflammatory and immune system B-Cell Tyrosine phosphorylation autoimmune Mice Inbred C57BL Cryptochromes 030104 developmental biology Emerging Infectious Diseases chemistry Gene Expression Regulation Immunology Spleen |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America, vol 114, iss 47 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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