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Sci Rep. 2016 Jun 21;6:28065. doi: 10.1038/srep28065.

High salt promotes autoimmunity by TET2-induced DNA demethylation and driving the differentiation of Tfh cells.

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Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Changsha Blood Center, Changsha, Hunan, China.
Clinical medical research center, the Second Clinical medical college of Jinan University (Shenzhen People's Hospital), Shenzhen, Guangdong, China.
Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, USA.
Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.


Follicular helper T cells (Tfh) have been well documented to play a critical role in autoimmunity, such as systemic lupus erythematosus (SLE), by helping B cells. In this study, high salt (sodium chloride, NaCl), under physiological conditions, was demonstrated to increase the differentiation of Tfh. A high-salt diet markedly increased lupus features in MRL/lpr mice. The mechanism is NaCl-induced DNA demethylation via the recruitment of the hydroxytransferase Ten-Eleven Translocation 2 (TET2). Gene silencing of TET2 obviously diminished NaCl-induced Tfh cell polarization in vitro. In addition, the gene expression of sh2d1a, map3k1, spn and stat5b was enhanced after NaCl treatment, consistent with the findings in lupus CD4(+)T cells. However, only spn was directly regulated by TET2, and spn was not the sole target for NaCl. Our findings not only explain the epigenetic mechanisms of high-salt induced autoimmunity but also provide an attractive molecular target for intervention strategies of patients.

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