CRAC Channel Controls the Differentiation of Pathogenic B Cells in Lupus Nephritis

作者：Xue Li, Qin Zeng, Shuyi Wang, Mengyuan Li, Xionghui Chen, Yuefang Huang, Binfeng Chen, Mianjing Zhou, Yimei Lai, Chaohuan Guo, Siyuan Zhao, Hui Zhang, Niansheng Yang · 发表于：Frontiers in Immunology · 年份：2021 · DOI：10.3389/fimmu.2021.779560 · 被引用次数：8 · 研究领域：Ion Channels and Receptors、Systemic Lupus Erythematosus Research、Immune Cell Function and Interaction

Store-operated Ca 2+ release-activated Ca 2+ (CRAC) channel is the main Ca 2+ influx pathway in lymphocytes and is essential for immune response. Lupus nephritis (LN) is an autoimmune disease characterized by the production of autoantibodies due to widespread loss of immune tolerance. In this study, RNA-seq analysis revealed that calcium transmembrane transport and calcium channel activity were enhanced in naive B cells from patients with LN. The increased expression of ORAI1, ORAI2, and STIM2 in naive B cells from patients with LN was confirmed by flow cytometry and Western blot, implying a role of CRAC channel in B-cell dysregulation in LN. For in vitro study, CRAC channel inhibition by YM-58483 or downregulation by ORAI1-specific small-interfering RNA (siRNA) decreased the phosphorylation of Ca 2+ /calmodulin-dependent protein kinase2 (CaMK2) and suppressed Blimp-1 expression in primary human B cells, resulting in decreased B-cell differentiation and immunoglobulin G (IgG) production. B cells treated with CaMK2-specific siRNA showed defects in plasma cell differentiation and IgG production. For in vivo study, YM-58483 not only ameliorated the progression of LN but also prevented the development of LN. MRL/ lpr lupus mice treated with YM-58483 showed lower percentage of plasma cells in the spleen and reduced concentration of anti-double-stranded DNA antibodies in the sera significantly. Importantly, mice treated with YM-58483 showed decreased immune deposition in the glomer...