CRAC Channel Controls the Differentiation of Pathogenic B Cells in Lupus Nephritis.
CRAC Channel Controls the Differentiation of Pathogenic B Cells in Lupus Nephritis.
复制标题
DOI：
10.3389/fimmu.2021.779560
复制
发表时间：
2021
影响因子：
7.3
通讯作者：
Yang N
中科院分区：
文献类型：
--
作者：
Li X;Zeng Q;Wang S;Li M;Chen X;Huang Y;Chen B;Zhou M;Lai Y;Guo C;Zhao S;Zhang H;Yang N
钙库操作的钙释放激活的钙通道(CRAC)是淋巴细胞内钙内流的主要途径，在免疫应答中起重要作用。狼疮性肾炎(LN)是一种自身免疫性疾病，其特征是由于免疫耐受的广泛丧失而产生自身抗体。在本研究中，RNA-seq分析显示LN患者幼稚B细胞的钙跨膜转运和钙通道活性增强。流式细胞仪和Western印迹分析证实LN患者幼稚B细胞中ORAI1、ORAI2和STIM2的表达增加，提示CRAC通道在LN的B细胞调节异常中起作用。在体外研究中，YM-58483抑制CRAc通道或ORAI1特异性小干扰核糖核酸下调人B细胞中钙/钙调蛋白依赖性蛋白激酶2的磷酸化，抑制Blimp-1的表达，导致B细胞分化和免疫球蛋白G产生减少。经CaMK2特异性siRNA处理的B细胞在浆细胞分化和免疫球蛋白生成方面存在缺陷。在体内实验中，YM-58483不仅改善了LN的进展，而且还阻止了LN的发展。经YM-58483治疗后，狼疮小鼠脾内浆细胞百分率明显降低，血清中抗双链抗体浓度明显降低。重要的是，用YM-58483治疗的小鼠显示出肾小球中免疫沉积的减少和肾脏损伤的减轻，这在NZM2328狼疮小鼠中得到了进一步证实。总之，CRAC通道控制了致病B细胞的分化，促进了LN的进展。本研究为探讨LN的发病机制和CRAC通道可能成为治疗LN的潜在靶点提供了新的思路。
Store-operated Ca2+ release-activated Ca2+ (CRAC) channel is the main Ca2+ 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 Ca2+/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 glomeruli and alleviated kidney damage, which was further confirmed in NZM2328 lupus mice. Collectively, CRAC channel controlled the differentiation of pathogenic B cells and promoted the progression of LN. This study provides insights into the pathogenic mechanisms of LN and that CRAC channel could serve as a potential therapeutic target for LN.
登录
查看更多内容
影响因子：
7.3
作者：
Ferretti AP;Bhargava R;Dahan S;Tsokos MG;Tsokos GC
通讯作者：
Tsokos GC
影响因子：
4
作者：
Berry CT;May MJ;Freedman BD
通讯作者：
Freedman BD
影响因子：
158.5
作者：
Furie, Richard;Rovin, Brad H.;Roth, David A.
通讯作者：
Roth, David A.
影响因子：
64.8
作者：
Lewis, Richard S.
通讯作者：
Lewis, Richard S.
影响因子：
32.4
作者：
Jenks SA;Cashman KS;Zumaquero E;Marigorta UM;Patel AV;Wang X;Tomar D;Woodruff MC;Simon Z;Bugrovsky R;Blalock EL;Scharer CD;Tipton CM;Wei C;Lim SS;Petri M;Niewold TB;Anolik JH;Gibson G;Lee FE;Boss JM;Lund FE;Sanz I
通讯作者：
Sanz I