免疫球蛋白类转换
生物
CD19
系统性红斑狼疮
B细胞
生发中心
幼稚B细胞
CD40
XBP1型
分子生物学
免疫学
T细胞
抗体
流式细胞术
核糖核酸
体外
免疫系统
细胞毒性T细胞
抗原提呈细胞
内科学
医学
基因
生物化学
RNA剪接
疾病
作者
Xiaoqing Zheng,Mikhail G. Dozmorov,Colleen E Strohlein,Sheldon Bastacky,Amr H. Sawalha
摘要
Objectives EZH2 regulates B cell development and differentiation. We previously demonstrated increased EZH2 expression in peripheral blood mononuclear cells from lupus patients. The goal of this study was to evaluate the role of EZH2 expression in B cells in the pathogenesis of lupus. Methods We generated an MRL/ lpr mouse with floxed Ezh2 , which was crossed with CD19‐Cre mice to examine the effect of B cell EZH2 deficiency in MRL/ lpr lupus‐prone mice. Differentiation of B cells was assessed using flow cytometry. Single‐cell RNA sequencing and single‐cell B cell receptor sequencing were performed. In vitro B cell culture with an X‐box binding protein 1 (XBP1) inhibitor was performed. EZH2 and XBP1 messenger RNA levels in CD19+ B cells isolated from lupus patients and healthy controls were analyzed. Results We show that Ezh2 deletion in B cells significantly decreased autoantibody production and improved glomerulonephritis. B cell development was altered in the bone marrow and spleen of EZH2‐deficient mice. Differentiation of germinal center B cells and plasmablasts was impaired. Single‐cell RNA sequencing showed that XBP1, a key transcription factor in B cell development, is down‐regulated in the absence of EZH2. Inhibiting XBP1 in vitro impairs plasmablast development similar to EZH2 deficiency in mice. Single‐cell B cell receptor RNA sequencing revealed defective immunoglobulin class‐switch recombination in EZH2‐deficient mice. In human lupus B cells, we observed a strong correlation between EZH2 and XBP1 messenger RNA expression levels. Conclusion EZH2 overexpression in B cells contributes to disease pathogenesis in lupus. image
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