The transcription factor ZEB2 drives the formation of age-associated B cells

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Science Pub Date : 2024-01-25 DOI:10.1126/science.adf8531

Dai Dai, Shuangshuang Gu, Xiaxia Han, Huihua Ding, Yang Jiang, Xiaoou Zhang, Chao Yao, Soonmin Hong, Jinsong Zhang, Yiwei Shen, Guojun Hou, Bo Qu, Haibo Zhou, Yuting Qin, Yuke He, Jianyang Ma, Zhihua Yin, Zhizhong Ye, Jie Qian, Qian Jiang, Lihua Wu, Qiang Guo, Sheng Chen, Chuanxin Huang, Leah C. Kottyan, Matthew T. Weirauch, Carola G. Vinuesa, Nan Shen

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Abstract

Age-associated B cells (ABCs) accumulate during infection, aging, and autoimmunity, contributing to lupus pathogenesis. In this study, we screened for transcription factors driving ABC formation and found that zinc finger E-box binding homeobox 2 (ZEB2) is required for human and mouse ABC differentiation in vitro. ABCs are reduced in ZEB2 haploinsufficient individuals and in mice lacking Zeb2 in B cells. In mice with toll-like receptor 7 (TLR7)–driven lupus, ZEB2 is essential for ABC formation and autoimmune pathology. ZEB2 binds to +20-kb myocyte enhancer factor 2b (Mef2b)’s intronic enhancer, repressing MEF2B-mediated germinal center B cell differentiation and promoting ABC formation. ZEB2 also targets genes important for ABC specification and function, including Itgax. ZEB2-driven ABC differentiation requires JAK-STAT (Janus kinase-signal transducer and activator of transcription), and treatment with JAK1/3 inhibitor reduces ABC accumulation in autoimmune mice and patients. Thus, ZEB2 emerges as a driver of B cell autoimmunity.

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转录因子 ZEB2 驱动年龄相关 B 细胞的形成。

年龄相关 B 细胞（ABC）会在感染、衰老和自身免疫过程中积聚，导致狼疮发病。在这项研究中，我们筛选了驱动ABC形成的转录因子，发现锌指E盒结合同源框2（ZEB2）是人类和小鼠体外ABC分化所必需的。在 ZEB2 单倍性不足的个体和 B 细胞中缺乏 Zeb2 的小鼠中，ABC 会减少。在收费样受体 7（TLR7）驱动的红斑狼疮小鼠中，ZEB2 对 ABC 的形成和自身免疫病理学至关重要。ZEB2与+20-kb肌细胞增强因子2b（Mef2b）的内含子增强子结合，抑制MEF2B介导的生殖中心B细胞分化，促进ABC的形成。ZEB2 还靶向对 ABC 规格和功能很重要的基因，包括 Itgax。ZEB2驱动的ABC分化需要JAK-STAT（Janus激酶-信号转导和转录激活因子），用JAK1/3抑制剂治疗可减少自身免疫小鼠和患者体内的ABC积累。因此，ZEB2 成为 B 细胞自身免疫的驱动因素。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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