Q1 · CROSS-FIELD
Article
Author: Dai, Dai ; Qin, Yuting ; Vinuesa, Carola G. ; Qian, Jie ; Shen, Nan ; Ding, Huihua ; Ma, Jianyang ; Weirauch, Matthew T. ; Jiang, Qian ; Zhang, Jinsong ; Hong, Soonmin ; Ye, Zhizhong ; Gu, Shuangshuang ; Huang, Chuanxin ; Zhang, Xiaoou ; Kottyan, Leah C. ; Wu, Lihua ; Zhou, Haibo ; Yao, Chao ; Chen, Sheng ; He, Yuke ; Hou, Guojun ; Shen, Yiwei ; Qu, Bo ; Guo, Qiang ; Jiang, Yang ; Yin, Zhihua ; Han, Xiaxia
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.