%0 Journal Article
%T The transcription factor ZEB2 drives the formation of age-associated B cells.
%A Dai D
%A Gu S
%A Han X
%A Ding H
%A Jiang Y
%A Zhang X
%A Yao C
%A Hong S
%A Zhang J
%A Shen Y
%A Hou G
%A Qu B
%A Zhou H
%A Qin Y
%A He Y
%A Ma J
%A Yin Z
%A Ye Z
%A Qian J
%A Jiang Q
%A Wu L
%A Guo Q
%A Chen S
%A Huang C
%A Kottyan LC
%A Weirauch MT
%A Vinuesa CG
%A Shen N
%J Science
%V 383
%N 6681
%D 2024 Jan 26
%M 38271512
%F 63.714
%R 10.1126/science.adf8531
%X 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.