{Reference Type}: Journal Article
{Title}: The transcription factor ZEB2 drives the formation of age-associated B cells.
{Author}: Dai D;Gu S;Han X;Ding H;Jiang Y;Zhang X;Yao C;Hong S;Zhang J;Shen Y;Hou G;Qu B;Zhou H;Qin Y;He Y;Ma J;Yin Z;Ye Z;Qian J;Jiang Q;Wu L;Guo Q;Chen S;Huang C;Kottyan LC;Weirauch MT;Vinuesa CG;Shen N;
{Journal}: Science
{Volume}: 383
{Issue}: 6681
{Year}: 2024 Jan 26
{Factor}: 63.714
{DOI}: 10.1126/science.adf8531
{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.