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The transcription factor ZEB2 drives the formation of age-associated B cells.
Dai, Dai; Gu, Shuangshuang; Han, Xiaxia; Ding, Huihua; Jiang, Yang; Zhang, Xiaoou; Yao, Chao; Hong, Soonmin; Zhang, Jinsong; Shen, Yiwei; Hou, Guojun; Qu, Bo; Zhou, Haibo; Qin, Yuting; He, Yuke; Ma, Jianyang; Yin, Zhihua; Ye, Zhizhong; Qian, Jie; Jiang, Qian; Wu, Lihua; Guo, Qiang; Chen, Sheng; Huang, Chuanxin; Kottyan, Leah C; Weirauch, Matthew T; Vinuesa, Carola G; Shen, Nan.
Affiliation
  • Dai D; Shanghai Institute of Rheumatology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine (SJTUSM), Shanghai, China.
  • Gu S; Centre for Personalised Immunology (CACPI), Shanghai Renji Hospital, SJTUSM, Shanghai, China.
  • Han X; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Renji Hospital, SJTUSM, Shanghai, China.
  • Ding H; Shanghai Institute of Rheumatology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine (SJTUSM), Shanghai, China.
  • Jiang Y; Shanghai Institute of Rheumatology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine (SJTUSM), Shanghai, China.
  • Zhang X; Shanghai Institute of Rheumatology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine (SJTUSM), Shanghai, China.
  • Yao C; Centre for Personalised Immunology (CACPI), Shanghai Renji Hospital, SJTUSM, Shanghai, China.
  • Hong S; Shanghai Institute of Rheumatology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine (SJTUSM), Shanghai, China.
  • Zhang J; Shanghai Key Laboratory of Maternal and Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai, China.
  • Shen Y; Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
  • Hou G; Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • Qu B; Shanghai Institute of Rheumatology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine (SJTUSM), Shanghai, China.
  • Zhou H; Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • Qin Y; Shanghai Institute of Rheumatology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine (SJTUSM), Shanghai, China.
  • He Y; Shanghai Institute of Rheumatology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine (SJTUSM), Shanghai, China.
  • Ma J; Centre for Personalised Immunology (CACPI), Shanghai Renji Hospital, SJTUSM, Shanghai, China.
  • Yin Z; Shanghai Institute of Rheumatology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine (SJTUSM), Shanghai, China.
  • Ye Z; Centre for Personalised Immunology (CACPI), Shanghai Renji Hospital, SJTUSM, Shanghai, China.
  • Qian J; Shanghai Institute of Rheumatology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine (SJTUSM), Shanghai, China.
  • Jiang Q; Centre for Personalised Immunology (CACPI), Shanghai Renji Hospital, SJTUSM, Shanghai, China.
  • Wu L; Shanghai Institute of Rheumatology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine (SJTUSM), Shanghai, China.
  • Guo Q; Centre for Personalised Immunology (CACPI), Shanghai Renji Hospital, SJTUSM, Shanghai, China.
  • Chen S; Shanghai Institute of Rheumatology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine (SJTUSM), Shanghai, China.
  • Huang C; Centre for Personalised Immunology (CACPI), Shanghai Renji Hospital, SJTUSM, Shanghai, China.
  • Kottyan LC; Shanghai Institute of Rheumatology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine (SJTUSM), Shanghai, China.
  • Weirauch MT; Centre for Personalised Immunology (CACPI), Shanghai Renji Hospital, SJTUSM, Shanghai, China.
  • Vinuesa CG; Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China.
  • Shen N; Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China.
Science ; 383(6681): 413-421, 2024 Jan 26.
Article in En | MEDLINE | ID: mdl-38271512
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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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: B-Lymphocytes / Autoimmunity / Cell Differentiation / Gene Expression Regulation / Zinc Finger E-box Binding Homeobox 2 / Lupus Erythematosus, Systemic Type of study: Prognostic_studies / Risk_factors_studies Limits: Animals / Female / Humans Language: En Journal: Science Year: 2024 Document type: Article Affiliation country:
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: B-Lymphocytes / Autoimmunity / Cell Differentiation / Gene Expression Regulation / Zinc Finger E-box Binding Homeobox 2 / Lupus Erythematosus, Systemic Type of study: Prognostic_studies / Risk_factors_studies Limits: Animals / Female / Humans Language: En Journal: Science Year: 2024 Document type: Article Affiliation country: