The transcription factor ZEB2 drives the formation of age-associated B cells-Reference-Cited by-同舟云学术

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

Published:2024-01-26 Issue:6681 Volume:383 Page:413-421
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Dai Dai¹²³^ORCID,Gu Shuangshuang¹^ORCID,Han Xiaxia¹^ORCID,Ding Huihua¹²^ORCID,Jiang Yang¹,Zhang Xiaoou⁴⁵^ORCID,Yao Chao⁶,Hong Soonmin¹^ORCID,Zhang Jinsong⁶,Shen Yiwei¹,Hou Guojun¹²,Qu Bo¹²^ORCID,Zhou Haibo¹²,Qin Yuting¹²,He Yuke¹²^ORCID,Ma Jianyang¹²,Yin Zhihua⁷,Ye Zhizhong⁷,Qian Jie¹,Jiang Qian⁸^ORCID,Wu Lihua⁸,Guo Qiang¹,Chen Sheng¹,Huang Chuanxin⁹^ORCID,Kottyan Leah C.¹⁰¹¹^ORCID,Weirauch Matthew T.¹⁰¹¹^ORCID,Vinuesa Carola G.²¹²^ORCID,Shen Nan¹²³⁷¹⁰^ORCID

Affiliation:

1. Shanghai Institute of Rheumatology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine (SJTUSM), Shanghai, China.

2. Centre for Personalised Immunology (CACPI), Shanghai Renji Hospital, SJTUSM, Shanghai, China.

3. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Renji Hospital, SJTUSM, Shanghai, China.

4. Shanghai Key Laboratory of Maternal and Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai, China.

5. Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.

6. Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.

7. Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China.

8. Department of Medical Genetics, Capital Institute of Pediatrics, Beijing, China.

9. Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, SJTUSM, Shanghai, China.

10. Center of Autoimmune Genomics and Etiology, Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA.

11. Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.

12. Francis Crick Institute, London, UK.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Link

https://www.science.org/doi/pdf/10.1126/science.adf8531

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