DDIT3 deficiency ameliorates systemic lupus erythematosus by regulating B cell activation and differentiation

Xin Dai; Jiali Yu; Yunfei Zhang; Zhiming Wang; Yunyan Dai; Ying Hu; Xiaocui Wang; Binbin Tian; Minhui Wu; Hao Chen; Ruigao Song; Dan Ma; Cong-yi Wang; Dawei Ye; Ziliang Zheng; Liyun Zhang; Jing Luo; Yukai Jing

doi:10.1093/lifemedi/lnaf009

Life Medicine ›› 2025, Vol. 4 ›› Issue (1) : lnaf009 DOI: 10.1093/lifemedi/lnaf009

Article

DDIT3 deficiency ameliorates systemic lupus erythematosus by regulating B cell activation and differentiation

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¹. Institute of Clinical Medicine, Central People's Hospital of Zhanjiang, Zhanjiang 524045, China

². Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan 030009, China

³. Department of Clinical Laboratory, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan 040030, China

⁴. Department of General Surgery, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan 040030, China

⁵. Department of Critical Care Medicine, Central People's Hospital of Zhanjiang, Zhanjiang 524045, China

⁶. Key Laboratory of Biomedical Information Engineering of Ministry of Education, Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China

⁷. Center of Reproductive Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China

⁸. Department of Rheumatology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China

⁹. Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

¹⁰. Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

¹¹. Laboratory of Molecular Imaging, Fifth hospital of Shanxi Medical University (Shanxi Provincial People's Hospital), Taiyuan 030032, China

¹². Department of Clinical Laboratory, Shanxi Province Clinical Research Center for Dermatologic and Immunologic Diseases (Rheumatic diseases), Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China

¹³. Shanxi Academy of Advanced Research and Innovation, Taiyuan 030032, China

daixin415@126.com (X.D.)

zzlsxty@sxmu.edu.cn (Z.Z.)

zhangly@sxbqeh.com.cn (L.Z.)

ljty966@hotmail.com (J.L.)

jyk238507@sxmu.edu.cn (Y.J.)

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Abstract

Systemic lupus erythematosus (SLE) is characterized by the overproduction of autoantibodies, and B cells are considered to be the primary cells involved in the development of SLE. Studies have shown that DNA damage responses play a role in B cell activity in SLE. However, the exact role of DNA damage-induced transcript 3 (DDIT3) in humoral immune response and SLE pathogenesis remains unknown. We observed increased expression of DDIT3 in B cells of SLE patients and this expression was positively correlated with disease activity. In DDIT3-knockout mice, we observed disturbances in B cell development and differentiation, inhibition of B cell activation, and BCR signaling. In addition, DDIT3 deficiency leads to a reduction in T-cell-dependent humoral immune responses. Mechanistically, we found that DDIT3 promotes the transcription and expression of Itgad, which enhances PI3K signaling and B cell activation. Finally, we found that DDIT3 deficiency attenuated lupus autoimmunity and reduced germinal center responses. In conclusion, our study reveals for the first time the role of DDIT3 in adaptive immune responses, especially in B cell homeostasis, B cell activation, BCR signaling, and B cell function. These findings provide a new potential target for therapeutic intervention in SLE.

Keywords

systemic lupus erythematosus / B cells / DDIT3 / PI3K

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Xin Dai, Jiali Yu, Yunfei Zhang, Zhiming Wang, Yunyan Dai, Ying Hu, Xiaocui Wang, Binbin Tian, Minhui Wu, Hao Chen, Ruigao Song, Dan Ma, Cong-yi Wang, Dawei Ye, Ziliang Zheng, Liyun Zhang, Jing Luo, Yukai Jing. DDIT3 deficiency ameliorates systemic lupus erythematosus by regulating B cell activation and differentiation. Life Medicine, 2025, 4(1): lnaf009 DOI:10.1093/lifemedi/lnaf009

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