2. Academic Validation
  3. M6A modification of RRM2 drives B cell hyperactivity in primary Sjögren's syndrome

M6A modification of RRM2 drives B cell hyperactivity in primary Sjögren's syndrome

  • Life Sci. 2025 Jul 31:123884. doi: 10.1016/j.lfs.2025.123884.
Yiying Yang 1,  Ke Liu 2,  Huali Zhang 2,  Yisha Li 3,  Muyao Guo 4
Affiliations

Affiliations

  • 1 Department of Rheumatology and Immunology, Xiangya Hospital, Department of Pathophysiology, Xiangya School of Basic Medicine Science, Central South University, Changsha, Hunan, China; Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, Hunan, China; National Medicine Functional Experimental Teaching Center, Central South University, Changsha, Hunan, China; Postdoctoral Research Station of Biology, Xiangya School of Basic Medicine Science, Central South University, Changsha, Hunan, China.
  • 2 Department of Rheumatology and Immunology, Xiangya Hospital, Department of Pathophysiology, Xiangya School of Basic Medicine Science, Central South University, Changsha, Hunan, China; Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, Hunan, China; National Medicine Functional Experimental Teaching Center, Central South University, Changsha, Hunan, China.
  • 3 Department of Rheumatology and Immunology, Xiangya Hospital, Department of Pathophysiology, Xiangya School of Basic Medicine Science, Central South University, Changsha, Hunan, China; Provincial Clinical Research Center for Rheumatic and Immunologic Diseases, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China. Electronic address: liyisha@csu.edu.cn.
  • 4 Department of Rheumatology and Immunology, Xiangya Hospital, Department of Pathophysiology, Xiangya School of Basic Medicine Science, Central South University, Changsha, Hunan, China; Provincial Clinical Research Center for Rheumatic and Immunologic Diseases, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China. Electronic address: gmuyao@csu.edu.cn.
PMID: 40752678 DOI: 10.1016/j.lfs.2025.123884
Abstract

Background: The mechanisms underlying B cell dysfunction in primary Sjögren's syndrome (pSS) remain unclear. This study investigates the expression and role of ribonucleotide reductase M2 (RRM2) in pSS B cells, focusing on its contribution to B cell hyperreactivity and potential as a biomarker for disease activity.

Methods: Transcriptomic data (GSE199868) of pSS B cells were analyzed to identify differentially expressed genes, with a focus on RRM2. The expression of RRM2 in B-cell subsets and salivary glands (SGs) from pSS patients was validated using flow cytometry and immunohistochemistry. In vitro, the role of RRM2 in B cell activation, differentiation, and antibody production was assessed by treating cells with the RRM2 inhibitor Osalmid. Additionally, the involvement of METTL3-mediated m6A modification in regulating RRM2 expression was explored using m6A-RIP-qPCR and actinomycin D assays.

Results: RRM2 expression was significantly upregulated in pSS B cells and SGs. Higher RRM2 levels correlated with increased disease activity (ESSDAI score), elevated IgG levels, and reduced salivary flow rate. Functionally, RRM2 promoted B cell activation, enhanced differentiation into CD38+CD27+ plasma cells, and increased production of IgG, IgM, and antinuclear antibodies. Mechanistically, METTL3-mediated m6A modification enhanced RRM2 mRNA stability, which contributed to its increased expression in B cells.

Conclusion: RRM2 is upregulated in pSS B cells and SGs, and correlates with disease activity. METTL3-mediated m6A modification regulates RRM2 expression, providing new insights into the molecular mechanisms driving the immune dysfunction in pSS. RRM2 may serve as a potential biomarker and a novel therapeutic target for modulating B-cell hyperactivity in pSS.

Keywords

Autoantibody production; B cell; RRM2; m6A modification; pSS.

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