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

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.

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.

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.

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.