Increased METTL1 expression in B cell subsets correlates with disease activity and immunological features in SLE

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by aberrant B cell activation, excessive plasma cell differentiation, and pathogenic autoantibody production. Epitranscriptomic modifications have emerged as important regulators of immune cell function. Among these, N7-methylguanosine (m7G) modification, catalyzed by methyltransferase-like 1 (METTL1), has been implicated in immune regulation and autoimmune diseases. However, the expression pattern of METTL1 across peripheral B cell subsets and its clinical relevance in SLE remain incompletely characterized.

m7G levels and METTL1 expression were examined in mouse B cells and plasma cells using dot blot and RT-qPCR. METTL1 expression in peripheral blood mononuclear cells (PBMCs) and B cell subsets from patients with SLE and healthy controls was assessed by RT-qPCR and flow cytometry. Spearman correlation analyses were performed to evaluate associations between METTL1 expression and disease activity, clinical manifestations, autoantibodies, and laboratory parameters, with multiple testing controlled using the Benjamini-Hochberg false discovery rate (FDR) procedure. To explore molecular programs associated with METTL1, RNA sequencing was conducted in B cells isolated from wild-type and Mettl1-deficient mice, followed by Gene Ontology, gene set enrichment, protein-protein interaction, and motif analyses.

m7G modification and METTL1 expression were significantly elevated in mouse plasma cells compared with B cells. In patients with SLE, METTL1 was markedly upregulated in PBMCs and across B cell subsets, with the highest expression observed in plasmablasts (PBs). Importantly, METTL1 expression was positively correlated with SLE Disease Activity Index (SLEDAI) scores in total B cells, NBs, MBs, and PBs, and all four associations remained significant after FDR correction. Transcriptomic profiling revealed that METTL1 deficiency was associated with downregulation of immune-related processes and proliferative pathways, including MYC targets, E2F targets, and G2M checkpoint signaling.

METTL1 is highly expressed in B cells, particularly PBs, in SLE and is consistently associated with disease activity as measured by SLEDAI. Transcriptomic analyses further link METTL1 to key transcriptional programs involved in B cell function. These findings provide a subset-resolved characterization of METTL1 in SLE and support further investigation of its clinical and biological relevance in B cell dysregulation.