Identification of gene modules associated with B cell activation and tissue remodeling in primary Sjögren's syndrome

Primary Sjögren's syndrome (pSS) is a systemic autoimmune exocrinopathy affecting salivary and lacrimal glands. This study presents an exploratory single-cell transcriptomic analysis of labial salivary glands to generate hypotheses about B-cell-associated gene modules in pSS, and to uncover novel therapeutic targets for B cell modulation in pSS.

The high-dimensional weighted gene co-expression network analysis (hdWGCNA) was performed on gene expression data obtained from single-cell RNA sequencing (scRNA-seq) of 32,337 cells from labial glands of three pSS patients and three healthy controls. Gene Ontology (GO) enrichment analysis was subsequently conducted to investigate the functional roles of the identified gene modules. Additionally, the scRank method was applied to evaluate the responsiveness of key B cell-related targets across different cell types, providing new insights into the role of B cells in the pathogenesis of pSS.

Through hdWGCNA analysis, we resolved seven co-expression modules in pSS. Module 5, restricted to plasma cells, contains POU2AF1, SLAMF7, SPCS2, CD79A and PDIA6 and is highly enriched for COPI/II-mediated vesicle trafficking and B-cell-receptor signaling, thereby driving autoantibody production and chronic inflammation. Modules 1, 2, 4, 6 and 7 align with extracellular-matrix remodeling, epithelial stress and metabolic reprogramming, underscoring the disease's multifactorial pathobiology. scRank ranked Module 5 as the most drug-responsive cluster and highlighted POU2AF1, SLAMF7 and CD79A as tractable B-cell targets for restoring immune homeostasis in pSS.

Our study identified distinct gene modules associated with pSS, with a particular emphasis on B cells, unveiling novel potential therapeutic targets. The activation of B cells, coupled with immune dysregulation and epithelial dysfunction, appears to play a critical role in pSS pathogenesis, offering valuable insights for developing targeted therapeutic strategies that address both immune activation and tissue repair. These findings nominate B-cell-associated modules-including a plasma cell-enriched module featuring POU2AF1, SLAMF7, and CD79A-as hypotheses for future functional validation.