Alternative splicing signatures correlate with disease severity and clinical subtypes in primary Sjögren's syndrome

Primary Sjögren's Syndrome (pSS) is a chronic, systemic autoimmune disease characterized by sicca symptoms due to exocrine gland involvement, but also presenting with a wide range of extraglandular manifestations and diverse subjective burdens, leading to significant clinical heterogeneity that complicates accurate diagnosis and objective assessment of disease activity. While transcriptome sequencing technologies have revolutionized the global analysis of alternative splicing (AS) events and aberrant AS has been implicated in the pathogenesis of various autoimmune diseases, research into AS in pSS remains limited to individual genes. Therefore, this study analyzed peripheral blood transcriptomes from pSS patients and healthy controls, utilizing key co-expression module eigengene values to stratify patients into homogeneous subgroups. Clear differential AS analysis was further obtained. Ten genes with significant AS events were identified, with AS in WARS1, OASL, DDX60, C2, RMI2, PALM2AKAP2, and MYO7B significantly associated with various laboratory indicators. Furthermore, by combining expression and usage rate changes with protein sequence structure predictions, their detailed functional implications in pSS were fully discussed. In conclusion, novel AS signatures significantly associated with pSS severity were revealed, which may serve as potential biomarkers for disease stratification and therapeutic targets in pSS, further providing opportunities for mechanistic research. • This study reveals novel alternative splicing signatures in peripheral blood that are critically associated with disease severity in primary Sjögren's Syndrome. • Through transcriptomic analysis, we stratified pSS patients into distinct subgroups and identified ten genes with significant AS events. • Notably, the alternative splicing of key genes—WARS1, OASL, DDX60, C2, RMI2, PALM2AKAP2, and MYO7B—showed strong correlations with various laboratory indicators and severity scores. • Functional predictions suggest these splicing events alter protein function, positioning them as promising biomarkers for patient stratification and potential therapeutic targets in pSS.