Transcriptomic profiling of Sjögren’s disease salivary glands identifies signatures associated with both follicular and extrafollicular responses linked to rheumatoid factor and anti-La/SSB seropositivity

Objectives: This study aims to identify salivary gland (SG) transcriptomic signatures associated with peripheral and histological biomarkers of disease activity and lymphoma risk factors to inform on Sjogren's disease (SjD) stratification. Methods: Bulk RNA-sequencing of labial SG from exploratory Queen Mary University of London (QMUL) cohort (SjD [n = 55] and non specific-chronic-sialadenitis [sicca, n = 44]) and trial for anti-B-cell therapy in Sjogren's syndrome (TRACTISS)validation cohort (SjD, n = 29) analysed integrating transcriptomic, clinical, serological, and histological data. Results: Unsupervised gene clustering confirmed clear transcriptome segregation between sicca and SjD. The most differentially expressed genes were either common to all SjD's versus sicca or specific to SjD's glands with lymphocytic infiltrates with features of ectopic lymphoid structures (ELS). In SjD, principal component analysis identified a significant proportion of variability associated with rheumatoid factor (RF)-seropositivity, exceeding that associated with SG-ELS and anti-Ro/Sjogren's syndrome antigen-A (SSA) seropositivity. Transcriptomes of SjD-SG with ELS from patients with positivity for either RF, anti-Ro/SSA, and anti-La/SSB showed mainly genes associated with germinal centre formation. Conversely, SG without ELS from patients with