Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease characterized by the dysfunction of salivary and lacrimal glands associated with diverse systemic manifestations, affecting approximately 0.03%–0.1% of the general population worldwide [1,2]. Accumulating evidence indicates that RNA editing, as a co- or post-transcriptional modification, is a critical modulator of the immune system, which is closely correlated with the pathogenesis of autoimmune diseases [[3], [4], [5], [6]]. However, the involvement of RNA-editing in pSS development and progression has not been comprehensively explored.

Studies based on genome-wide RNA sequencing (RNA-seq) analyses have revealed several important RNA editing events in genes involved in a variety of autoimmune disorders [[7], [8], [9]]. A recent RNA-seq analysis of 99 SLE patients reported excessive editing, which was predicted to potentially increase autoantigen presentation by major histocompatibility molecules and trigger subsequent autoimmune responses [9]. Similarly, cathepsin S, a cysteine protease involved in antigen presentation and immune responses, has been reported to reveal the elevated RNA editing levels in 152 patients with RA, implicating cathepsin S in this disease [7]. Of note, transcriptome-wide analysis of RNA editing in 78 psoriatic lesions confirmed the decreased editing levels in both COPA and IGFBP7, two genes known to be associated with autoimmune diseases [8]. Furthermore, ADAR1-mediated RNA editing deficiency has been linked to Aicardi–Goutieres syndrome (AGS), which was further validated by ADAR1 knockout mice with AGS-like symptoms [10,11]. These various observations imply the critical role of RNA editing in regulating the immune system in autoimmune diseases; therefore, elucidating the characteristics and clinical relevance of RNA editing in pSS is essential to understand the pathogenesis of the disease.

Here, we performed RNA-seq with minor salivary gland (MSG) tissues obtained from 569 subjects (including 439 pSS, 101 non-pSS and 29 healthy controls). Ninety-seven strand-specific RNA-seq samples were used as the discovery cohort, and 472 polyA-selected RNA-seq samples were used as the validation cohort to generate comprehensive RNA editing profiles in pSS. We found that the genome-wide landscape of A-to-I editing reflected a set of differential RNA editing (DRE) sites concentrated on Alu elements between pSS and non-pSS controls. Among these DRE sites, six specific RNA editing sites exhibited strong clinical relevance in pSS, which may serve as drivers and provide potential novel candidates for diagnosis and future therapeutic targets.