BackgroundPrimary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterised by aberrant B cell hyperactivation, whose mechanism is partially understood.MethodsWe performed whole transcriptome sequencing of B cells from three pSS patients and three matched healthy controls (HC). Differentially expression genes (DEGs) were confirmed with B cells from 40 pSS patients and 40 HC by quantitative PCR and western blot. We measured the proliferation potential and immunoglobulins production of siRNA-transfected or plasmid-transfected B cells stimulated with cytosine-phosphate-guanine (CpG) or anti-IgM. We also explored Toll-like receptor 9 (TLR9) signalling to reveal the potential mechanism of B cell hyperactivation in pSS.ResultsWe identified 77 upregulated and 32 downregulated DEGs in pSS B cells. We confirmed that epithelial stromal interaction (EPST1) expression in pSS B cells was significantly higher than that from HCs. EPSTI1-silencing B cells stimulated with CpG were less proliferated and produced lower level of IgG and IgM comparing with control B cells. EPSTI1-silencing B cells expressed lower level of p-p65 and higher level of IκBα, and B cells with overexpressed EPSTI1 showed higher level of p-p65 and lower level of IκBα. Finally, IκBα degradation inhibitor Dehydrocostus Lactone treatment attenuated p65 phosphorylation promoted by EPSTI1.ConclusionElevated EPSTI1 expression in pSS B cells promoted TLR9 signalling activation and contributed to the abnormal B cell activation, which was promoted by facilitating p65 phosphorylation and activation of NF-κB signalling via promoting IκBα degradation. EPSTI1 might be implicated in pSS pathogenesis and was a potential therapeutic target of pSS.

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease characterized by exocrinopathy, with an estimated prevalence of 0.33%-0.77% in China and 0.06% worldwide. 1,2 pSS patients primarily suffer from xerophthalmia and xerostomia and 30%-40% of pSS patients present extra-glandular manifestations including arthritis, nephritis, and neuropathy. 3 Interstitial lung diseases (ILD) are a group of heterogeneous inflammatory and fibrotic pulmonary parenchymal disorders, which are frequently complicated in connective tissue diseases. 4,5 ILDs are diagnosed based on clinical presentations, high-resolution computed tomography (HRCT), pulmonary function test (PFT), and lung biopsy. 6,7 HRCT is a sensitive diagnostic tool for ILD, and is strongly correlated with pulmonary histology and PFT, with nonspecific interstitial pneumonia (NSIP), usual interstitial pneumonia, lymphoid interstitial pneumonia, organizing pneumonia, and bronchiolitis as the most common HRCT patterns in pSS patients. 8,9 Interstitial lung diseases is a poor prognosis factor and accounts for one-tenth of deaths in pSS patients. 10,11 However, the reported prevalence of ILD in pSS patients varies significantly, ranging from 1.5% to 78%. 9,12 Furthermore, the risk factors for ILD in pSS patients