Background Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterised by aberrant B cell hyperactivation, whose mechanism is partially understood. Methods We 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. Results We 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. Conclusion Elevated 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.

中文翻译：

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升高的EPSTI1通过NF-κB信号传导促进原发性干燥综合征患者的B细胞过度活化

背景 原发性干燥综合征 (pSS) 是一种以异常 B 细胞过度激活为特征的全身性自身免疫性疾病，其机制已部分了解。方法 我们对来自三名 pSS 患者和三名匹配的健康对照 (HC) 的 B 细胞进行了全转录组测序。通过定量 PCR 和蛋白质印迹，用来自 40 名 pSS 患者和 40 名 HC 的 B 细胞确认了差异表达基因 (DEG)。我们测量了用胞嘧啶-磷酸-鸟嘌呤 (CpG) 或抗 IgM 刺激的 siRNA 转染或质粒转染的 B 细胞的增殖潜力和免疫球蛋白的产生。我们还探索了 Toll 样受体 9 (TLR9​​) 信号以揭示 pSS 中 B 细胞过度活化的潜在机制。结果我们在 pSS B 细胞中鉴定了 77 个上调和 32 个下调的 DEG。我们证实 pSS B 细胞中的上皮基质相互作用 (EPST1) 表达显着高于 HC。与对照 B 细胞相比，用 CpG 刺激的 EPSTI1 沉默 B 细胞增殖较少，产生的 IgG 和 IgM 水平较低。EPSTI1 沉默 B 细胞表达较低水平的 p-p65 和较高水平的 IκBα，而过表达 EPSTI1 的 B 细胞显示较高水平的 p-p65 和较低水平的 IκBα。最后，IκBα 降解抑制剂 Dehydrocostus Lactone 处理减弱了 EPSTI1 促进的 p65 磷酸化。结论 pSS B细胞EPSTI1表达升高促进了TLR9信号激活并导致B细胞异常激活，其通过促进p65磷酸化和NF-κB信号激活通过促进IκBα降解来促进。