Elevated EPSTI1 promote B cell hyperactivation through NF-κB signalling in patients with primary Sjogren's syndrome
- 29 February 2020
- journal article
- research article
- Published by BMJ in Annals Of The Rheumatic Diseases
- Vol. 79 (4), 518-524
- https://doi.org/10.1136/annrheumdis-2019-216428
Abstract
Background Primary Sjogren'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 I kappa B alpha, and B cells with overexpressed EPSTI1 showed higher level of p-p65 and lower level of I kappa B alpha. Finally, I kappa B alpha 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-kappa B signalling via promoting I kappa B alpha degradation. EPSTI1 might be implicated in pSS pathogenesis and was a potential therapeutic target of pSS.Funding Information
- National Natural Science Fund (81571594, 81771764)
- the Fundamental Research Funds for the Central Universities (3332016005)
- PUMC Youth Fund (3332016005)
- 2016 PUMCH Science Fund for Junior Faculty (PUMCH-2016-1.7)
- CAMS Innovation Fund for Medical Sciences (2016-I2M-1-003, 2017-I2M-3-007)
- National Key R&D Program of China (2016YFA0101003, 2016YFC0903901)
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