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.
- sjøgren's syndrome
- B cells
- autoimmune diseases
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Handling editor Josef S Smolen
HC and F-cZ contributed equally.
Contributors HC and FZ conceptualised and designed the project and supervised the project; JS, SL and HZ performed all the experiments and JS wrote the manuscript with contributions from all authors; HC revised the manuscript. CL, ZC, TS, SZ, LZ, CH, MW and WZ participated in the sample collection and clinical analysis. All authors read and approved the manuscript.
Funding This study was supported by National Key R&D Program of China (2016YFC0903901, 2016YFA0101003), National Natural Science Fund (81571594, 81771764), CAMS Innovation Fund for Medical Sciences (2016-I2M-1-003, 2017-I2M-3-007), PUMC Youth Fund (3332016005), the Fundamental Research Funds for the Central Universities (3332016005) and 2016 PUMCH Science Fund for Junior Faculty (PUMCH-2016-1.7). The funders had no role in the research or assistance with manuscript preparation.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research.
Patient consent for publication Obtained.
Ethics approval Institutional review board of Peking Union Medical College Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available from the corresponding author upon reasonable request.
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