Endogenous retroelement activation is implicated in IFN-a production and anti-CCP autoantibody generation in early RA
Endogenous retroelement activation is implicated in IFN-a production and anti-CCP autoantibody generation in early RA
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内源性逆转录因子激活与早期 RA 中 IFN-a 的产生和抗 CCP 自身抗体的产生有关
DOI：
10.1101/2024.01.17.24301287
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Cooles F
中科院分区：
文献类型：
--
作者：
Cooles F
目的内源性逆转录因子（endogenous retroelements，ERE）刺激1型干扰素（type 1 interferon，IFN-I）的产生，但在风湿性关节炎（Rheumatoid Arthritis，RA）中作为潜在的干扰素原触发因子尚未被探索。我们研究了ERE表达在早期RA（eRA），一个时期，IFN-I是increased.MethodsERE表达DMARD初治eRA全血（LINE 1; RT-PCR）和散装滑膜组织（LTR 5，LINE 1，SINE; Nanostring）一起检查IFN-α活性。循环淋巴细胞亚群，包括B细胞亚群，从eRA患者和早期银屑病关节炎（PsA），流式细胞仪分选和类似的检查。现有的RA和骨关节炎（OA）滑膜单细胞测序数据被重新询问，以确定重复元件，并探讨相关性。（n=22，p<0.0001），全血LINE 1表达（n=56）和循环IFN-α蛋白（p=0.018）和抗CCP滴度（p<0.0001）。与PsA相比，ERE在循环eRA B细胞中表达最高，特别是幼稚B细胞，与SAMDH 1参与的ERE调节有关，并再次观察到与IFN的关联。最后，在已建立的RA滑膜中，与OA相比，RA的LTR，特别是ERVK增加最多，（单核细胞、B细胞、T细胞和成纤维细胞），与IFN-I信号传导增加相关的ERE表达结论首次在eRA患者外周血和滑膜中检测到ERE表达，强调了ERE和IFN-γ之间的潜在因果关系。I的产生以及与抗CCP自身抗体的有趣关联。这表明ERE可能有助于RA的病理生理学，并对未来的新治疗策略产生影响。
ObjectivesEndogenous retroelements (EREs) stimulate type 1 interferon (IFN-I) production but have not been explored as potential interferonogenic triggers in Rheumatoid Arthritis (RA). We investigated ERE expression in early RA (eRA), a period where IFN-I is increased.MethodsERE expression in DMARD naïve eRA whole blood (LINE1; RT-PCR) and bulk synovial tissue (LTR5, LINE1, SINE; Nanostring) was examined alongside IFN-α activity. Circulating lymphocyte subsets, including B cell subsets, from eRA patients and early psoriatic arthritis (PsA), were flow cytometrically sorted and similarly examined. Existing established RA and osteoarthritis (OA) synovial single-cell sequencing data was re-interrogated to identify repeat elements, and associations explored.ResultsThere was significant co-expression of all ERE classes andIFNAin eRA synovial tissue (n=22, p<0.0001) and significant positive associations between whole blood LINE1 expression (n=56) and circulating IFN-α protein (p=0.018) and anti-CCP titres (p<0.0001). ERE expression was highest in circulating eRA B cells, particularly naïve B cells compared with PsA, with ERE regulation by SAMDH1 implicated and associations withIFNAagain observed. Finally, in established RA synovium, LTRs, particularly ERVK, were most increased in RA compared with OA where, for all synovial subsets (monocytes, B cells, T cells and fibroblasts), ERE expression associated with increased IFN-I signalling (p<0.001).ConclusionsPeripheral blood and synovial ERE expression is examined for the first time in eRA highlighting both a potential causal relationship between ERE and IFN-I production and an intriguing association with anti-CCP autoantibodies. This suggests EREs may contribute to RA pathophysiology with implications for future novel therapeutic strategies.