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Uncovering A Shared Epitope-Activated Protein Citrullination Pathway
The Journal of Immunology ( IF 4.4 ) Pub Date : 2020-06-26 , DOI: 10.4049/jimmunol.1901108
Vincent van Drongelen 1 , Wahida H Ali 2 , Joseph Holoshitz 2
Affiliation  

Key Points LPS increases cell surface expression of the SE receptor CRT. SE–CRT interaction increases [Ca2+], PAD activation, and protein citrullination. In SE-expressing Tg mice, LPS activates PAD, ACPA, and bone erosions. Rheumatoid arthritis (RA) is closely associated with shared epitope (SE)–coding HLA-DRB1 alleles and circulating anticitrullinated protein Abs (ACPA), but neither the respective pathogenic roles of SE and ACPA in RA nor the mechanisms underlying their coassociation are known. It was recently shown that the SE functions as a signal transduction ligand that activates a cell surface calreticulin-mediated, proarthritogenic, bone erosive pathway in an experimental model of RA. In this study, we demonstrate that stimulation of murine macrophages with LPS or DTT facilitated cell surface translocation of calreticulin, which in turn enabled increased SE-activated calcium signaling and activation of peptidylarginine deiminase with the resultant increased cellular abundance of citrullinated proteins. The i.p. administration of LPS to transgenic mice carrying a human SE-coding HLA-DRB1 allele lead to increased serum levels of TNF-α and anticitrullinated cyclic peptide Abs, along with terminal phalanx bone destruction. These data uncover a previously unknown signal transduction pathway by which the SE facilitates protein citrullination, ACPA production, and bone destruction.

中文翻译:

发现共享表位激活蛋白瓜氨酸化途径

关键点 LPS 增加 SE 受体 CRT 的细胞表面表达。SE-CRT 相互作用增加 [Ca2+]、PAD 活化和蛋白质瓜氨酸化。在表达 SE 的 Tg 小鼠中,LPS 激活 PAD、ACPA 和骨侵蚀。类风湿性关节炎 (RA) 与编码共享表位 (SE) 的 HLA-DRB1 等位基因和循环抗瓜氨酸蛋白抗体 (ACPA) 密切相关,但 SE 和 ACPA 在 RA 中的各自致病作用以及它们联合的机制尚不清楚。最近表明,在 RA 实验模型中,SE 作为信号转导配体激活细胞表面钙网蛋白介导的、促关节炎的、骨侵蚀途径。在这项研究中,我们证明用 LPS 或 DTT 刺激鼠巨噬细胞促进了钙网蛋白的细胞表面易位,这反过来又增加了 SE 激活的钙信号传导和肽基精氨酸脱亚胺酶的激活,从而增加了瓜氨酸蛋白的细胞丰度。向携带人类 SE 编码 HLA-DRB1 等位基因的转基因小鼠腹腔注射 LPS 会导致 TNF-α 和抗瓜氨酸环肽抗体的血清水平增加,以及末端指骨骨破坏。这些数据揭示了一种以前未知的信号转导途径,SE 通过该途径促进蛋白质瓜氨酸化、ACPA 产生和骨破坏。向携带人类 SE 编码 HLA-DRB1 等位基因的转基因小鼠施用 LPS 导致 TNF-α 和抗瓜氨酸环肽 Abs 的血清水平增加,以及末端指骨骨破坏。这些数据揭示了一种以前未知的信号转导途径,SE 通过该途径促进蛋白质瓜氨酸化、ACPA 产生和骨破坏。向携带人类 SE 编码 HLA-DRB1 等位基因的转基因小鼠施用 LPS 导致 TNF-α 和抗瓜氨酸环肽 Abs 的血清水平增加,以及末端指骨骨破坏。这些数据揭示了一种以前未知的信号转导途径,SE 通过该途径促进蛋白质瓜氨酸化、ACPA 产生和骨破坏。
更新日期:2020-06-26
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