Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI 48109
Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI 48109.
J Immunol. 2020 Aug 1;205(3):579-586. doi: 10.4049/jimmunol.1901108. Epub 2020 Jun 26.
Rheumatoid arthritis (RA) is closely associated with shared epitope (SE)-coding 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 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.
类风湿关节炎（RA）与共享表位（SE）编码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共同关联的机制尚不清楚。最近的研究表明，SE 作为信号转导配体，在 RA 的实验模型中激活细胞表面钙网蛋白介导的、促关节炎、骨侵蚀途径。在这项研究中，我们证明了 LPS 或 DTT 刺激小鼠巨噬细胞促进钙网蛋白的细胞表面易位，进而使 SE 激活的钙信号增加，并激活肽基精氨酸脱亚氨酶，导致细胞内瓜氨酸化蛋白增加。向携带人类 SE 编码等位基因的转基因小鼠腹腔内注射 LPS 会导致 TNF-α 和抗瓜氨酸环肽抗体的血清水平升高，以及末端指骨骨破坏。这些数据揭示了一个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。
