Local production of complement proteins in rheumatoid arthritis synovium
Local production of complement proteins in rheumatoid arthritis synovium
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DOI：
10.1002/art.10183
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发表时间：
2002-04-01
影响因子：
--
通讯作者：
Müller-Ladner, U
中科院分区：
文献类型：
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作者：
Neumann, E;Barnum, SR;Müller-Ladner, U
客观的。研究显示，RA 患者血浆、滑液 (SF) 和滑膜组织 (ST) 中天然补体成分水平降低，而补体代谢物水平升高，因此补体反复与类风湿性关节炎 (RA) 的发病机制有关。然而，关于 RA 滑膜中补体级联关键因子的局部产生和激活及其通过新型抗细胞因子疗法的潜在调节的信息有限。本研究旨在表征 RA SF 和 ST 中补体蛋白和受体的表达。方法。使用原位杂交、免疫组织化学和蛋白质印迹技术，我们评估了类风湿滑膜中补体蛋白 C3、因子 B (FB) 和 C5b-9 的存在，以及补体受体 C3aR 和 C5aR 的表达。 SF 中的 C3 和 FB 水平通过酶联免疫吸附测定法测定。通过检查可溶性肿瘤坏死因子受体 (sTNFR) p55 基因转移在 RA SCID 小鼠模型中的影响来进行功能评估。结果。补体蛋白和受体可以定位于所有 RA 滑膜标本中，而在骨关节炎 (OA) 滑膜中，只有少数单细胞表达补体蛋白和受体。 SF 中 RA 和 OA 之间的 C3 浓度没有差异；然而，与 OA SF 相比，RA 中的 FB 水平显着降低。与 OA 滑膜相反，在 RA 滑膜中，补体因子和补体受体信使 RNA 的局部表达遍布各个 ST 区室，表明补体级联的激活发生在类风湿滑膜的所有部分。此外，通过基于腺病毒的基因转移过度表达sTNFR p55后，C5aR表达上调。结论。总之，局部补体产生和激活可能在 RA 中发挥重要作用，并且局部补体产生的特异性调节和抑制可能是 RA 有吸引力的治疗靶点。
Objective. Complement has been repeatedly implicated in the pathogenesis of rheumatoid arthritis (RA) based on studies showing reduced levels of native complement components and increased levels of complement metabolites in plasma, synovial fluid (SF), and synovial tissue (ST) of RA patients. However, there is limited information on local production and activation of key factors of the complement cascade in RA synovium and their potential modulation by novel anticytokine therapies. This study was undertaken to characterize the expression of complement proteins and receptors in RA SF and ST.Methods. Using in situ hybridization, immunohistochemistry, and Western blot techniques, we assessed the presence of complement proteins C3, factor B (FB), and C5b-9, as well as the expression of complement receptors C3aR and C5aR in rheumatoid synovium. C3 and FB levels in SF were determined by enzyme-linked immunosorbent assay. Functional assessment was performed by examining the effects of soluble tumor necrosis factor receptor (sTNFR) p55 gene transfer in the SCID mouse model of RA.Results. Complement proteins and receptors could be localized in all RA synovial specimens, whereas in osteoarthritis (OA) synovium, only a few, single cells expressed complement proteins and receptors. No differences were noted in the concentration of C3 between RA and OA in SF; however, FB levels were markedly reduced in RA versus OA SF. In RA synovium, in contrast to OA synovium, local expression of complement factor and complement receptor messenger RNA was found throughout the various ST compartments, suggesting that activation of the complement cascade occurs in all parts of the rheumatoid synovium. Moreover, C5aR expression was up-regulated following overexpression of sTNFR p55 by adenovirus-based gene transfer.Conclusion. In summary, local complement production and activation may play an important role in RA, and specific modulation and inhibition of local complement production could be an attractive therapeutic target for RA.