T cell dependence of chronic destructive murine arthritis induced by repeated local activation of toll-like receptor-driven pathways
T cell dependence of chronic destructive murine arthritis induced by repeated local activation of toll-like receptor-driven pathways
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DOI：
10.1002/art.23152
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发表时间：
2008-01-01
影响因子：
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通讯作者：
van den Berg, Wirn B.
中科院分区：
文献类型：
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作者：
Joosten, Leo A. B.;Abdollahi-Roodsaz, Shahla;van den Berg, Wirn B.
目标。类风湿性关节炎的发病机制通常与细菌感染有关。本研究旨在建立小鼠关节内反复暴露细菌细胞壁碎片所致的慢性破坏性关节炎模型，并探讨该模型对细胞因子的依赖性。在第0天、第7天、第14天和第21天，给缺乏多种细胞因子的小鼠IA注射化脓性链球菌的细胞壁片段。比较缺乏不同细胞因子的小鼠的慢性破坏性关节炎的发展情况，以评估哪些细胞因子在慢性破坏性关节炎的发展中起关键作用。关节反复暴露于S化脓性胞壁碎片可导致慢性破坏性关节炎的发生。在缺乏重组激活基因2的小鼠中，发现了链球菌细胞壁(SCW)导向的T细胞反应性，并且没有发生慢性关节炎，这表明T细胞参与了SCW诱导的慢性关节炎的发生。白细胞介素17(IL-17)受体缺陷小鼠在慢性期关节破坏减少，暗示最近发现的产生IL-17的辅助性T细胞(Th17细胞)的有害作用。IL-23在关节炎晚期有明显表达。在最后一次闪光后，关节肿胀不再依赖于肿瘤坏死因子α(TNFα)，28天后，在肿瘤坏死因子α缺陷小鼠中发现了显著的软骨损伤。相反，IL-1β缺陷小鼠在疾病的晚期完全保护了关节肿胀和软骨和骨骼的破坏。这些发现表明，在侵蚀性阶段，关节炎对肿瘤坏死因子α的依赖消失，此时Th17细胞变得至关重要。IL-Iβ依赖性仍然很强，这与其在Th17细胞生成中的关键作用一致。
Objective. The pathogenesis of rheumatoid arthritis is often linked to bacterial infections. The present study was undertaken to develop a mouse model of chronic destructive arthritis induced by repeated intra-articular (IA) exposure to bacterial cell wall fragments and to investigate the cytokine dependence of this model.Methods. Mice that were deficient in various cytokines were injected IA with cell wall fragments of Streptococcus pyogenes on days 0, 7, 14, and 21. The development of chronic destructive arthritis was comp ared between groups of mice lacking different cytokines, to assess which cytokines were crucial for development of chronic destructive arthritis.Results. Repeated exposure of a joint to S pyogenes cell wall fragments resulted in the development of chronic destructive arthritis. In mice deficient in recombination-activating gene 2, streptococcal cell wall (SCW)-directed T cell reactivity was found and chronic arthritis did not develop, implicating T cells in the generation of chronic SCW-induced arthritis. Interleukin-17 (IL-17) receptor-deficient mice showed a reduction of joint destruction in the chronic stage, implicating a detrimental role of the recently discovered IL-17-producing T helper cells (Th17 cells). IL-23 expression was apparent during the late stages of arthritis. Joint swelling was no longer dependent on tumor necrosis factor a (TNF alpha) after the last flare, and pronounced cartilage damage was found after 28 days in TNF alpha-deficient mice. In contrast, IL-1 beta-deficient mice were fully protected against joint swelling and cartilage and bone destruction during the late stages of disease.Conclusion. These findings indicate that the TNF alpha dependence of arthritis is lost during the erosive stage, when Th17 cells become crucial. IL-I beta dependence remains strong, consistent with its pivotal role in the generation of Th17 cells.