Complement drives Th17 cell differentiation and triggers autoimmune arthritis.
Complement drives Th17 cell differentiation and triggers autoimmune arthritis.
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DOI：
10.1084/jem.20092301
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发表时间：
2010-06-07
期刊：
影响因子：
--
通讯作者：
Sakaguchi S
中科院分区：
文献类型：
--
作者：
Hashimoto M;Hirota K;Yoshitomi H;Maeda S;Teradaira S;Akizuki S;Prieto-Martin P;Nomura T;Sakaguchi N;Köhl J;Heyman B;Takahashi M;Fujita T;Mimori T;Sakaguchi S
在动物模型中，血清补体的激活触发Th17细胞依赖的自发性自身免疫性疾病。在遗传自体免疫倾向的SKG小鼠中，给予甘露聚糖或β-葡聚糖，两者都能激活血清补体，诱发Th17细胞介导的慢性自身免疫性关节炎。补体激活的主要成分C5a通过所有三种补体途径(即凝集素、经典途径和替代途径)产生，刺激组织驻留的巨噬细胞产生包括IL-6在内的炎性细胞因子，与Toll样受体信号或特别是粒细胞/巨噬细胞集落刺激因子(GM-CSF)协同作用。活化T细胞分泌的GM-CSF在体外可促进C5a刺激的巨噬细胞产生IL-6。在体内，C5a受体(C5aR)缺陷抑制了甘露聚糖或β-葡聚糖治疗后Th1 7细胞的分化/扩增，从而抑制了关节炎的发展。转移SKG T细胞可诱导C5aR充分重组激活基因(RAG)−/−小鼠Th1 7细胞分化/扩增，并引起关节炎，但对C5aR缺陷RAG−/−小鼠无明显影响。体内巨噬细胞的耗尽也抑制了SKG小鼠的疾病发展。总之，这些数据表明，在某些自身免疫性疾病中，通过外源性或内源性刺激激活补体可以启动Th17细胞的分化和扩张，可能在微生物感染中也是如此。因此，阻断C5aR可能有利于控制Th17介导的炎症和自身免疫性疾病。
Activation of serum complement triggers Th17 cell–dependent spontaneous autoimmune disease in an animal model. In genetically autoimmune-prone SKG mice, administration of mannan or β-glucan, both of which activate serum complement, evoked Th17 cell–mediated chronic autoimmune arthritis. C5a, a chief component of complement activation produced via all three complement pathways (i.e., lectin, classical, and alternative), stimulated tissue-resident macrophages, but not dendritic cells, to produce inflammatory cytokines including IL-6, in synergy with Toll-like receptor signaling or, notably, granulocyte/macrophage colony-stimulating factor (GM-CSF). GM-CSF secreted by activated T cells indeed enhanced in vitro IL-6 production by C5a-stimulated macrophages. In vivo, C5a receptor (C5aR) deficiency in SKG mice inhibited the differentiation/expansion of Th17 cells after mannan or β-glucan treatment, and consequently suppressed the development of arthritis. Transfer of SKG T cells induced Th17 cell differentiation/expansion and produced arthritis in C5aR-sufficient recombination activating gene (RAG)−/− mice but not in C5aR-deficient RAG−/− recipients. In vivo macrophage depletion also inhibited disease development in SKG mice. Collectively, the data suggest that complement activation by exogenous or endogenous stimulation can initiate Th17 cell differentiation and expansion in certain autoimmune diseases and presumably in microbial infections. Blockade of C5aR may thus be beneficial for controlling Th17-mediated inflammation and autoimmune disease.
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影响因子：
158.5
作者：
Remmers, Elaine F.;Plenge, Robert M.;Gregersen, Peter K.
通讯作者：
Gregersen, Peter K.
DOI：
10.1084/jem.20071119
发表时间：
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期刊：
The Journal of experimental medicine
影响因子：
--
作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
4.4
作者：
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影响因子：
64.8
作者：
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通讯作者：
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