Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category.
Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category.
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DOI：
10.1084/jem.20071258
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发表时间：
2008-04-14
期刊：
影响因子：
--
通讯作者：
Caspi RR
中科院分区：
文献类型：
--
作者：
Luger D;Silver PB;Tang J;Cua D;Chen Z;Iwakura Y;Bowman EP;Sgambellone NM;Chan CC;Caspi RR
实验性自身免疫性葡萄膜炎（EAU）代表人类的自身免疫性葡萄膜炎。我们研究了白细胞介素（IL）-23-IL-17和IL-12-辅助性T细胞（Th）1通路在EAU发病机制中的作用。IL-23而不是IL-12是通过用完全弗氏佐剂中的视网膜抗原（Ag）感光细胞间类维生素A结合蛋白（IRBP）免疫引起疾病所必需的。IL-17在该模型中起主导作用;其中和作用预防或逆转疾病，并且Th 17效应细胞在不存在干扰素（IFN）-γ的情况下诱导EAU。然而，在转移模型中，极化的Th 1细胞系可以诱导严重的EAU独立于宿主IL-17。此外，用IRBP脉冲的成熟树突状细胞诱导EAU需要产生产生IFN-γ的效应子应答，而IL-17应答本身不足以引起病理学。最后，IL-17的遗传缺陷并没有消除EAU的易感性。因此，根据模型，自身免疫病理学可以在Th 17或Th 1效应子应答的背景下发展。这些数据表明，显性效应表型可能至少部分由初始暴露于Ag期间存在的条件决定，包括Toll样受体刺激的质量/数量和/或Ag呈递细胞的类型。这些数据还提出了EAU中IL-23的非冗余需求可能超出其促进Th 17效应器应答的作用，并有助于在当前Th 1与Th 17范式中提供平衡的可能性。
Experimental autoimmune uveitis (EAU) represents autoimmune uveitis in humans. We examined the role of the interleukin (IL)-23–IL-17 and IL-12–T helper cell (Th)1 pathways in the pathogenesis of EAU. IL–23 but not IL-12 was necessary to elicit disease by immunization with the retinal antigen (Ag) interphotoreceptor retinoid-binding protein (IRBP) in complete Freund's adjuvant. IL-17 played a dominant role in this model; its neutralization prevented or reversed disease, and Th17 effector cells induced EAU in the absence of interferon (IFN)-γ. In a transfer model, however, a polarized Th1 line could induce severe EAU independently of host IL-17. Furthermore, induction of EAU with IRBP-pulsed mature dendritic cells required generation of an IFN-γ–producing effector response, and an IL-17 response by itself was insufficient to elicit pathology. Finally, genetic deficiency of IL-17 did not abrogate EAU susceptibility. Thus, autoimmune pathology can develop in the context of either a Th17 or a Th1 effector response depending on the model. The data suggest that the dominant effector phenotype may be determined at least in part by conditions present during initial exposure to Ag, including the quality/quantity of Toll-like receptor stimulation and/or type of Ag-presenting cells. These data also raise the possibility that the nonredundant requirement for IL-23 in EAU may extend beyond its role in promoting the Th17 effector response and help provide a balance in the current Th1 versus Th17 paradigm.
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