A dysbiotic microbiome triggers T(H)17 cells to mediate oral mucosal immunopathology in mice and humans.
A dysbiotic microbiome triggers T(H)17 cells to mediate oral mucosal immunopathology in mice and humans.
复制标题
DOI：
10.1126/scitranslmed.aat0797
复制
发表时间：
2018-10-17
影响因子：
17.1
通讯作者：
Moutsopoulos NM
中科院分区：
文献类型：
--
作者：
Dutzan N;Kajikawa T;Abusleme L;Greenwell-Wild T;Zuazo CE;Ikeuchi T;Brenchley L;Abe T;Hurabielle C;Martin D;Morell RJ;Freeman AF;Lazarevic V;Trinchieri G;Diaz PI;Holland SM;Belkaid Y;Hajishengallis G;Moutsopoulos NM
人类和动物模型的联合研究最终表明，微生物群触发的口腔黏膜Th17细胞是牙周炎局部免疫病理和治疗靶点的驱动因素。牙周炎是人类最常见的炎症性疾病之一，但驱动免疫病理和治疗靶向的机制尚不明确。在这里，我们证明了常驻记忆Th17细胞在人类牙周炎中的扩展。模仿人类，Th17细胞通过局部增殖在小鼠实验性牙周炎中扩增。与稳态口腔Th17细胞不同，Th17细胞以不依赖于共生体和依赖于IL-6的方式积累，牙周炎相关的Th17细胞的扩张依赖于局部的益生菌群，并且需要IL-6和IL-23。重要的是，Th17细胞和相关的中性粒细胞积累对于实验性牙周炎的炎症组织破坏是必要的。遗传或药理学抑制Th17细胞分化可保护其免受免疫病理的影响。在Th17细胞分化中存在遗传缺陷的独特患者群体中进行的研究为我们的小鼠实验研究建立了人类相关性。事实上，在口腔中，尽管复发性口腔真菌感染的患病率增加，但人类Th17细胞缺陷与牙周炎症和骨质流失的减少有关。我们的研究突出了Th17细胞在口腔免疫和炎症中的独特功能，为治疗牙周炎的新靶向治疗方法铺平了道路。
Combined human and animal model studies conclusively implicate microbiota-triggered oral mucosal Th17 cells as drivers of local immunopathology and therapeutic targets in periodontitis. Periodontitis is one of the most common human inflammatory diseases, yet the mechanisms that drive immunopathology and could be therapeutically targeted are not well defined. Here, we demonstrate an expansion of resident memory Th17 cells in human periodontitis. Phenocopying humans, Th17 cells expanded in murine experimental periodontitis through local proliferation. Unlike homeostatic oral Th17 cells, which accumulate in a commensal-independent and IL-6-dependent manner, periodontitis-associated expansion of Th17 cells was dependent upon the local dysbiotic microbiome and required both IL-6 and IL-23. Importantly, Th17 cells and associated neutrophil accumulation were necessary for inflammatory tissue destruction in experimental periodontitis. Genetic or pharmacological inhibition of Th17 cell differentiation conferred protection from immunopathology. Studies in a unique patient population with a genetic defect in Th17 cell differentiation established human relevance for our murine experimental studies. Indeed, in the oral cavity, human Th17 cell defects were associated with diminished periodontal inflammation and bone loss, despite increased prevalence of recurrent oral fungal infections. Our study highlights distinct functions of Th17 cells in oral immunity and inflammation and paves the way to a new targeted therapeutic approach for the treatment of periodontitis.
登录
查看更多内容
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
15.9
作者：
Hajishengallis G;Lamont RJ
通讯作者：
Lamont RJ
影响因子：
6.7
作者：
Allam, Jean-Pierre;Duan, Yonggang;Novak, Natalija
通讯作者：
Novak, Natalija
影响因子：
2.2
作者：
Abe, Toshiharu;Hajishengallis, George
通讯作者：
Hajishengallis, George
影响因子：
3.8
作者：
Abusleme L;Moutsopoulos NM
通讯作者：
Moutsopoulos NM