T helper cell responses in Tanerella forsythia-induced alveolar bone destruction

描述（由申请人提供）：人类最常见的炎症性骨破坏形式发生在牙周病（PD）中。PD的特点是牙龈慢性炎症，导致颌骨牙槽骨破骨细胞生成增强，牙周韧带和其他牙齿支撑结构破坏。PD的发生和发展是由厌氧细菌的复杂生态引起的，特别是牙龈卟啉单胞菌（P. gingivalis），密螺旋体和本应用的主要焦点，连翘Tanerella（以前的连翘拟杆菌）的“红色复合体”。然而，PD的大部分病理和骨破坏实际上是由不适当的免疫反应介导的，通过炎症细胞因子、T淋巴细胞和B淋巴细胞以及适应性免疫和先天免疫等方面的共同作用，导致破骨细胞生成失衡。辅助性T细胞在PD发病机制中的作用一直存在争议。对人类和实验动物的研究表明，T细胞具有稳态作用，甚至对细胞介导的免疫具有保护作用。也有证据表明，在晚期牙周炎中，T细胞介导的免疫受到抑制，而P. gingivalis对小鼠的CD4+细胞有下调作用。相反，缺乏T细胞或各种T细胞因子的小鼠几乎完全免受牙槽骨破坏，并且某些亚型的T辅助细胞是人类和小鼠进行性PD病变的特征。因此，目前尚不清楚T细胞如何参与PD的宿主防御/病理。部分混乱可能源于辅助性T细胞生物学尚未完全理解这一事实。在过去的几年里，随着一种新的分泌IL-17的Th细胞群的发现，在理解CD4+ Th亚群方面发生了重大革命，因此被称为“Th17”。Th17细胞不同于经典的Th1和Th2细胞群，已被发现是宿主防御细胞外病原体的主要T细胞介质，也是自身免疫慢性炎症的激活剂。我们最近证明IL-17信号可以防止PD小鼠模型中的骨质流失，这与IL-17炎症信号促进PD骨质流失的直观预测相反。因此，本应用的总体目标是利用T细胞亚群或Th特异性细胞因子靶向缺失的小鼠模型，评估三种主要类型的Th细胞在介导牙槽骨丢失和/或宿主防御连翘中的作用。项目描述：人类最常见的骨质流失形式之一发生在牙周病（PD）中。PD是由厌氧菌如连珠天杆菌（Tanerella forsythia）等在牙齿附近牙龈间隙定植并侵入口腔引发的，但真正引发骨质流失的是免疫系统介导的炎症事件。考虑到T细胞免疫学领域的最新进展，本应用程序的目的是定义由连翘天疱疮介导的牙周骨丢失炎症T细胞反应的性质。

DESCRIPTION (provided by applicant): The most common form of inflammatory bone destruction in humans occurs in periodontal disease (PD). PD is characterized by a chronic inflammation of the gingiva that leads to enhanced osteoclastogenesis of alveolar bone in the jaw and destruction of periodontal ligaments and other tooth-supporting structures. Initiation and progression of PD is caused by a complex ecology of anaerobic bacteria, particularly the "red complex" of Porphyromonas gingivalis (P. gingivalis), Treponema denticola and the main focus of this application, Tanerella forsythia (formerly Bacteroides forsythus). However, most of the pathology and bone destruction in PD are actually mediated by an inappropriate immune response, which leads to an imbalance in osteoclastogenesis through the combined action of inflammatory cytokines, T and B lymphocytes, and other aspects of adaptive and innate immunity. The role of T helper cells in PD pathogenesis has been controversial. Studies in humans and experimental animals have suggested a homeostatic role for T cells or even a protective role for cell-mediated immunity. There is also some evidence for suppression of T cell-mediated immunity in advanced periodontitis, and P. gingivalis exerts a downregulatory effect on CD4+ cells in mice. Conversely, mice deficient in T cells or various T cell cytokines are almost completely protected from alveolar bone destruction, and certain subtypes of T helper cells are characteristic of progressive PD lesions in humans and mice. Thus, it is still not clear how T cells contribute to host defense/pathology in PD. Part of the confusion may stem from the fact that T helper (Th) cell biology is incompletely understood. In the last few years, a major revolution in understanding CD4+ Th subsets occurred with the discovery of a new population of Th cells that secrete IL-17, and hence are termed "Th17." Th17 cells are distinct from the classic Th1 and Th2 populations, and have been found to be the major T cell mediators of host defense against extracellular pathogens but also activators of chronic inflammation in autoimmunity. We have recently demonstrated that IL-17 signaling protects against bone loss in a mouse model of PD, contrary to the intuitive prediction that IL- 17 inflammatory signaling promotes bone loss in PD. Therefore, the overall goal of this application is to assess the contributions of the three major types of Th cells to mediating alveolar bone loss and/or host defense against T. forsythia, using mouse models with targeted deletions in T cell subsets or Th-specific cytokines. Project Narrative: One of the most common forms of bone loss in humans occurs in periodontal disease (PD). PD is initiated by anaerobic bacteria such as Tanerella forsythia that colonize and invade the oral cavity in the gingival space adjacent to teeth, but it is the inflammatory events mediated by the immune system that actually triggers bone loss. The goal of this application is to define the nature of the inflammatory T cell response to periodontal bone loss mediated by Tanerella forsythia, taking into account recent advances in the field of T cell immunology.