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

描述(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)。帕金森病的特征是牙龈的慢性炎症，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持结构遭到破坏。帕金森病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.gigivalis)、齿密螺旋体(Treponema Denticola)和这一应用的主要焦点--连城坦纳氏菌(Tanerella Forsythia)(前身为福赛氏杆菌)的红色复合体。然而，帕金森病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，这种免疫反应通过炎性细胞因子、T和B淋巴细胞以及适应性和先天免疫的其他方面的共同作用导致破骨细胞生成的失衡。辅助性T细胞在帕金森病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细胞具有体内平衡作用，甚至对细胞介导的免疫具有保护作用。在晚期牙周炎中也有一些证据表明T细胞介导的免疫功能受到抑制，而牙龈假单胞菌对小鼠的CD4+细胞有下调作用。相反，缺乏T细胞或各种T细胞细胞因子的小鼠几乎完全免受牙槽骨破坏，某些亚型的T辅助细胞是人类和小鼠进行性帕金森病损害的特征。因此，目前仍不清楚T细胞在帕金森病的宿主防御/病理中的作用。部分混淆可能源于T辅助(Th)细胞生物学尚不完全了解的事实。在过去的几年里，随着一种新的Th细胞群的发现，在理解CD4+Th亚群方面发生了一场重大革命，Th细胞可以分泌IL-17，因此被称为“Th17”。Th17细胞不同于经典的Th1和Th2细胞群，被发现是宿主抵抗细胞外病原体的主要T细胞介质，也是自身免疫中慢性炎症的激活物。我们最近在帕金森病小鼠模型中证明了IL-17信号对防止骨丢失的保护作用，这与IL-17炎症信号促进帕金森病患者骨丢失的直观预测相反。因此，这项应用的总体目标是评估三种主要类型的Th细胞在介导牙槽骨丢失和/或宿主对连翘的防御中的作用，使用T细胞亚群或Th特异性细胞因子的靶向缺失的小鼠模型。项目简介：人类最常见的骨丢失形式之一发生在牙周病(PD)中。帕金森病是由厌氧菌引发的，如连翘假单胞菌，它们在牙齿附近的牙龈空间定居并入侵口腔，但实际上是由免疫系统介导的炎症事件触发了骨丢失。考虑到T细胞免疫学领域的最新进展，这项应用的目的是确定由连翘假单胞菌介导的牙周骨丢失引起的炎症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.