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

连翘塔内菌诱导的牙槽骨破坏中 T 辅助细胞反应

基本信息

批准号：
8104124
负责人：
Sarah L Gaffen
金额：
$ 37.48万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-18 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8104124
关键词：
Abbreviations Accounting Alveolar Bone Loss Anaerobic Bacteria Animals Antigen-Presenting Cells Antigens Autoimmunity B-Lymphocytes Bacteroides forsythus CCR6 gene CD4 Positive T Lymphocytes CXC Chemokines Carboxymethylcellulose Cells Cellular Immunity Cellular biology Cervical Characteristics Chronic Chronic Obstructive Airway Disease Coculture Techniques Collagen Arthritis Complex Confusion Dendritic Cells Ecology Event Experimental Autoimmune Encephalomyelitis Forsythia Gingiva Goals Helper-Inducer T-Lymphocyte Host Defense Human Immune response Immune system Immunology In Vitro Infection Inflammation Inflammatory Interleukin-12 Interleukin-17 Interleukin-4 Interleukins Invaded Jaw Knock-out Lesion Ligands Lipopolysaccharides Mediating Mediator of activation protein Mus Natural Immunity Nature Oral cavity Osteoblasts Osteoclasts Pathogenesis Pathology Pattern recognition receptor Periodontal Diseases Periodontal Ligament Periodontitis Periodontium Phenotype Population Porphyromonas gingivalis Production Relative (related person)Rheumatoid Arthritis Role SCID Mice STAT protein STAT6 gene Signal Transduction Staining method Stains T cell response T-Lymphocyte T-Lymphocyte Subsets TNFSF11 gene Th1 Cells Th2 Cells Toll-like receptors Tooth Cervix Tooth structure Treponema denticola adaptive immunity alveolar bone bone bone loss chemokine receptor cytokine defined contribution extracellular human CXCL5 protein interleukin-12 subunit p35 interleukin-22 interleukin-23 macrophage mouse model oral infection oropharyngeal thrush osteoclastogenesis pathogen receptor receptor expression response stem

项目摘要

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.

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的特征是牙龈慢性炎症，导致颌骨牙槽骨破骨细胞生成增强，并破坏牙周韧带和其他牙齿支撑结构。 PD 的起始和进展是由厌氧菌的复杂生态引起的，特别是牙龈卟啉单胞菌 (P. gingivalis)、齿垢密螺旋体的“红色复合体”和本申请的主要焦点福赛坦纳菌 (以前称为福赛拟杆菌)。然而，PD中的大多数病理和骨破坏实际上是由不适当的免疫反应介导的，这通过炎症细胞因子、T和B淋巴细胞以及适应性和先天免疫的其他方面的联合作用导致破骨细胞生成失衡。 T辅助细胞在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。还有一些证据表明，晚期牙周炎中 T 细胞介导的免疫受到抑制，牙龈卟啉单胞菌对小鼠的 CD4+ 细胞发挥下调作用。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，并且T辅助细胞的某些亚型是人和小鼠进行性PD病变的特征。因此，目前尚不清楚 T 细胞如何促进 PD 中的宿主防御/病理学。部分混乱可能源于辅助性 T (Th) 细胞生物学尚未完全了解这一事实。在过去几年中，随着分泌 IL-17 的新 Th 细胞群的发现，人们对 CD4+ Th 亚群的理解发生了重大革命，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，也是自身免疫中慢性炎症的激活剂。我们最近证明，IL-17 信号传导可以防止 PD 小鼠模型中的骨质流失，这与 IL-17 炎症信号传导促进 PD 中骨质流失的直观预测相反。因此，本申请的总体目标是使用具有 T 细胞亚群或 Th 特异性的靶向删除的小鼠模型，评估三种主要类型 Th 细胞对介导牙槽骨丢失和/或宿主针对连翘的防御的贡献。细胞因子。项目叙述：人类最常见的骨质流失形式之一是牙周病 (PD)。 PD 是由厌氧细菌（如连翘坦纳菌）引发的，这些细菌在牙齿附近的牙龈空间定植并侵入口腔，但实际上引发骨质流失的是免疫系统介导的炎症事件。本申请的目的是结合 T 细胞免疫学领域的最新进展，确定炎症 T 细胞对连翘 Tanerella forsythia 介导的牙周骨丢失反应的性质。