Inflammatory Periodontal Disease and Induction of Arthritis

描述（由申请人提供）：牙周病是一种炎症性感染，影响10-15%的成年人。病原菌牙龈卟啉卟啉（Pg）与疾病激活有关。牙周炎的慢性表明，它可能作为一个持续的、低级别的微生物和细胞因子传递系统，影响远处的疾病。临床研究表明，牙周病与其他疾病，如类风湿关节炎（RA）之间存在关联。然而，双向疾病相互作用阻碍了两种疾病联系机制的阐明。类风湿性关节炎是一种自身免疫性疾病，影响着130万美国成年人。类风湿性关节炎是一种多因素疾病，可导致关节炎症和破坏。强有力的证据表明，辅助性T - 17 （Th17）细胞在RA的发展中起重要作用。细胞因子IL-17和th17诱导剂IL-1和IL- 6也被证明在牙周病的发展中发挥重要作用。由于细胞因子微环境的控制会影响T细胞的活化，我们假设慢性牙周感染会导致细胞因子表达的改变，并通过Th17细胞促进关节炎骨破坏的发生和/或进展。本研究和培训计划提出了两个目标：具体目标1：利用小鼠慢性牙周炎模型比较不同菌株牙龈卟啉单胞菌的全身细胞获得性免疫反应。这种方法的目的是确定是否慢性牙周感染不同菌株的Pg导致不同的全身免疫反应。用以下毒力强的Pg菌株A7A1-28、W83和W50灌胃诱导小鼠牙周病。在牙周病诱导后，通过血清细胞因子表达和脾细胞分析来评估获得性免疫反应。基于这些结果，我们将确定与影响Th17免疫反应和启动骨质流失最相关的Pg菌株，并将其用于特定的目的2。特异性目的2：确定慢性牙周病在实验性RA小鼠发展过程中的获得性免疫效应。小鼠将被诱导牙周病，然后是胶原诱导的关节炎。利用树突状细胞和T细胞的体外研究将为理解Pg引起的T细胞活化的改变提供一种机制方法，这种改变可能影响关节炎的发展。血清细胞因子和脾细胞分析将确定T细胞活化和获得效应功能的变化。这些研究将为研究提供良好的培训环境，包括牙周病学、病理学和免疫学领域的专家。本建议的目的是为了更好地理解口腔感染作为环境辅助因素影响关节炎的免疫机制。

DESCRIPTION (provided by applicant): Periodontal disease is an inflammatory infection that affects 10-15% of the adult population. The pathogen P. gingivalis (Pg) is implicated in disease activation. The chronicity of periodontitis suggests that it may act as a constant, low-grade delivery system of microorganisms and cytokines that influence diseases at distant sites. Clinical studies suggest an association between periodontal disease and other illnesses, such as rheumatoid arthritis (RA). However, the bi-directional disease interaction impedes the clarification of a mechanism linking both diseases. RA is an autoimmune disease that affects 1.3 million U.S. adults. RA is a multi-factorial disease that leads to inflammation and destruction of the joints. Strong evidence suggests that T helper type 17 (Th17) cells play an important role in RA development. The cytokine IL-17 and Th17-inducers IL-1 and IL- 6 are also shown to play an important role in periodontal disease development. Because the control of the cytokine microenvironment influences T cell activation, we hypothesize that a chronic periodontal infection leads to a shift in cytokine expression and contributes to the development and/or progression of arthritic bone destruction via Th17 cells. This research and training program proposes two aims: Specific Aim 1: Compare the systemic cellular acquired immunological response of different strains of P. gingivalis using a murine chronic periodontitis model. The aim of this approach is to identify whether the chronic periodontal infection of different strains of Pg leads to distinct systemic immunological responses. Mice will be induced for periodontal disease by oral gavage with the following virulent Pg strains A7A1-28, W83, and W50. The acquired immunological response will be evaluated by serum cytokine expression and splenocyte analysis after periodontal disease induction. Based on the results, the Pg strains most relevant for influencing the Th17 immune response and initiating bone loss will be determined and utilized in specific aim 2. Specific Aim 2: Determine the acquired immunological effect of chronic periodontal disease during experimental RA development in mice. Mice will undergo induction of periodontal disease followed by collagen-induced arthritis. In vitro studies utilizing dendritic cells and T cells will provide a mechanistic approach for understanding alterations in T cell activation caused by Pg that may affect arthritis development. Serum cytokine and splenocyte analyses will identify changes in T cell activation and the acquisition of effector functions. These studies will provide an excellent training environment for research, involving experts in the fields of periodontology, pathology and immunology. The goal of this proposal is to better understand the immunologic mechanism(s) by which an oral infection could act as an environmental co-factor and influence arthritis. PUBLIC HEALTH RELEVANCE: Clinical studies demonstrate the existence of an association between periodontal disease and rheumatoid arthritis patients. However, the bi-directional influence of one disease on the other impedes the clarification of a mechanism linking both diseases. Strong evidence indicates that T helper type 17 cells drive both diseases, suggesting that the immune system is an important link between periodontitis and rheumatoid arthritis. The proposed research will help investigate the direct influence of periodontal disease in arthritis development. A mouse model will be induced for chronic periodontitis and arthritis for further exploration of the systemic acquired immune response. Identification of potential pathogen-host response modifiers that affect these two chronic, disabling diseases may advance understanding of disease pathogenesis and potential treatment approaches.