Inflammatory Periodontal Disease and Induction of Arthritis

炎症性牙周病和关节炎的诱发

基本信息

批准号：
8250220
负责人：
Julie Teresa Marchesan
金额：
$ 6.8万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8250220
关键词：
A Mouse Abscess Adult Affect Alveolar Bone Loss Antibodies Antigen Presentation Pathway Antigens Arthritis Autoimmune Diseases Cells Cessation of life Chronic Clinical Research Collagen Arthritis Complement Critiques DBA/1J Mouse Dendritic Cells Development Disease Distant Environment Evaluation Freund&apos s Adjuvant Funding Mechanisms Goals Human Immune response Immune system Immunologics Immunology In Vitro Infection Inflammation Inflammatory Interleukin-1 Interleukin-17 Interleukin-6 Knowledge Link Modeling Mus Nature Oral Pathogenesis Pathology Patients Periodontal Diseases Periodontal Infection Periodontitis Play Population Porphyromonas gingivalis Process Research Research Training Rheumatoid Arthritis Role Serum Site Splenocyte System T cell response T-Cell Activation T-Lymphocyte Training Training Programs Virulent base bone bone loss cytokine disabling disease in vivo incomplete Freund&apos s adjuvant joint destruction microorganism mouse model oral infection pathogen response soft tissue

项目摘要

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.

描述（由申请人提供）：牙周疾病是一种炎症感染，影响成年人群的10-15％。病原体牙龈疟原虫（PG）与疾病激活有关。牙周炎的慢性性表明，它可能是影响遥远部位疾病的微生物和细胞因子的恒定低级递送系统。临床研究表明，牙周疾病与其他疾病（例如类风湿关节炎（RA））之间存在关联。然而，双向疾病的相互作用阻碍了连接两种疾病的机制。 RA是一种自身免疫性疾病，影响130万美国成年人。 RA是一种多因素疾病，导致关节发炎和破坏。有力的证据表明，T辅助型17（TH17）细胞在RA发育中起着重要作用。细胞因子IL-17和Th17诱导剂IL-1和IL-6还显示出在牙周疾病发展中起重要作用。由于细胞因子微环境的控制会影响T细胞的激活，因此我们假设慢性牙周感染会导致细胞因子表达的变化，并有助于通过TH17细胞通过TH17细胞的关节骨破坏的发展和/或进展。该研究和培训计划提出了两个目标：特定目标1：比较使用鼠类慢性牙周炎模型的全身细胞获得的不同菌株的牙龈疟原虫菌株的免疫学反应。这种方法的目的是确定不同PG菌株的慢性牙周感染是否导致不同的系统性免疫反应。小鼠将通过口服肿瘤诱导牙周疾病，并具有以下有毒的PG菌株A7A1-28，W83和W50。牙周疾病诱导后，将通过血清细胞因子表达和脾细胞分析来评估获得的免疫反应。根据结果，将在特定目标2中确定并使用PG菌株与影响TH17免疫反应和引发骨质损失最相关的PG菌株。具体目标2：确定小鼠实验性RA发育过程中慢性牙周疾病的获得的免疫学效应。小鼠将诱导牙周疾病，然后患有胶原蛋白诱导的关节炎。利用树突状细胞和T细胞的体外研究将提供一种理解由PG引起的T细胞激活改变的机械方法，可能会影响关节炎的发展。血清细胞因子和脾细胞分析将确定T细胞激活和效应功能的获取的变化。这些研究将为研究提供出色的培训环境，涉及牙周病学，病理学和免疫学领域的专家。该提案的目的是更好地了解口腔感染可以作为环境共同因素并影响关节炎的免疫机制。公共卫生相关性：临床研究表明牙周疾病与类风湿关节炎患者之间存在关联。但是，一种疾病对另一种疾病的双向影响阻碍了将两种疾病联系起来的机制。有力的证据表明，T辅助型17型细胞驱动两种疾病，表明免疫系统是牙周炎与类风湿关节炎之间的重要联系。拟议的研究将有助于研究牙周疾病在关节炎发育中的直接影响。小鼠模型将被诱导用于慢性牙周炎和关节炎，以进一步探索全身性获得的免疫反应。鉴定影响这两种慢性疾病的潜在病原体宿主反应修饰符可能会提高对疾病发病机理和潜在治疗方法的了解。