Inflammatory Periodontal Disease and Induction of Arthritis

炎症性牙周病和关节炎的诱发

• 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
• 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' 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' s adjuvant; joint destruction; microorganism; mouse model; oral infection; pathogen; response; soft tissue

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）：牙周病是一种炎症感染，影响 10-15% 的成年人口。病原体牙龈卟啉单胞菌 (Pg) 与疾病的激活有关。牙周炎的慢性性表明，它可能作为微生物和细胞因子的持续、低级传递系统，影响远处的疾病。临床研究表明牙周病与其他疾病（例如类风湿性关节炎（RA））之间存在关联。然而，疾病的双向相互作用阻碍了阐明这两种疾病之间的联系机制。 RA 是一种自身免疫性疾病，影响着 130 万美国成年人。 RA 是一种多因素疾病，会导致关节炎症和破坏。强有力的证据表明 17 型辅助 T (Th17) 细胞在 RA 发展中发挥重要作用。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，因此我们推测慢性牙周感染会导致细胞因子表达的变化，并通过 Th17 细胞促进关节炎骨破坏的发生和/或进展。该研究和培训计划提出了两个目标： 具体目标 1：使用小鼠慢性牙周炎模型比较不同牙龈卟啉单胞菌菌株的全身细胞获得性免疫反应。该方法的目的是确定不同 Pg 菌株的慢性牙周感染是否会导致不同的全身免疫反应。通过用以下强毒力Pg菌株A7A1-28、W83和W50口服强饲来诱导小鼠患牙周病。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的免疫反应。根据结果​​，将确定与影响 Th17 免疫反应和引发骨质流失最相关的 Pg 菌株，并将其用于特定目标 2。特定目标 2：确定小鼠实验性 RA 发展过程中慢性牙周病的获得性免疫效应。小鼠将经历牙周病的诱导，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 细胞活化变化提供一种机制方法，这种变化可能会影响关节炎的发展。血清细胞因子和脾细胞分析将识别 T 细胞激活和效应功能获得的变化。这些研究将为牙周病学、病理学和免疫学领域的专家参与的研究提供良好的培训环境。该提案的目的是更好地了解口腔感染作为环境辅助因素并影响关节炎的免疫机制。 公众健康相关性：临床研究表明牙周病与类风湿性关节炎患者之间存在关联。然而，一种疾病对另一种疾病的双向影响阻碍了阐明这两种疾病之间的联系机制。强有力的证据表明，17 型辅助 T 细胞驱动这两种疾病，表明免疫系统是牙周炎和类风湿性关节炎之间的重要联系。拟议的研究将有助于调查牙周病对关节炎发展的直接影响。将诱导慢性牙周炎和关节炎小鼠模型，以进一步探索全身获得性免疫反应。识别影响这两种慢性致残性疾病的潜在病原体-宿主反应调节剂可能会促进对疾病发病机制和潜在治疗方法的了解。