Inflammatory Periodontal Disease and Induction of Arthritis

炎症性牙周病和关节炎的诱发

• 批准号: 8331699
• 负责人: Julie Teresa Marchesan
• 金额: $ 4.66万
• 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 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8331699
• 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; abstracting; base; bone; bone loss; cytokine; disabling disease; in vivo; incomplete Freund' s adjuvant; joint destruction; microorganism; mouse model; oral infection; pathogen; response; soft tissue

Abstract 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 Th 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.

摘要 牙周病是一种炎症性感染，影响10-15%的成年人口。病原体牙龈卟啉单胞菌（Pg）与疾病激活有关。牙周炎的慢性性表明它可能作为一个恒定的，低级别的微生物和细胞因子的传递系统，影响疾病在遥远的网站。临床研究表明牙周病和其他疾病，如类风湿性关节炎（RA）之间的联系。然而，双向疾病的相互作用阻碍了两种疾病之间的联系机制的澄清。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，导致关节炎症和破坏。强有力的证据表明，辅助性T细胞17型（Th 17）在RA的发展中发挥重要作用。细胞因子IL-17和Th 17诱导剂IL-1和IL- 6也显示在牙周病发展中起重要作用。由于细胞因子微环境的控制影响Th细胞的活化，我们假设慢性牙周感染导致细胞因子表达的转变，并通过Th 17细胞促进关节炎骨破坏的发展和/或进展。 该研究和培训方案提出了两个目标： 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应答。 这种方法的目的是确定是否慢性牙周感染的不同菌株的Pg导致不同的全身免疫反应。将通过经口灌胃以下强毒Pg菌株A7 A1 -28、W83和W50诱导小鼠的牙周病。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性免疫应答。根据结果，将确定与影响Th 17免疫应答和引发骨丢失最相关的Pg菌株，并将其用于特定目标2。 具体目标2：确定慢性牙周病在小鼠实验性RA发展过程中的获得性免疫效应。 小鼠将经历牙周病的诱导，然后是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机制的方法来理解由Pg引起的T细胞活化的改变，这可能会影响关节炎的发展。血清细胞因子和脾细胞分析将鉴定T细胞活化和效应子功能获得的变化。这些研究将为研究提供一个极好的培训环境，涉及牙周病学、病理学和免疫学领域的专家。该提案的目标是更好地了解口腔感染可能作为环境辅助因素并影响关节炎的免疫机制。