Elucidating the Mechanisms that link the Shared Epitope, Periodontal Disease and Arthritis

阐明共享表位、牙周病和关节炎之间的联系机制

• 批准号: 9352706
• 负责人: DAVID D. BRAND
• 金额: --
• 依托单位: MEMPHIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9352706
• 关键词: Acute; Address; Adult; Affect; Alleles; Alveolar; Alveolar Bone Loss; Anaerobic Bacteria; Animals; Antibodies; Antigen-Antibody Complex; Arthritis; Autoantibodies; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Automobile Driving; Bacteria; Bacterial Infections; Behavioral; Binding; Blood; Cartilage; Cartilage injury; Cells; Cervical lymph node group; Chronic; Citrulline; Collagen Type II; Collagen-Induced Arthritis; Complement; Country; DR1 gene; Data; Degenerative Disorder; Degenerative polyarthritis; Development; Disease; Engineering; Enzymes; Epitopes; Equilibrium; Exhibits; Frequencies; Generations; Genetic; Gingiva; Goals; HLA-DR1 Antigen; Health; Histocompatibility; Human; Immune response; Immunization; Immunize; Incidence; Income; Infection; Inflammation; Inflammatory; Inflammatory Arthritis; Injury; Joints; Knock-out; Lead; Life Style; Link; Measurable; Measures; Mediating; Modeling; Modification; Morbidity - disease rate; Mus; Oral; Oral Administration; Oral cavity; Organism; Pathogenesis; Pathogenicity; Pathway interactions; Periodontal Diseases; Periodontitis; Phenotype; Play; Population; Porphyromonas gingivalis; Preventive measure; Production; Proteins; Protocols documentation; Regulatory T-Lymphocyte; Reporter; Research Project Grants; Rheumatoid Arthritis; Role; Smoking; Stream; Susceptibility Gene; T-Cell Development; T-Lymphocyte; Testing; Tissues; Tobacco use; Tooth structure; Transgenes; Variant; Vascular Permeabilities; Veterans; Visit; alveolar bone; alveolar destruction; arthropathies; autoimmune arthritis; base; bone; bone loss; citrullinated protein; cortical bone; cytokine; design; experimental study; humanized mouse; incomplete Freund' s adjuvant; oral infection; pathogen; pathogenic bacteria; permissiveness; prevent; programs; response; screening; substantia spongiosa

Periodontal disease (PD) and Rheumatoid Arthritis (RA) have many features in common. PD is a chronic inflammatory disease of the periodontium, the soft and hard tissues supporting the teeth, and is characterized by the destruction of the alveolar bone as a result of the chronic bacterial challenge and a compromised immune response. RA is a chronic inflammatory disease of the diarthrodial joints which results in reduced mobility. Both diseases exhibit a strong genetic component, the “shared epitope” (SE) HLA-DRβ1 as well as a lifestyle component such as tobacco use, a lifestyle choice that is prevalent among veterans. We have previously demonstrated that when the shared epitope is added as a transgene to a mouse that is known not to be susceptible to collagen-induced arthritis (CIA), this mouse (B10.M) becomes susceptible to CIA. C57BL/6 (B6) mice have been described as not being susceptible to bone loss or oral colonization with the putative PD pathogen, the gram negative anaerobe Porphyromonas gingivalis in studies of PD. We have engineered a B6 mouse to express a chimeric mouse/human SE as a transgene in the absence of its murine class II (B6.DR1 mouse), and we have begun studies to determine if expression of this HLA-DRβ1 transgene can provide the B6 mouse with the appropriate set of susceptibility genes necessary for colonization with P. gingivalis and for all the pathways that lead to bone destruction. The overarching goal of this program of study is to directly address the mechanistic basis behind the association between periodontitis and the development of arthritis. We hypothesize that periodontitis in the context of permissive tissue types (such as those bearing the SE) will provide the necessary pPAD enzymes to promote host protein citrulline modifications that drive T cell development and subsequent ACPA production. We further hypothesize that ACPAs form immune complexes that enhance vascular permeability and allow binding of any number of joint specific antibodies to the cartilage where innate mechanisms such as complement and FcR binding to propagate arthritis. This study is significant because it has very important implications for veterans bearing the shared epitope. Should our hypothesis prove correct, it will suggest that aggressive preventative measures including a more pro-active periodontal screening with an enhanced frequency of visits may be necessary to prevent arthritis in veterans bearing any allelic variation of the shared epitope. This might also include arthritis that develops following acute injury to the joint. Our preliminary data demonstrate 1) that we can establish an Pg oral infection model in the humanized B6.DR1 mice and that the bacteria are present for a prolong period in the oral cavity, and can be detected in the blood stream, 2) that infection of the oral cavity induces an immune response that can be detected by the presence of ACPA, the generation of Th17 cells, and the induction of several proinflammatory cytokines, 3) that the ACPA response is dependent on the expression of the HLA-DR1 molecule, 4) that Pg infection leads to significant bone loss both in periodontal bones as well as peri- articular bones, and 5) Pg infection induces the development of autoimmune arthritis in mice that have an established autoimmune response but otherwise lack overt signs of disease. Collectively, these data provide critical evidence in support of our primary hypothesis, and the specific aims we propose to use to test this hypothesis.

牙周病（PD）和类风湿性关节炎（RA）有许多共同点，PD都是一种慢性病。 牙周组织（支撑牙齿的软组织和硬组织）的炎症性疾病， 其特点是由于慢性细菌的攻击和牙槽骨的破坏 免疫反应受损是一种慢性关节炎症性疾病。 这两种疾病都表现出强大的遗传成分，即“共享表位”（SE）。 HLA-DRβ1 以及生活方式的组成部分，例如吸烟，这是一种普遍的生活方式选择 我们之前已经证明，当共享表位作为转基因添加时。 已知对胶原诱导性关节炎 (CIA) 不敏感的小鼠，这只小鼠 (B10.M) C57BL/6 (B6) 小鼠被描述为对骨不敏感。 推定的帕金森病病原体（革兰氏阴性厌氧菌卟啉单胞菌）丢失或口腔定植 我们设计了 B6 小鼠来表达嵌合小鼠/人类 SE 作为 PD 研究中的牙龈线虫。 在缺乏小鼠 II 类（B6.DR1 小鼠）的情况下进行转基因，我们已经开始研究以确定 如果该 HLA-DRβ1 转基因的表达可以为 B6 小鼠提供适当的一组 牙龈卟啉单胞菌定植和所有通往骨的途径所必需的易感基因 破坏。 该研究计划的总体目标是直接解决背后的机制基础 牙周炎与关节炎的发展之间的关联我们勇敢地承认牙周炎。 允许的组织类型（例如具有 SE 的组织类型）的背景将提供必要的 pPAD 促进宿主蛋白瓜氨酸修饰的酶，从而驱动 T 细胞发育和后续 我们进一步研究 ACPA 形成增强血管的免疫复合物。 渗透性并允许任意数量的关节特异性抗体与固有的软骨结合 补体和 FcR 结合等机制可传播关节炎。 这项研究意义重大，因为它对承担共同责任的退伍军人具有非常重要的意义。 如果我们的假设被证明是正确的，它将建议采取积极的预防措施。 可能需要进行更主动的牙周筛查并增加就诊频率 预防携带共享表位的任何等位基因变异的退伍军人的关节炎。 关节急性损伤后发生的关节炎。 我们的初步数据表明1）我们可以在人源化模型中建立Pg口腔感染模型 B6.DR1 小鼠，并且细菌在口腔中存在很长一段时间，并且可以 在血流中检测到，2) 口腔感染会诱发免疫反应，该反应可以 通过 ACPA 的存在、Th17 细胞的产生以及多种细胞的诱导来检测 促炎细胞因子，3) ACPA 反应依赖于 HLA-DR1 的表达 分子，4）表明 Pg 感染导致牙周骨和牙周骨显着骨质流失 关节骨，5) Pg 感染会诱导患有自身免疫性关节炎的小鼠发生自身免疫性关节炎 总体而言，这些数据缺乏明确的自身免疫反应，但缺乏明显的疾病迹象。 提供关键证据来支持我们的主要假设，以及我们建议使用的具体目标 来检验这个假设。