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.

牙周疾病（PD）和类风湿关节炎（RA）具有许多共同特征。 PD是慢性 牙周的炎症性疾病，柔软的和硬的时机支撑牙齿，是 由于慢性细菌挑战而导致肺泡骨破坏的特征 免疫反应受损。 RA是腹膜关节的慢性炎症性疾病 导致迁移率降低。两种疾病都表现出强大的遗传成分，即“共享表位”（SE） HLA-DRβ1以及诸如烟草使用之类的生活方式组成部分，一种普遍存在的生活方式选择 在退伍军人中。我们以前已经证明，当添加共享表位作为转换 对于不容易受到胶原蛋白引起的关节炎（CIA）的小鼠，该小鼠（B10.M） 变得容易受到中央情报局的影响。 C57BL/6（B6）小鼠已被描述为不易骨头 推定的PD病原体损失或口服定植，革兰氏阴性厌氧porphyromonas 牙龈研究在PD研究中。我们已经设计了一只B6鼠标，以表达嵌合鼠/人SE 在没有鼠II类（B6.DR1小鼠）的情况下转基因，我们已经开始研究以确定 如果此HLA-DRβ1转换的表达可以为B6小鼠提供适当的一组 用牙龈疟原虫定殖所需的易感基因以及导致骨的所有途径 破坏。 该研究计划的总体目标是直接解决背后的机械基础 牙周炎与关节炎的发展之间的关联。我们假设牙周炎 允许组织类型（例如具有SE的宽松组织类型）将提供必要的PPAD 酶促进宿主蛋白柠檬氨酸的修饰，以驱动T细胞的发育及随后 ACPA生产。我们进一步假设ACPA会形成免疫复合物，从而增强血管 渗透性并允许任何数量的联合特定抗体结合到先天性的软骨 诸如完成和FCR结合到传播关节炎之类的机制。 这项研究很重要，因为它对拥有共同的退伍军人具有非常重要的影响 表位。如果我们的假设是正确的，它将表明积极的预防措施 可能需要进行更积极的牙周筛查，并且可能需要提高访问频率 为了防止退伍军人的关节炎，具有共享表位的任何sillic差异。这也可能包括 关节急性损伤后发生的关节炎。 我们的初步数据证明1）我们可以在人源化中建立PG口腔感染模型 B6.DR1小鼠，细菌存在于口腔中延长的时间，可以是 在血液中检测到2）口腔感染会诱导可免疫反应 通过ACPA的存在，Th17细胞的产生和诱导几个检测 促进弹性细胞因子，3）ACPA响应取决于HLA-DR1的表达 分子，4）PG感染导致牙周骨骼和周围的骨质损失显着 关节骨骼和5）PG感染诱导具有的小鼠自身免疫性关节炎的发展 已建立的自身免疫反应，但否则缺乏明显的疾病迹象。这些数据集体 提供支持我们主要假设的关键证据，我们建议使用的特定目标 检验这一假设。