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
基本信息
- 批准号:9898304
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AcuteAddressAdultAffectAllelesAlveolarAlveolar Bone LossAnaerobic BacteriaAnimalsAntibodiesAntigen-Antibody ComplexArthritisAutoantibodiesAutoimmune DiseasesAutoimmune ResponsesAutoimmunityAutomobile DrivingBacteriaBacterial InfectionsBehavioralBindingBloodCartilageCartilage injuryCellsCervical lymph node groupChronicCitrullineCollagen ArthritisCollagen Type IIComplementCountryDR1 geneDataDegenerative DisorderDegenerative polyarthritisDevelopmentDiseaseEngineeringEnzymesEpitopesEquilibriumExhibitsFrequenciesGenerationsGeneticGingivaGoalsHLA-DR1 AntigenHealthHistocompatibilityHumanImmune responseImmunizationImmunizeIncidenceIncomeInfectionInflammationInflammatoryInflammatory ArthritisInjuryJointsKnock-outLeadLife StyleLinkMeasurableMeasuresMediatingModelingModificationMorbidity - disease rateMusOralOral AdministrationOral cavityOrganismPathogenesisPathogenicityPathway interactionsPeriodontal DiseasesPeriodontitisPhenotypePlayPopulationPorphyromonas gingivalisPreventive measureProductionProteinsProtocols documentationRegulatory T-LymphocyteReporterResearch Project GrantsRheumatoid ArthritisRoleSmokingStreamSusceptibility GeneT-Cell DevelopmentT-LymphocyteTestingTissuesTobacco useTooth structureTransgenesVariantVascular PermeabilitiesVeteransVisitalveolar bonealveolar destructionarthropathiesautoimmune arthritisbasebonebone losschronic inflammatory diseasecitrullinated proteincortical bonecytokinedesignexperimental studyhumanized mouseincomplete Freund&aposs adjuvantneoantigensoral infectionpathogenpathogenic bacteriapreventprogramsresponsescreeningsubstantia spongiosa
项目摘要
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.
风湿性关节炎(RA)和牙周病(PD)有许多共同的特点。PD是一种慢性
在牙周炎性疾病中,牙周组织是支撑牙齿的软组织和硬组织,
其特征在于由于慢性细菌挑战而导致牙槽骨的破坏,
免疫反应受损类风湿性关节炎是一种慢性关节炎性疾病,
导致流动性降低。这两种疾病都表现出很强的遗传成分,即“共享表位”(SE)
HLA-DRβ1以及一种生活方式成分,如烟草使用,这是一种流行的生活方式选择
在退伍军人中。我们以前已经证明,当共享表位作为转基因加入时,
对于已知对胶原诱导的关节炎(CIA)不敏感的小鼠,该小鼠(B10.M)
变得容易受到中情局的影响C57 BL/6(B6)小鼠被描述为对骨不敏感
丧失或口服定植假定的PD病原体,革兰氏阴性厌氧菌卟啉单胞菌
牙龈炎的研究。我们已经改造了B6小鼠,使其表达嵌合小鼠/人SE,
转基因的情况下,其小鼠II类(B6.DR1小鼠),我们已经开始研究,以确定
如果这种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所必需的易感基因和导致骨形成的所有途径
杀伤性
这项研究计划的总体目标是直接解决机械背后的基础,
牙周炎和关节炎的发展之间的联系。我们假设,牙周炎,
允许的组织类型(例如携带SE的组织)的背景将提供必要的pPAD
酶促进宿主蛋白质瓜氨酸修饰,从而驱动T细胞发育和随后的
ACPA生产。我们进一步假设ACPA形成免疫复合物,
渗透性,并允许任何数量的关节特异性抗体与软骨结合,
例如补体和FcR结合以传播关节炎的机制。
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。
表位如果我们的假设被证明是正确的,这将表明积极的预防措施
包括一个更积极的牙周检查与增加访问的频率可能是必要的
以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。这可能还包括
关节急性损伤后出现的关节炎。
我们的初步数据表明:1)我们可以建立人源化的Pg口腔感染模型,
B6.DR1小鼠,并且细菌在口腔中存在较长时间,并且可以被
2)口腔感染会诱导免疫反应,
通过ACPA的存在、Th 17细胞的产生和几种细胞因子的诱导来检测。
促炎性细胞因子,3)ACPA反应依赖于HLA-DR 1的表达
分子,4)Pg感染导致牙周骨和牙周组织中的显著骨丢失,
关节骨,和5)Pg感染诱导小鼠自身免疫性关节炎的发展,
一种建立的自身免疫反应,但缺乏明显的疾病迹象。这些数据共同
提供关键证据支持我们的主要假设,以及我们建议使用的具体目标
来验证这个假设
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A self-organising biomimetic collagen/nano-hydroxyapatite-glycosaminoglycan scaffold for spinal fusion.
用于脊柱融合的自组织仿生胶原蛋白/纳米羟基磷灰石-糖胺聚糖支架。
- DOI:10.1007/s10853-017-1229-9
- 发表时间:2017
- 期刊:
- 影响因子:4.5
- 作者:Sharma,Aman;Brand,David;Fairbank,Jeremy;Ye,Hua;Lavy,Chris;Czernuszka,Jan
- 通讯作者:Czernuszka,Jan
Collagen-Induced Arthritis Mouse Model.
- DOI:10.1002/cpz1.313
- 发表时间:2021-12-01
- 期刊:
- 影响因子:0
- 作者:Rosloniec, Edward F;Whittington, Karen;Brand, David D
- 通讯作者:Brand, David D
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{{ truncateString('DAVID D. BRAND', 18)}}的其他基金
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 - 财政年份:2017
- 资助金额:
-- - 项目类别:
Program Project for Mechanisms and Treatment of Arthritis
关节炎的机制和治疗计划项目
- 批准号:
8598790 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Program Project for Mechanisms and Treatment of Arthritis
关节炎的机制和治疗计划项目
- 批准号:
8246345 - 财政年份:2012
- 资助金额:
-- - 项目类别:
GENETIC SUSCEPTIBILITY TO COLLAGEN INDUCED ARTHRITIS
对胶原蛋白引起的关节炎的遗传易感性
- 批准号:
2078077 - 财政年份:1994
- 资助金额:
-- - 项目类别:
GENETIC SUSCEPTIBILITY TO COLLAGEN INDUCED ARTHRITIS
对胶原蛋白引起的关节炎的遗传易感性
- 批准号:
2078076 - 财政年份:1993
- 资助金额:
-- - 项目类别:
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