Peripheral blood dendritic cells and periodontitis

描述(申请人提供)：树突状细胞(DC)在免疫反应中发挥许多重要功能，包括捕获外周微生物，通过淋巴管向次级淋巴器官运输，以及将抗原呈递给初始T细胞。DC向淋巴结的转运能力受到包括DC成熟状态在内的多种因素的严格调控。人类病原体如HIV-1、结核分枝杆菌、幽门螺杆菌和牙龈卟啉单胞菌等能够感染DC，扰乱DC成熟，导致免疫抑制。这也可能误导DC的交通，导致DC从组织直接进入血液的反向转移，这一过程称为病原体贩运。树突状细胞通过血液转运到全身部位所涉及的炎症因子尚不清楚。动脉粥样硬化(ATH)的发展特征是以活化的DC和其他白细胞侵入动脉壁为特征。这些树突状细胞表达特定的致动脉粥样硬化生物标志物，可促进斑块破裂、血栓形成，并增加心脏病发作和中风的风险。我们目前对动员DC进入血液、刺激它们形成动脉粥样硬化并侵袭ATH斑块的致病因素知之甚少。慢性牙周炎(CP)是由牙龈假单胞菌(PG)和其他细菌引起的，是ATH的重要危险因素，接近吸烟和甘油三酯升高。大多数证据表明，PG感染和PG的血清学暴露是ATH的重要危险因素。我们课题组发表的工作已经证实了HIV-1受体DC-SIGN在CP的组织病理学和PG感染DC中的重要作用。DC-SIGN是一种C型凝集素内源性受体，可维持DC处于半成熟的免疫抑制/迁移状态，并与内皮细胞上的ICAM-2结合。我们现在在几个患者队列中有了足够多的统计推断的新证据，表明相对于健康对照组，CP患者和急性冠脉综合征患者DC-SIGN+和BDCA-1+DC发生了动员。我们还通过基因测序证实了我们的PG 16S rDNA探针的特异性，并通过巢式qRT-PCR显示其水平增加。这些研究的短期目标是进一步建立对病原体贩运的概念验证。长期目标是证实病原体在动脉粥样硬化斑块中的原位运输，来自一组患有CP的冠状动脉疾病患者。我们建议最终开发免疫治疗策略，以防止冠状动脉疾病高危患者的病原体贩运树突状细胞。 公共卫生相关性：这项研究的目的是确定感染性病原体如何侵入口腔粘膜，并在称为树突状细胞的白细胞内在全身传播。我们现在已经发表了我们的新发现，即口腔病原体牙龈卟啉单胞菌如何靶向HIV-1用来感染树突状细胞并被携带到T细胞上的树突状细胞上的受体(即DC-SIGN)，从而诱导获得性免疫缺陷综合征(AIDS)。有趣的是，这些树突状细胞在慢性牙周炎(CP)中渗入口腔粘膜，在炎症性疾病动脉粥样硬化(ATH)或动脉硬化中也渗入不稳定的动脉粥样硬化斑块。CP是ATH的一个主要危险因素，但我们目前还不清楚原因。我们的研究表明，口腔粘膜中的树突状细胞可能会感染牙龈假单胞菌，引发树突状细胞迁移到血流和心脏附近的动脉，从而导致ATH。这些拟议的人体研究将确定CP患者血液中的树突状细胞，以及它们是如何感染牙龈假单胞菌的。

DESCRIPTION (provided by applicant): Dendritic cells (DCs) serve many important functions in the immune response, including the capture of microbes in the periphery, trafficking through the lymphatics to the secondary lymphoid organs, and antigen presentation to naive T cells. The trafficking ability of DCs to lymph nodes is tightly regulated by many factors including the DC maturation state. Human pathogens such as HIV-1, Mycobacterium tuberculosis, Helicobacter pylori and Porphyromonas gingivalis are able to infect DCs and disrupt DC maturation, leading to immunosuppression. This may also misdirect DC traffic, resulting in reverse transmigration of DCs from tissues directly into the bloodstream, in a process called pathogen trafficking. The inflammatory factors involved in pathogen trafficking of DCs to systemic sites through the blood are unclear. The development of atherosclerosis (ATH) is characterized by invasion of the arterial wall with activated DCs and other leukocytes. These DCs express specific atherogenic biomarkers that can promote plaque rupture, thrombus formation, and increase risk of heart attack and stroke. We presently understand very little about the pathogenic factors that mobilize DCs into the blood, that stimulate them to become atherogenic and invade ATH plaques. Chronic periodontitis (CP), initiated by P. gingivalis (Pg) and other bacterial species, is a significant risk factor for ATH, approaching that of smoking and elevated triglycerides. Most evidence points to infection with Pg and serologic exposure to Pg as being important risk factors for ATH. Published work from our group has identified an important role for the HIV-1 receptor DC-SIGN in the histopathology of CP and in infection of DCs by Pg. DC-SIGN is a C-type lectin endocytic receptor that appears to maintain DCs in an semi-mature immunosuppressive/migratory state and also binds to ICAM-2 on endothelial cells. We now have new evidence in several patient cohorts, in sufficient numbers for statistical inference, indicating that DC-SIGN+ and BDCA- 1+ DCs undergo mobilization in CP patients in response to S&RP and in acute coronary syndrome patients, relative to healthy controls. We have also confirmed the specificity of our Pg 16s rDNA probes by gene sequencing and have shown increased levels by nested qRt-PCR. The short term objectives of these studies are to further establish proof- of- concept for pathogen trafficking DCs. The long term objectives are to corroborate pathogen trafficking DCs in situ in atherosclerotic plaques from a cohort of coronary artery disease patients with CP. We propose to ultimately develop immunotherapeutic strategies for the prevention of pathogen trafficking DCs in patients at high risk for developing coronary artery disease. PUBLIC HEALTH RELEVANCE: The purpose of this study is to determine how infectious agents may invade the oral mucosa and disseminate throughout the body within white blood cells called dendritic cells. We have now published our novel findings on how the oral pathogen Porphyromonas gingivalis targets the receptor on dendritic cells (i.e. DC-SIGN) that HIV-1 uses to infect dendritic cells and get carried to T cells, thereby inducing acquired immunodeficiency syndrome (AIDS). Interestingly, these DCs infiltrate the oral mucosa in chronic periodontitis (CP) and also infiltrate unstable atheromatous plaques in the inflammatory disease atherosclerosis (ATH) or hardening of the arteries. CP is a major risk factor for ATH, but we don't presently understand why. Our studies suggest that dendritic cells from the oral mucosa may become infected with P. gingivalis, triggering the migration of dendritic into the bloodstream and to and arteries near your heart, contributing to ATH. These proposed studies in humans will identify these dendritic cells in the blood of CP patients and how they become infected by P. gingivalis.