Peripheral blood dendritic cells and periodontitis

描述（由申请人提供）：树突状细胞（dc）在免疫应答中起着许多重要的作用，包括捕获外周的微生物，通过淋巴管运输到次级淋巴器官，以及将抗原呈递到幼稚T细胞。树突状细胞向淋巴结的转运能力受到包括树突状细胞成熟状态在内的许多因素的严格调控。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能够感染DC并破坏DC成熟，导致免疫抑制。这也可能误导DC运输，导致DC从组织直接反向转运到血液中，这一过程称为病原体运输。参与dc病原体通过血液运输到全身部位的炎症因子尚不清楚。动脉粥样硬化（ATH）的发展以活化的dc和其他白细胞侵袭动脉壁为特征。这些dc表达特定的动脉粥样硬化生物标志物，可以促进斑块破裂，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、刺激它们成为动脉粥样硬化和侵入ATH斑块的致病因素了解甚少。慢性牙周炎（CP），由牙龈卟啉卟啉菌（Pg）和其他细菌引起，是ATH的重要危险因素，接近吸烟和甘油三酯升高的危险因素。大多数证据表明，Pg感染和血清学暴露于Pg是ATH的重要危险因素。我们小组发表的工作已经确定了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型凝集素内噬受体，似乎可以维持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新的证据，有足够的数量进行统计推断，表明相对于健康对照，CP患者和急性冠状动脉综合征患者的DC-SIGN+和BDCA- 1+ dc在S&RP反应中发生动员。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显示其水平有所提高。这些研究的短期目标是进一步建立病原体贩运dc的概念证明。长期目标是在一组冠心病CP患者的动脉粥样硬化斑块中原位证实病原体转运dc。我们建议最终制定免疫治疗策略，以预防高风险冠心病患者的病原体转运dc。

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.