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Periodontitis, Anti-phospholipids, Dendritic Cells, and Atherosclerosis

牙周炎、抗磷脂、树突状细胞和动脉粥样硬化

基本信息

批准号：
7595038
负责人：
HARVEY Allen SCHENKEIN
金额：
$ 32.16万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7595038
关键词：
Actinobacillus actinomycetemcomitans Address Allogenic Animal Model Antigen-Antibody Complex Antiphospholipid Antibodies Aorta Arterial Fatty Streak Arteries Arteriosclerosis Atherosclerosis Autologous Bacteria Biological Blood Cardiolipins Cardiovascular Diseases Cell Maturation Cells Chronic Complement 1q Complement Receptor Complex Coupled DNA Data Dendritic Cells Dyslipidemias E-Selectin Epidemiology Epidermis Etiology Excision Exhibits Exposure to Glycoproteins Goals Healthy People 2010 Heart Diseases Heat shock proteins Human Immune response Immunodeficient Mouse Inflammation Inflammatory Interleukin-12 Langerhans cell Lesion Leukocytes Link Longitudinal Studies Low-Density Lipoproteins Lymphocyte Lymphoid Tissue Mediating Membrane Minimally modified Low Density Lipoprotein Mixed Lymphocyte Culture Test NCAM1 gene Natural Killer Cells Opsonin Pathogenesis Patients Periodontitis Phenotype Phospholipids Phosphorylcholine Porphyromonas gingivalis Production Proteins Reagent Recurrence Research Personnel Serum Site Skin Stroke Subendothelial Layer T-Lymphocyte Testing Vascular Cell Adhesion Molecule-1 Work cardiovascular risk factor cytokine improved oxidation pathogen prevent response vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): A subset of periodontitis patients has elevated levels of anti-phospholipid Abs including anti-cardiolipin (anti- CL) and anti-phosphorylcholine (anti-PC). These Abs react with periodontal pathogens including P. gingivalis and A. actinomycetemcomitans and immune responses to periodontal bacteria appear to explain why these Abs are elevated. Markers of vascular inflammation including soluble VCAM-1 and E-selectin correlated with elevated levels of anti-CL in our periodontitis patients further supporting our hypothesis that the subset of patients with elevated anti-phospholipid antibodies may be at increased risk for cardiovascular sequelae. These anti-phospholipids also interact with minimally modified LDL (mmLDL) and form immune complexes (ICs) and ICs are rapidly trapped by immature dendritic cells (DCs) that are present in blood, along the subendothelial layer of non-diseased arterial wall, and in atheromas. Fc and complement receptors expressed on DCs facilitate 1C trapping and in the atherogenic plaque DCs express membrane C1q and this is also thought to assist in trapping ICs including mmLDL-ICs. DCs also efficiently trap bacteria in ICs and this may help explain why Ags and DNA from periodontal pathogens, including P. gingivalis, are in atherosclerotic plaque. A current concept is that atherosclerosis develops as a consequence of inflammatory mechanisms coupled with dyslipidaemia. Preliminary data indicate that P. gingivalis and LDL stimulate production of proinflammatory cytokines including IL-12 from DCs and IFN-y from DC stimulated NK cells. Furthermore, converting mmLDL or P. gingivalis into ICs with anti-phospholipid Abs enhanced proinflammatory cytokine production. These data prompt the hypothesis that IC-stimulated DCs induce NK cells, and T cells to produce elevated levels of proinflammatory cytokines and participate in the pathogenesis of atherosclerosis. Recurrent exposure to ICs could promote chronic inflammation and help explain epidemioloqical data suggesting that periodontitis patients are more likely to develop atherosclerosis. We propose to confirm and extend our data supporting this Ab mediated mechanism. A biological mechanism linking periodontitis and atherosclerosis would lend credibility to the epidemiological associations and help provide rationale for long-term longitudinal studies required to demonstrate causality.

描述（由申请人提供）：一部分牙周炎患者的抗磷脂抗体水平升高，包括抗心磷脂（抗CL）和抗磷酸胆碱（抗PC）。这些Ab与牙周病原体包括牙龈卟啉单胞菌和A.放线菌共生菌和牙周细菌的免疫反应似乎可以解释为什么这些抗体升高。在我们的牙周炎患者中，血管炎症标志物（包括可溶性VCAM-1和E-选择素）与抗CL水平升高相关，这进一步支持了我们的假设，即抗磷脂抗体升高的患者亚组可能患心血管后遗症的风险增加。这些抗磷脂还与最低限度修饰的LDL（mmLDL）相互作用并形成免疫复合物（IC），IC被血液中、沿着未患病动脉壁的内皮层下和动脉粥样硬化中存在的未成熟树突细胞（DC）迅速捕获。DC上表达的Fc和补体受体促进IC捕获，并且在致动脉粥样硬化斑块中，DC表达膜C1 q，这也被认为有助于捕获IC，包括mmLDL-IC。树突状细胞还有效地捕获IC中的细菌，这可能有助于解释为什么牙周病原体（包括牙龈卟啉单胞菌）的Ag和DNA存在于动脉粥样硬化斑块中。目前的概念是动脉粥样硬化的发展是炎症机制与血脂异常相结合的结果。初步数据表明牙龈卟啉单胞菌和LDL刺激促炎细胞因子的产生，包括来自DC的IL-12和来自DC刺激的NK细胞的IFN-γ。此外，用抗磷脂抗体将mmLDL或牙龈卟啉单胞菌转化为IC增强了促炎细胞因子的产生。这些数据提示了IC刺激的DC诱导NK细胞和T细胞产生高水平的促炎细胞因子并参与动脉粥样硬化的发病机制的假设。反复暴露于IC可以促进慢性炎症，并有助于解释流行病学数据表明，牙周炎患者更容易发展为动脉粥样硬化。我们建议确认和扩展我们的数据支持这种抗体介导的机制。牙周炎和动脉粥样硬化之间的生物学机制将为流行病学关联提供可信度，并有助于为证明因果关系所需的长期纵向研究提供理论基础。