Periodontitis, Anti-phospholipids, Dendritic Cells, and Atherosclerosis

描述(申请人提供)：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)和抗磷胆碱(抗PC)。这些抗体与牙周病原体包括牙龈假单胞菌和伴生放线菌发生反应，对牙周细菌的免疫反应似乎解释了这些抗体升高的原因。包括可溶性VCAM-1和E-选择素在内的血管炎症标志物与我们的牙周炎患者中抗CL水平的升高相关，进一步支持了我们的假设，即抗磷脂抗体升高的患者亚群可能有更高的心血管后遗症风险。这些抗磷脂还与最小修饰低密度脂蛋白(MmLDL)相互作用，形成免疫复合物(IC)，IC迅速被存在于血液、非病变动脉壁内皮下层和动脉粥样硬化中的未成熟树突状细胞(DC)捕获。DC上表达的Fc和补体受体促进了1C的捕获，在动脉粥样硬化斑块中，DC表达C1q膜，这也被认为有助于捕获ICs，包括MmLDLICs。DC还能有效地捕获ICs中的细菌，这可能有助于解释为什么牙周病原体(包括牙周病原体)的AGS和DNA会出现在动脉粥样硬化斑块中。目前的一个概念是，动脉粥样硬化的形成是炎症机制与血脂异常相结合的结果。初步数据表明，牙龈假单胞菌和低密度脂蛋白能刺激DC产生IL-12和DC刺激的NK细胞产生干扰素-γ等促炎细胞因子。此外，用抗磷脂抗体将MmLDL或P.gigivalis转化为ICs可促进促炎细胞因子的产生。这些数据提示假设，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。反复接触ICs可能会促进慢性炎症，并有助于解释流行病学数据显示牙周炎患者更有可能发展为动脉粥样硬化。我们建议证实和扩展我们的数据支持这一抗体介导的机制。将牙周炎和动脉粥样硬化联系起来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。

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.