Antiphospholipids and vascular inflammation in aggressive periodontitis

描述(由申请人提供)：最近的数据表明牙周炎是许多全身疾病的危险因素，但牙周感染调节全身反应的机制尚不清楚。我们注意到牙周炎患者的血清抗磷脂抗体水平升高。这类抗体，包括β2糖蛋白1依赖的抗心磷脂(anti-CL)，存在于自身免疫性疾病患者中，如系统性红斑狼疮和抗磷脂综合征，并可能由各种微生物感染诱导。这些抗体的作用是诱导血栓前状态，并可能导致中风、早期动脉粥样硬化和不良妊娠结局，如胎儿退缩、早产和低出生体重。这些抗CL升高的后遗症与牙周感染可能的后遗症之间的相似性促使我们进一步研究牙周炎患者的这些抗体。我们观察到，在牙周炎患者中，即使在非吸烟者中，抗CL水平的升高与血清细胞黏附分子浓度的升高也有显著的相关性，如sVCAM-1和sE-选择素。此外，在全身性侵袭性牙周炎(GAgP)患者中，抗CL升高与血清sICAM-1、sVCAM-1、sE-选择素和CRP升高相关，这表明这些患者表现出全身血管炎症指标的升高。我们建议通过在使用内皮细胞和巨噬细胞的体外系统中检测纯化的抗体来确定侵袭性牙周炎患者的抗CL是否是致病的。此外，我们将确定通过积极治疗解决GAgP患者的牙周感染是否也会降低抗CL和炎症介质水平。我们将检测血管炎症和血栓形成的其他标记物，以确定牙周炎患者抗CL可能影响全身炎症的途径。最后，我们将评估牙周病病原体诱导致病性抗CL的能力，方法是用含有假定的针对Beta2GP1的交叉反应肽序列的细菌免疫小鼠，并测试产生的抗体的致病性。这些研究可能解释为什么牙周炎患者的某些亚组患以血管炎症为特征的疾病的风险增加，如动脉粥样硬化、中风和不良妊娠结局。他们还将建议在牙周炎患者中应用可用的抗磷脂诊断测试以及有益的治疗方法。最近的数据表明，牙周病可以影响全身健康的参数，但其发生的机制尚不清楚。我们的研究将检查口腔中的细菌促进抗体产生的能力，这种抗体已知会在其他疾病中诱导血管炎症和促凝血活性。如果这被证明是将口腔微生物群与身体其他部位联系起来的重要机制，那么对患有系统性红斑狼疮等疾病的患者进行常规实验室检测可以很容易地应用于牙周炎患者，以预测系统性后遗症的风险，并可以系统地应用支持性或预防性护理。

DESCRIPTION (provided by applicant): Recent data implicate periodontitis as a risk factor for a number of systemic conditions but mechanisms whereby periodontal infections mediate systemic responses are not clear. We have noted that patients with periodontitis have elevated serum levels of antiphospholipid antibodies. Such antibodies, including beta 2 glycoprotein 1-dependant anti-cardiolipin (anti-CL) are present in patients with autoimmune diseases such as SLE and the Antiphospholipid Syndrome and may be induced by a variety of microbial infections. These antibodies function to induce a prothrombotic state and can cause stroke, early atherosclerosis, and adverse pregnancy outcomes such as fetal involution, prematurity, and low birth weight. The similarity between these sequelae of elevated anti-CL and putative sequelae of periodontal infection have led us to further study these antibodies in periodontitis patients. We have observed that there are significant associations between elevated levels of anti-CL and elevated serum concentrations of cell-adhesion molecules such as sVCAM-1 and sE- selectin in periodontitis patients, even in non-smokers. Furthermore, in generalized aggressive periodontitis (GAgP) patients, elevated anti-CL are associated with elevated serum sICAM-1, sVCAM-1, sE-selectin, and CRP, indicating that such patients demonstrated elevated systemic measures of vascular inflammation. We propose to determine whether anti-CL in aggressive periodontitis patients are pathogenic by testing purified antibodies in in vitro systems employing endothelial cells and macrophages. Additionally, we will determine if resolution of periodontal infection in GAgP by aggressive therapy also decreases both anti-CL and inflammatory mediator levels. We will examine additional markers of vascular inflammation and thrombosis to determine the pathways whereby anti-CL in periodontitis patients may influence systemic inflammation. Finally, we will assess the ability of periodontal disease pathogens to induce pathogenic anti-CL by immunizing mice with bacteria containing putative cross-reactive peptide sequences to beta2GP1 and testing resultant antibodies for pathogenicity. These studies may explain why some subsets of periodontitis patients are at increased risk for diseases characterized by vascular inflammation, such as atherosclerosis, stroke, and adverse pregnancy outcomes. They will also suggest applications of available diagnostic tests for antiphospholipids in periodontitis patients as well as beneficial therapeutic approaches. Recent data indicate that periodontal disease can influence parameters of systemic health but the mechanisms whereby this occurs are not clear. Our studies will examine the ability of bacteria in the oral cavity to promote production of an antibody that is known to induce vascular inflammation and procoagulant activity in other diseases. Should this prove to be an important mechanism linking the oral microflora with other parts of the body, laboratory tests routinely administered to patients with diseases such as systemic lupus erythematosis could be readily applied to periodontitis patients to predict risk for systemic sequelae, and supportive or preventive care could be systematically applied.