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性疾病的危险因素，但牙周感染介导全身反应的机制尚不清楚。我们注意到牙周炎患者血清抗磷脂抗体水平升高。此类抗体，包括β 2糖蛋白1依赖性抗心磷脂（抗CL），存在于自身免疫性疾病（例如SLE和抗磷脂综合征）患者中，并且可能由多种微生物感染诱导。这些抗体的功能是诱导血栓前状态，并可导致中风、早期动脉粥样硬化和不良妊娠结局，如胎儿退化、早产和低出生体重。抗CL升高的这些后遗症和牙周感染的假定后遗症之间的相似性使我们进一步研究牙周炎患者中的这些抗体。我们已经观察到，在牙周炎患者中，甚至在非吸烟者中，抗CL水平升高与细胞粘附分子如sVCAM-1和sE-选择素的血清浓度升高之间存在显著关联。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，表明此类患者表现出血管炎症的全身指标升高。我们建议，以确定是否抗CL在侵袭性牙周炎患者的致病性测试纯化的抗体在体外系统采用内皮细胞和巨噬细胞。此外，我们将确定是否解决牙周感染的GAgP积极的治疗也降低了抗CL和炎症介质的水平。我们将检查血管炎症和血栓形成的其他标志物，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，免疫小鼠与细菌含有假定的交叉反应肽序列β 2GP 1和测试产生的抗体的致病性。这些研究可以解释为什么牙周炎患者的某些子集患血管炎症疾病的风险增加，如动脉粥样硬化，中风和不良妊娠结局。他们还将建议应用现有的诊断测试抗磷脂在牙周炎患者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，但发生这种情况的机制尚不清楚。我们的研究将检查口腔中的细菌促进抗体产生的能力，该抗体已知在其他疾病中诱导血管炎症和促凝血活性。如果这被证明是一个重要的机制，连接口腔微生物菌群与身体的其他部位，实验室检查常规管理的疾病，如系统性红斑狼疮牙周炎患者可以很容易地应用于牙周炎患者，以预测全身后遗症的风险，支持或预防护理可以系统地应用。

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.