Antiphospholipids and vascular inflammation in aggressive periodontitis

侵袭性牙周炎中的抗磷脂和血管炎症

基本信息

批准号：
8033111
负责人：
HARVEY Allen SCHENKEIN
金额：
$ 34.7万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8033111
关键词：
Actinobacillus actinomycetemcomitans Address Antibodies Antibody Formation Antiphospholipid Antibodies Antiphospholipid Syndrome Atherosclerosis Autoantibodies Autoimmune Diseases Bacteria Body part CCL2 gene Cardiolipins Cardiovascular Diseases Cardiovascular system Caring Cell Adhesion Molecules Chronic Complex Data Diagnostic tests Disease Endothelial Cells Gelatinase B Glycoproteins Health Immune response In Vitro Infection Inflammation Inflammation Mediators Inflammatory Response Interleukin-6 Laboratories Lead Link Lipids Low Birth Weight Infant Measures Mediating Mediator of activation protein Mus Opsonin Oral Oral cavity Pathogenicity Pathology Pathway interactions Patients Periodontal Diseases Periodontal Infection Periodontitis Periodontium Phospholipids Porphyromonas gingivalis Pregnancy Outcome Preventive Production Resolution Risk Risk Factors Role Selectins Sequence Homology Serum Specificity Stroke System Systemic Lupus Erythematosus Testing Therapeutic Thrombosis absorption aggressive therapy disorder risk fetal inflammatory marker interest macrophage microbial non-smoker pathogen premature protein aminoacid sequence response vascular inflammation

项目摘要

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.

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，牙周炎患者的血清抗磷脂抗体水平升高。此类抗体，包括β2糖蛋白1依赖性抗心磷脂（抗CL），存在于患有系统性红斑狼疮和抗磷脂综合征等自身免疫性疾病的患者中，并且可能由多种微生物感染诱导。这些抗体可诱导血栓形成前状态，并可导致中风、早期动脉粥样硬化和不良妊娠结局，例如胎儿复旧、早产和低出生体重。抗 CL 升高的这些后遗症与牙周感染的推定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，甚至在非吸烟者中，抗 CL 水平升高与细胞粘附分子（例如 sVCAM-1 和 sE-选择素）血清浓度升高之间存在显着相关性。此外，在广泛性侵袭性牙周炎 (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测量值升高。我们建议通过在使用内皮细胞和巨噬细胞的体外系统中测试纯化的抗体来确定侵袭性牙周炎患者中的抗CL是否具有致病性。此外，我们将确定通过积极治疗解决 GAgP 牙周感染是否也会降低抗 CL 和炎症介质水平。我们将检查血管炎症和血栓形成的其他标志物，以确定牙周炎患者中的抗 CL 可能影响全身炎症的途径。最后，我们将通过用含有假定的β2GP1交叉反应肽序列的细菌对小鼠进行免疫接种并测试所得抗体的致病性，来评估牙周病病原体诱导致病性抗CL的能力。这些研究可以解释为什么某些牙周炎患者患以血管炎症为特征的疾病的风险增加，例如动脉粥样硬化、中风和不良妊娠结局。他们还将建议牙周炎患者中可用的抗磷脂诊断测试的应用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发血管炎症和促凝血活性。如果这被证明是连接口腔微生物群与身体其他部位的重要机制，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，以预测全身性后遗症的风险，并进行支持性或预防性治疗。可以系统地进行护理。