Antiphospholipids in periodontitis

抗磷脂在牙周炎中的作用

基本信息

批准号：
9232123
负责人：
HARVEY Allen SCHENKEIN
金额：
$ 38.13万
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 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9232123
关键词：
Affect Annexins Antibodies Antibody Response Anticardiolipin Antibodies Antigen Targeting Antigens Antiphospholipid Syndrome Atherosclerosis Autoimmune Diseases Binding Binding Sites Biological C5a anaphylatoxin receptor Cardiovascular Diseases Cell Adhesion Molecules Cell Line Cells Choriocarcinoma Chronic Clinical Clinical Research Complement Complement 5a Complement Activation Data Decidua Dependence Deposition Development Diabetes Mellitus Diagnostic tests Endothelial Cells Excision Failure Fetal Development Fetal Growth Retardation Fibrin First Pregnancy Trimester Foundations Functional disorder Future Glycoproteins Health Human Human Chorionic Gonadotropin Immunization Immunoglobulin G Immunoglobulin M In Vitro Infection Inflammation Inflammatory Inflammatory Response Injury Intervention Link Low Birth Weight Infant Modeling Molecular Mimicry Mouse Strains Mus Oral Outcome Pathologic Patients Periodontal Diseases Periodontal Infection Periodontitis Persons Phosphatidylserines Placentation Porphyromonas gingivalis Pre-Eclampsia Pregnancy Pregnancy Outcome Pregnancy loss Preparation Prevention Production Receptor Cell Risk Role Sampling Sequence Homologs Serum Serum Proteins Site Solid Source Systemic Lupus Erythematosus Systemic disease TLR2 gene TLR4 gene TLR8 gene Thrombosis Thrombus Trophoblastic Cell Vascular Endothelial Cell Woman adverse outcome adverse pregnancy outcome annexin A5 beta 2-glycoprotein I cell motility cell type cross reactivity crosslink cytokine experimental study fetal immunoreactivity in vivo inhibitor/antagonist microorganism migration monolayer mouse model pathogen patient population pregnant premature protein aminoacid sequence public health relevance receptor response trophoblast vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Anticardiolipin antibodies (aCL), which are commonly present in autoimmune diseases such as systemic lupus erythematosus and the antiphospholipid syndrome (APS), are also present in 15-20% of serum samples from patients with chronic or generalized aggressive periodontitis. In APS, these antibodies are associated with thrombus formation, fetal loss and fetal growth restriction, preeclampsia, and atherosclerosis. In periodontitis, it is likely that these antibodies are produced in response to oal bacterial pathogens such as Porphyromonas gingivalis and others, which have peptide sequences that are homologous to a key sequence on beta-2 glycoprotein-I (2GPI) the target antigen of aCL. aCL is thought to affect pregnancy in women with APS due to a variety of biological mechanisms with effects on placentation (impacting the decidua and trophoblast), thrombosis, and systemic and local inflammation. Our data indicate that aCL levels in periodontitis are associated with elevated markers of vascular inflammation, and that periodontal treatment decreases IgM aCL antibody levels (but not IgG levels), implicating the oral microflora as a source of antigen. aCL antibodies from periodontitis patients also induce inflammatory responses in cultured vascular endothelial cells (HUVEC). In addition, these antibodies promote competition of 2GPI with Annexin V for binding sites on phosphatidylserine. Annexin V binding to PS on trophoblasts is thought to be an important protective mechanism during fetal development, so the data indicate that such antibodies could cause trophoblast inflammatory responses and fibrin deposition leading to inflammation and defective cell migration. We further found that antibody raised against P. gingivalis contains aCL which causes fetal loss in a mouse pregnancy model. We therefore hypothesize that cross-reactive anticardiolipin antibodies induced by P. gingivalis promote inflammatory responses in endothelial cells and trophoblasts that are consistent with their ability to cause complement-dependent fetal loss in mice. We propose to further study the mechanisms by which aCL in anti- P. gingivalis interacts with receptors such as TLR2, TLR4, and TLR8, and with Annexin A2 on HUVEC to induce inflammatory cytokine production. We further propose to examine the interactions of aCL induced by P. gingivalis with trophoblastic cell lines. These studies will examine disruption of the Annexin V protective shield and examine effects on complement activation, cytokine production, human chorionic gonadotropin production, and cell migration. We will also examine the dependence of fetal loss due to anti- P. gingivalis on complement activation and on C5a-C5a receptor interaction in the mouse pregnancy model. We will integrate studies examining human aCL derived from periodontitis patients, evaluating their in vitro and in vivo effects in parallel experiments. Results of these studies, if consistent with our hypothesis, would implicate molecular mimicry of 2GPI by P. gingivalis as a likely mechanism linking periodontitis with adverse pregnancy outcomes in both the mouse pregnancy model and in human pregnancy.

描述（由申请人提供）：抗心磷脂抗体 (aCL) 常见于自身免疫性疾病，如系统性红斑狼疮和抗磷脂综合征 (APS)，也存在于 15-20% 的慢性或全身性疾病患者的血清样本中在 APS 中，这些抗体与血栓形成、胎儿流产和胎儿生长受限、先兆子痫和动脉粥样硬化有关。牙周炎中，这些抗体很可能是针对口腔细菌病原体（例如牙龈卟啉单胞菌等）而产生的，这些病原体的肽序列与 aCL 靶抗原 β-2 糖蛋白-I (2GPI) 上的关键序列同源由于多种生物学机制影响胎盘（影响蜕膜和滋养层）、血栓形成和妊娠，aCL 被认为会影响 APS 女性的妊娠。我们的数据表明，牙周炎中的 aCL 水平与血管炎症标志物升高有关，并且牙周治疗会降低 IgM aCL 抗体水平（但不会降低 IgG 水平），这表明口腔微生物群是 aCL 抗体的来源。来自牙周炎患者的抗体还会诱导培养的血管内皮细胞 (HUVEC) 的炎症反应。此外，这些抗体还促进 2GPI 与膜联蛋白 V 竞争结合位点。磷脂酰丝氨酸与滋养细胞上的 PS 结合被认为是胎儿发育过程中的重要保护机制，因此数据表明此类抗体可能引起滋养层炎症反应和纤维蛋白沉积，从而导致炎症和细胞迁移缺陷。抗牙龈卟啉单胞菌含有aCL，可导致小鼠妊娠模型中胎儿流产，因此我们认为牙龈卟啉单胞菌诱导的交叉反应性抗心磷脂抗体会促进小鼠的炎症反应。我们建议进一步研究抗牙龈卟啉单胞菌中的aCL与TLR2、TLR4和TLR8等受体相互作用的机制。 HUVEC 上的膜联蛋白 A2 诱导炎症细胞因子的产生，我们进一步建议检查牙龈卟啉单胞菌诱导的 aCL 与滋养层细胞系的相互作用。我们还将研究抗牙龈卟啉单胞菌引起的胎儿丢失对补体激活和 C5a-C5a 受体相互作用的依赖性。我们将整合来自牙周炎患者的人类 aCL 的研究，在平行实验中评估其体外和体内效果，如果这些研究结果与我们的假设一致，则意味着分子模拟。牙龈卟啉单胞菌的2GPI可能是小鼠妊娠模型和人类妊娠中牙周炎与不良妊娠结局相关的机制。