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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(申请人提供)：抗心磷脂抗体(ACL)，通常存在于自身免疫性疾病，如系统性红斑狼疮和抗磷脂综合征(APS)，也存在于15%-20%的慢性或全身性侵袭性牙周炎患者的血清样本中。在APS中，这些抗体与血栓形成、胎儿丢失和胎儿生长受限、先兆子痫和动脉粥样硬化有关。在牙周炎中，这些抗体很可能是对牙龈卟啉单胞菌等细菌病原体的反应产生的，这些病原体的多肽序列与acl的靶抗原β-2糖蛋白-I(2GPI)上的一个关键序列同源。由于多种生物学机制对胎盘形成(影响蜕膜和滋养层)、血栓形成以及全身和局部炎症的影响，ACL被认为会影响患有APS的妇女的妊娠。我们的数据表明，牙周炎的ACL水平与血管炎症标志物的升高有关，牙周治疗降低了IgM ACL抗体水平(但不降低Ig G水平)，暗示口腔微生物群是抗原的来源。牙周炎患者的ACL抗体也可诱导培养的血管内皮细胞(HUVEC)产生炎症反应。此外，这些抗体还促进2GPI与Annexin V竞争磷脂酰丝氨酸的结合部位。膜联蛋白V与滋养层细胞表面PS的结合被认为是胎儿发育过程中的一种重要保护机制，因此数据表明这种抗体可引起滋养层细胞的炎症反应和纤维蛋白沉积，从而导致炎症和缺陷细胞迁移。我们进一步发现，针对牙龈假单胞菌产生的抗体含有acl，在小鼠妊娠模型中会导致胎儿丢失。因此，我们假设牙龈假单胞菌诱导的交叉反应抗心磷脂抗体促进内皮细胞和滋养层细胞的炎症反应，这与它们导致小鼠补体依赖性胎儿丧失的能力一致。我们建议进一步研究抗牙龈假单胞菌中的ACL与TLR2、TLR4和TLR8等受体以及HUVEC上的Annexin A2相互作用诱导炎症细胞因子产生的机制。我们进一步建议研究牙龈假单胞菌诱导的前交叉韧带与滋养层细胞株的相互作用。这些研究将检查Annexin V保护屏障的破坏，并检查对补体激活、细胞因子产生、人绒毛膜促性腺激素产生和细胞迁移的影响。我们还将在小鼠妊娠模型中检查抗牙龈假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。我们将整合检测来自牙周炎患者的人类前交叉韧带的研究，在平行实验中评估它们的体外和体内效果。这些研究的结果，如果与我们的假设一致，将暗示牙龈假单胞菌对2GPI的分子模拟可能是在小鼠妊娠模型和人类妊娠模型中将牙周炎与不良妊娠结局联系起来的一种机制。