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.

Public Health Relevance

Periodontitis is associated with systemic conditions such as adverse pregnancy outcomes, cardiovascular diseases, and diabetes, but whether existing periodontal diseases increase risk for future development of these systemic conditions is unproven and a subject of considerable debate. We have found that many patients with periodontal diseases have serum antibodies, termed anticardiolipin, that can be induced by infection with periodontal pathogens and are themselves associated with thrombosis, adverse pregnancy outcomes, and atherosclerosis. Understanding how these antibodies may affect a person's health by examining their effects on models of pregnancy loss may suggest diagnostic tests and interventions that could reverse these potentially harmful effects.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Oral, Dental and Craniofacial Sciences Study Section (ODCS)
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Wang, Chiayeng
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Virginia Commonwealth University
Schools of Dentistry/Oral Hygn
United States
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Strauss 3rd, Jerome F; Romero, Roberto; Gomez-Lopez, Nardhy et al. (2018) Spontaneous preterm birth: advances toward the discovery of genetic predisposition. Am J Obstet Gynecol 218:294-314.e2
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