Pathogenic role of anti-β2-glycoprotein I antibodies on human placenta: functional effects related to implantation and roles of heparin

Abstract

Most of the clinical manifestations of the antiphospholipid syndrome (APS) can be related to thrombotic events; however, placental thrombosis cannot explain all of the pregnancy complications that occur in women with this syndrome. In this regard, it has been hypothesized that antiphospholipid (aPL) antibodies can directly attack trophoblasts, but it is still unclear what pathogenetic mechanisms play a role and which aPL antibodies subpopulations are involved. Although it has been assumed that aPL antibodies are directed against anionic phospholipids (PLs), current advances in the field suggest that antibodies to PL-binding plasma protein such as beta2-glycoprotein-I (beta2-GPI) are the clinically relevant aPL antibodies. It appears that following the attachment of beta2-GPI to PLs, both molecules undergo conformational changes that result in the exposure of cryptic epitopes within the structure of beta2-GPI allowing the subsequent binding of antibodies. aPL antibodies detected by anti-beta2-GPI assays are associated with fetal loss. However, there is still debate on how the antibodies might induce the obstetrical manifestations. The significantly improved outcome of pregnancies treated with heparin has stimulated interest in the drug's mechanisms of action. Several mechanisms could explain its beneficial effects, because in addition to a direct effect of heparin on the coagulation cascade, it might protect pregnancies by reducing the binding of aPL antibodies, reducing inflammation, facilitating implantation and/or inhibiting complement activation. Further investigations are needed to better understand how aPL antibodies induce obstetric complications and to better clarify the functional role of heparin in the human placenta leading to more successful therapeutic options.

In vivo distribution of β2 glycoprotein I under various pathophysiologic conditions

“…32 Trophoblast is another target of ␤2GPI that undergoes distinct functional changes on binding of specific antibodies including inhibition of intercytotrophoblast fusion process and reduced human chorionic gonadotropin secretion and trophoblast invasiveness. 33,34 These changes are responsible for the defective placentation and contribute to fetal loss.…”

Anti-β2-glycoprotein-I and anti-phosphatidylserine antibodies in women with spontaneous pregnancy loss

“…The most prevalent protein is b 2 GP1 (7,8). Considering that b 2 GPI is a main target of antiphospholipid antibodies, anti-b 2 GPI-ab may play a role in their pathogenesis and may also serve as a biological marker for APS (6,9).…”

The Management of Antiphospholipid Antibodies Affected Pregnancy

“…It is likely that the thrombotic insult of aβ2GPI to placental angiogenesis or circulation is causally associated with PIH. Additionally, β2GPI binds to trophoblast cells (41). The antibody binding to β2GPI downregulates trophoblast chorionic gonadotropin synthesis and secretion (42).…”