Anti-β2 glycoprotein I antibodies in complex with β2 glycoprotein I induce platelet activation via two receptors: apolipoprotein E receptor 2′ and glycoprotein I bα

Abstract

Anti-β2 glycoprotein I (anti-β2GPI ) antibodies are important contributors to thrombosis, especially in patients with antiphospholipid syndrome (APS). However, the mechanism by which anti-β2GPI antibodies are involved in the pathogenesis of thrombosis is not fully understood. In this report, we investigated the role of anti- β2GPI antibodies in complexes with β2GPI as mediators of platelet activation, which can serve as a potential source contributing to thrombosis. We examined the involvement of the apolipoprotein E receptor 2' (apoER2') and glycoprotein I ba (GP I ba) in platelet activation induced by the anti-β2GPI /β2GPI complex. The interaction between the anti-β2GPI /β2GPI complex and platelets was examined using in vitro methods, in which the Fc portion of the antibody was immobilized using protein A coated onto a microtiter plate. Platelet activation was assessed by measuring GPII b/III a activation and P-selectin expression and thromboxane B2 production as well as p38 mitogen-activated protein kinase phosphorylation. Our results revealed that the anti-β2GPI /β2GPI complex was able to activate platelets, and this activation was inhibited by either the anti-GP I bα antibody or the apoER2' inhibitor. Results showed that the anti-β2GPI /β2GPI complex induced platelet activation via GPI ba and apoER2', which may then contribute to the prothrombotic tendency in APS patients.

Tissue factor over-expression in platelets of patients with anti-phospholipid syndrome: induction role of anti-β2-GPI antibodies

“…The activation-signaling pathways of platelets consequent to the presence of β2-GPI and anti-β2-GPI antibodies are mediated by interaction with phospholipids on the cell surface (phosphatidylserine, phosphatidylethanolamine) or with platelet membrane receptors [5,8]. Their combination in complexes contributes to platelet activation in an apolipoprotein E receptor 2′ (apoER2′) and glycoprotein Ib-α (GPIb-α)-dependent manner.…”

“…Their combination in complexes contributes to platelet activation in an apolipoprotein E receptor 2′ (apoER2′) and glycoprotein Ib-α (GPIb-α)-dependent manner. This interaction induces the activation of the platelet signaling pathway, expressed by p38 mitogen-activated protein kinase (MAPK) phosphorylation, and the prothrombotic phenotype, expressed by GP IIb/IIIa conformational change, P-selectin expression and thromboxane B2 production [8]. This interaction induces the activation of the platelet signaling pathway, expressed by p38 mitogen-activated protein kinase (MAPK) phosphorylation, and the prothrombotic phenotype, expressed by GP IIb/IIIa conformational change, P-selectin expression and thromboxane B2 production [8].…”

Platelets activated by the anti-β2GPI/β2GPI complex release microRNAs to inhibit migration and tube formation of human umbilical vein endothelial cells

“…Platelet activation and microparticle (MP) release were induced upon incubation with 0.1 U/ml of thrombin (Sigma-Aldrich) or anti-β2GPI/β2GPI complex for 60 min at 37 °C with gentle agitation. Anti-β2GPI/β2GPI complex (anti-β2GPI:β2GPI = 5/50 μg/ml or 10/100 μg/ml) was dissolved in Tris-buffered saline (TBS) as previously described [ 3 ].…”

“…Our previous study reported on anti-β2GPI-dependent platelet activation by LRP8 receptors and the mitogen-activated protein kinase 14 (MAPK14) pathway [ 3 ]. Anti-β2GPI antibodies are also known to activate human endothelial cells [ 4 , 5 ].…”

Under crossfire: thromboembolic risk in systemic lupus erythematosus

“…In particular, in vitro studies suggest that Toll-like receptor (TLR) 4 and annexin A2 (a phospholipid-binding protein involved in endothelial activation and in the regulation of the coagulation cascade), possibly through reciprocal interactions, behave as β2GPI cell surface receptors and promote activation of the endothelium as well as of circulating leukocytes and platelets [50]. TLR 1, 2, 6 and apolipoprotein E receptor 2 might also redundantly recognise β2GPI on the cell surface [50][51][52].…”