Abstract

Antiphospholipid Syndrome (APS) is an autoimmune disease characterized by arterial and/or venous thrombosis and/or pregnancy morbidity, associated with circulating antiphospholipid antibodies (aPL). In some cases, patients with a clinical profile indicative of APS (thrombosis, recurrent miscarriages or fetal loss), who are persistently negative for conventional laboratory diagnostic criteria, are classified as “seronegative” APS patients (SN-APS). Several findings suggest that aPL, which target phospholipids and/or phospholipid binding proteins, mainly β-glycoprotein I (β-GPI), may contribute to thrombotic diathesis by interfering with hemostasis. Despite the strong association between aPL and thrombosis, the exact pathogenic mechanisms underlying thrombotic events and pregnancy morbidity in APS have not yet been fully elucidated and multiple mechanisms may be involved. Furthermore, in many SN-APS patients, it is possible to demonstrate the presence of unconventional aPL (“non-criteria” aPL) or to detect aPL with alternative laboratory methods. These findings allowed the scientists to study the pathogenic mechanism of SN-APS. This review is focused on the evidence showing that these antibodies may play a functional role in the signal transduction pathway(s) leading to thrombosis and pregnancy morbidity in SN-APS. A better comprehension of the molecular mechanisms triggered by aPL may drive development of potential therapeutic strategies in APS patients.

Highlights

  • Antiphospholipid Syndrome (APS) is an autoimmune disease, characterized by recurrent thrombosis and/or obstetrical morbidity and a series of systemic manifestations induced by the persistent presence of aPL, including lupus anticoagulant (LA), anti-β2-glycoprotein I (β2-GPI) and/or anti-cardiolipin antibodies.In 2006, shared criteria were defined for the diagnosis of APS [1]

  • The aPL recognized in the international criteria include antibodies (IgG or IgM) aCL higher than 40 phospholipid units IgG or IgM or anti-β2-glycoprotein I (β2-GPI) antibodies with titers above the 99th percentile and lupus LA detected according to guidelines published by the International Society on Thrombosis and Hemostasis (ISTH)

  • Lipid raft involvement was mandatory for triggering this signaling pathway, since anti-β2-GPI antibodies failed to induce interleukin-1 receptor–associated kinase (IRAK) phosphorylation and NF-κB translocation in the presence of the raft-disrupting agent methyl-beta-cyclodextrin [85]. This finding strongly supported the view that lipid rafts play a key role in the signal transduction pathway triggered by anti-β2-GPI antibodies and that raft-dependent anti-β2-GPI triggering resulted in the release of TNF-α, as well as of Tissue Factor (TF), which may contribute to the pathogenesis of thrombosis in patients with APS [90,91]

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Summary

Introduction

APS is an autoimmune disease, characterized by recurrent thrombosis and/or obstetrical morbidity and a series of systemic manifestations induced by the persistent presence of aPL, including lupus anticoagulant (LA), anti-β2-GPI and/or anti-cardiolipin (aCL) antibodies. Several reports show that in monocytes and endothelial cells, anti-β2-GPI antibodies may lead to an up-regulation of Tissue Factor (TF), which plays a pivotal role in initiating the extrinsic coagulation cascade [29] Another mechanism involves the Annexin A5 protein, this is a natural and physiological anti-coagulant which binds to PS on the cell surface, and forms a shield to prevent the activation of procoagulant complexes. The commonly accepted model predicts that in plasma β2-GPI is present primarily (>90%) in the closed circular conformation, with the epitope on domain I not accessible for autoantibodies This assumption is consistent with the observation that circulating immunocomplexes between β2-GPI and antibodies are usually not detected in APS patients’ sera. This mechanism may be a highly specific phenomenon responsible for pathogenic structure of β2-GPI making it more antigenic

Post-Translational Modifications and Pathogenesis of APS
Signal Transduction Pathways Triggered by aPL
Signaling and Pregnancy Complications
Role of Antiphospholipid Antibodies in Seronegative APS
Findings
Conclusions
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