Molecular Mechanisms of "Antiphospholipid Antibodies" and Their Paradoxical Role in the Pathogenesis of "Seronegative APS"

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.

Keywords: PTMs; SN-APS; TLR-4 pathways; lipid rafts; β2GPI; “non-criteria” aPL.

Figure 1

Schematic representation of β2-GPI structure and conformation. β2-GPI consist in five domains (I-V) with two disulfide bonds in each domain and an additional disulfide bond in domain V. Phospholipid binding by domain V and some PTMs of the protein result in a conformational change from the circular (closed) form to open configuration. This unfolded conformation may facilitate the exposition of ‘‘cryptic epitope’’ and autoantibodies binding. The amino acids most involved in the PTMs are Lysine, Arginine and Cysteine. Increased oxidative stress may alter the configuration of β2-GPI to a dimeric form that enhance antibody affinity.

Figure 2

Signaling pathway induced by aPL. Schematic drawing depicting the signaling transduction pathways triggered by aPL via TLR-4, through lipid rafts. This pathway leads to NF-κB activation and translocation to the nucleus, with an increase of proinflammatory cytokines and chemokines production, adhesion molecules expression and tissue factor release.

Figure 3

Putative pathogenetic mechanism of SN-APS. Molecular mechanisms of non-criteria aPL may involve endothelial cells and trophoblast cells with monocyte and platelet cooperation, leading to a proinflammatory and procoagulant state that underlies thrombosis and pregnancy complications.