Anti-beta-2 glycoprotein I epitope specificity: from experimental models to diagnostic tools

Abstract

Beta-2 glycoprotein I (b2GPI) is the main antigenic target for anti-phospholipid antibodies (aPL), the serological markers of anti-phospholipid syndrome (APS). Conformational changes of the molecule seem to be essential for exposing the cryptic epitope for aPL binding and to trigger pathogenic pathways. There is increasing evidence that a conformational epitope located in the Domain I (DI) of the molecule is the main epitope targeted by human autoantibodies. The pathogenic role of the DI epitope has been recently supported by in vivo models and by immuno-histopathological findings in APS patients. Antibodies targeting b2GPI-DI are more frequently detected in patients with full-blown APS compared to asymptomatic aPL carriers or patients with infectious diseases who have antibodies directed against the whole molecule. Anti-DI antibodies are positively correlated with medium to high titres of aPL, with the presence of lupus anticoagulant and thrombotic and pregnancy manifestations, enabling identification of patients at higher risk of clinical events. However, some APS patients develop antibodies reacting against b2GPI epitopes other than DI, suggesting that other anti-b2GPI antibody subsets may be clinically relevant. Although preliminary results suggest that anti-DI antibodies can be detected by different assays in a comparable manner, further prospective studies are needed to support their use in the clinical setting and their predictive value. Lupus (2016) 25, 905-910.

Pathogenic Role of Complement in Antiphospholipid Syndrome and Therapeutic Implications

“…The initial observation by Branch and colleagues ( 46 ) that passive infusion of serum IgG from patients with aPL induced an increased rate of fetal resorptions in pregnant mice was the first evidence that suggested a role of the antibodies in the pathogenesis of fetal loss. These findings and similar data obtained by other groups ( 47 , 48 ) led to the conclusion that obstetric APS is a clinical disorder mediated by antibodies that are preferentially directed against β2GPI ( 4 ). The high degree of protein sequence homology between human and animal β2GPI explains the ability of human antibodies to cause fetal demise in mice.…”

“…Blood clots can occur in both venous and arterial vessels with preferential localization in the brain and coronary arteries, although other vascular districts can also be involved. Vascular thrombosis mediated by beta2 glycoprotein I (β2GPI)-dependent antiphospholipid antibodies (aPL) represents the main pathogenic mechanism that is responsible for the major clinical manifestations of the syndrome and it has been suggested to be the cause also for other non-classification clinical events ( 4 ).…”

Dimerized Domain V of Beta2-Glycoprotein I Is Sufficient to Upregulate Procoagulant Activity in PMA-Treated U937 Monocytes and Require Intact Residues in Two Phospholipid-Binding Loops

“…In the pathologically-active extended conformation of β2GPI, domain V is independent of other β2GPI domains. Anti-β2GPI antibodies in APS patients with thrombosis most often bind to domain I of β2GPI [28]. Current knowledge of how β2GPI/antibody complexes interact with receptors is incomplete.…”

Prevalence and Thrombotic Risk Assessment of Anti-β2 Glycoprotein I Domain I Antibodies: A Systematic Review

“…1 β 2 GPI is hypothesized to be the main antigenic target for aPL, especially in vascular tissues after conformational modification. 2 Although some evidence is available supporting a role for anti-β 2 GPI antibodies in contributing to thrombosis and pregnancy morbidity, 3,4 their pathogenicity remains a topic of heated discussion. In fact, not all patients positive for the presence of anti-β 2 GPI antibodies develop clinical aPL-related manifestations.…”