Posttranslational forms of beta 2-glycoprotein I in the pathogenesis of the antiphospholipid syndrome

The antiphospholipid syndrome (APS) is an autoimmune disease characterised by a procoagulant state that predisposes to recurrent thrombosis and miscarriages. Two major discoveries have advanced our understanding of the underlying complex pathogenesis of the APS. The first was the discovery that beta-2 glycoprotein-1 (β2GPI) is the major auto antigen in APS. The second was the discovery in more recent years that β2GPI contains allosteric disulphide bonds susceptible to posttranslational modification that may be involved in the development of autoantibodies in APS. The main allosteric disulphide bond in the fifth domain of β2GPI can exist in two redox states: free thiol or oxidised. It is the conformational transformation of β2GPI from its free thiol form to its more immunogenic oxidised form that exposes neo-epitopes on the first and fifth domains. The purpose of this review is to highlight the recent findings on the posttranslational forms of β2GPI in the pathogenesis of APS. We suggest that novel assays quantitating the different redox forms of β2GPI in plasma or serum may be used to supplement existing clinical and laboratory assays to more accurately stratify risk of thrombosis or miscarriage in APS patients.