Domain I of beta2-glycoprotein I: its role as an epitope and the potential to be developed as a specific target for the treatment of the antiphospholipid syndrome

Abstract

Antiphospholipid syndrome (APS) represents one of the most common acquired causes of thrombophilia and recurrent miscarriages. The only treatment of proven benefit is anticoagulation, often required at high intensity and life-long duration. This therapy can be associated with side effects such as bleeding and is not always effective. Hence, there remains a need for safer, targeted and ideally more effective therapies. Antiphospholipid antibodies (aPL) are pathogenic and promote thrombosis. Independent groups, including our own, have show that the major epitopes that pathogenic aPL targets lie within domain I of the protein beta2-glycoprotein I (beta2GPI). This review focuses on the evidence presented thus far which characterizes the immunodominant epitopes within domain I, demonstrating that the epitope is a conformational one centred around residues R39-G43 and also involving other residues within domain I, such as residues D8 and D9. The hypothesis is proposed that a recombinant domain I molecule, and a recombinant mutant domain I with enhanced aPL binding properties, may be used as an inhibitor of aPL binding and thus inhibit aPL-induced pathogenicity. In vivo proof-of-concept studies within the murine femoral vein injury model are presented supporting this hypothesis, and the rationale as well as potential benefits and problems of employing such an approach to treat APS are discussed.