title: Molecular pathophysiology of the antiphospholipid syndrome: the role of oxidative post-translational modification of beta 2 glycoprotein I.
abstract: It has been well established that antiphospholipid antibodies and specifically those directed against beta 2 glycoprotein I (β2GPI) are pathogenic for the development of thrombosis in the antiphospholipid syndrome (APS). Several groups have shown that anti-β2GPI antibodies, in complex with β2GPI, elicit effects on blood cells and coagulation-fibrinolysis proteins, which prime the arterial and venous vasculature for the development of thrombosis. However, much less is known about the mechanism initiating the production of autoantibodies against β2GPI, a physiological abundant protein of blood. In the current review, novel findings are presented regarding the structure and oxidative post-translational modifications of β2GPI, which trigger the immune response. The majority of circulating β2GPI exists in a form containing unpaired cysteines (free thiols), which constitutes the reduced form of β2GPI. The free thiols exposed on β2GPI are involved in the interaction with platelets and endothelial cells. We propose that this abundant pool of free thiols may serve as an antioxidant reservoir protecting cells or critical molecules from oxidative stress. Oxidation of β2GPI confers an increase in its immunogenicity through a Th1 immunological mechanism. The clinical significance of these observations is that serum from patients with APS, assessed by a novel ELISA assay, have a significant increase in oxidised β2GPI. These findings hold promise, not only for the delineation of the role of β2GPI as an immunological target, but also for the development of improved diagnostic and prognostic assays for APS.
authors.affiliation: Department of Immunology, Allergy and Infectious Diseases, St George Hospital, University of New South Wales, Sydney, Australia.
authors.forename: F H
authors.initials: FH
authors.lastname: Passam
authors.forename: B
authors.initials: B
authors.lastname: Giannakopoulos
authors.forename: P
authors.initials: P
authors.lastname: Mirarabshahi
authors.forename: S A
authors.initials: SA
authors.lastname: Krilis
mesh_terms: D017152:Antibodies, Antiphospholipid / Q000097:blood; D016736:Antiphospholipid Syndrome / Q000235:genetics*; D006801:Humans; D010084:Oxidation-Reduction; D011499:Protein Processing, Post-Translational; D053482:beta 2-Glycoprotein I / Q000378:metabolism*
chemical_list: D017152:Antibodies, Antiphospholipid; D053482:beta 2-Glycoprotein I