title: The Michael Mason Prize: Pathogenic antiphospholipid antibodies, stressed out antigens and the deployment of decoys.
abstract: The antiphospholipid syndrome is a common autoimmune cause of vascular thrombosis and recurrent miscarriages. aPLs that target the N-terminal domain [Domain I (DI)] of the phospholipid binding protein ß2-glycoprotein I (ß2GPI) represent the key sub-population of aPLs that promote thrombosis. This review describes two research arms relating to the study of this autoantigen. The first arm describes recent novel biochemical and functional insights into the molecular structure of ß2GPI in vivo and how this may be altered in APS. These findings support the emerging hypothesis that redox modification of ß2GPI may be relevant to the pathogenesis of APS and the development of pathogenic anti-ß2GPI antibodies. The second arm describes how a recombinant DI peptide engineered using a bacterial expression system was used to delineate the fine immunodominant epitopes on DI that pathogenic anti-ß2GPI antibodies target. The epitope was found to be conformational and revolve around arginine (R) 39 within DI. Thus, whole recombinant DI was used in an in vivo mouse model as a novel decoy peptide inhibitor of anti-ß2GPI antibodies. DI and a high binding mutant completely abrogated the pathogenic effects of aPL in this murine model, with loss of inhibition of pathogenicity observed upon mutating the residue R39 to serine. This proof-of-principle study supports the ongoing development of recombinant DI as a novel therapeutic inhibitory peptide for patients with APS.
authors: Centre for Rheumatology Research, UCL Division of Medicine, Room 411, 4th floor, Rayne Institute, 5 University Street, London WC1E 6JF, UK. y.ioannou@ucl.ac.uk
authors: Yiannis
authors: Y
authors: Ioannou
mesh_terms: D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000276:immunology*; D016736:Antiphospholipid Syndrome / Q000276:immunology*; D001363:Awards and Prizes; D049674:History, 21st Century; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D051379:Mice; D010084:Oxidation-Reduction; D011994:Recombinant Proteins / Q000276:immunology; D012219:Rheumatology / Q000266:history; D053482:beta 2-Glycoprotein I / Q000276:immunology* / Q000378:metabolism
chemical_list: D017152:Antibodies, Antiphospholipid; D016056:Immunodominant Epitopes; D011994:Recombinant Proteins; D053482:beta 2-Glycoprotein I