title: Pathogenic anti-beta2-glycoprotein I antibodies recognize domain I of beta2-glycoprotein I only after a conformational change.
abstract: Recently, we published the existence of 2 populations of anti-beta2-glycoprotein I (beta2-GPI) IgG antibodies. Type A antibodies recognize epitope G40-R43 in domain I of beta2-GPI and are strongly associated with thrombosis. Type B antibodies recognize other parts of beta2-GPI and are not associated with thrombosis. In this study we demonstrate that type A antibodies only recognize plasma-purified beta2-GPI when coated onto a negatively charged surface and not when coated onto a neutrally charged surface. The affinity of type B antibodies toward plasma-purified beta2-GPI was independent of the charge of the surface to which beta2-GPI was coated. Type A antibodies did not recognize plasma-purified beta2-GPI in solution, whereas they did recognize recombinant beta2-GPI both in solution and coated onto a neutrally charged plate. When the carbohydrate chains were removed from plasma-purified beta2-GPI, we found that type A antibodies did recognize the protein in solution. This supports the hypothesis that the difference in recognition of plasma-purified and recombinant beta2-GPI is caused by the difference in glycosylation and that epitope G40-R43 of plasma-purified beta2-GPI is covered by a carbohydrate chain. Type A anti-beta2-GPI antibodies can only recognize this epitope when this carbohydrate chain is displaced as a result of a conformational change. This finding has major implications both for the detection of pathogenic anti-beta2-GPI antibodies and the comprehension of the pathophysiology of the antiphospholipid syndrome.
authors.affiliation: Department of Haematology, G03.647, University Medical Center Utrecht, PO Box 85500, 3584CX Utrecht, Netherlands.
authors.forename: Bas
authors.initials: B
authors.lastname: de Laat
authors.forename: Ronald H W M
authors.initials: RH
authors.lastname: Derksen
authors.forename: Menno
authors.initials: M
authors.lastname: van Lummel
authors.forename: Maarten T T
authors.initials: MT
authors.lastname: Pennings
authors.forename: Philip G
authors.initials: PG
authors.lastname: de Groot
mesh_terms: D000918:Antibody Specificity / Q000276:immunology*; D016736:Antiphospholipid Syndrome / Q000150:complications / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens; D002241:Carbohydrates / Q000276:immunology; D005260:Female; D006023:Glycoproteins / Q000276:immunology*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000276:immunology*; D008297:Male; D011487:Protein Conformation; D017510:Protein Folding; D013927:Thrombosis / Q000209:etiology / Q000276:immunology; D053482:beta 2-Glycoprotein I
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D002241:Carbohydrates; D006023:Glycoproteins; D053482:beta 2-Glycoprotein I