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Blood, 1 March 2006, Vol. 107, No. 5, pp. 1916-1924.
Prepublished online as a Blood First Edition Paper on November 3, 2005; DOI 10.1182/blood-2005-05-1943.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Pathogenic anti- 2-glycoprotein I antibodies recognize domain I of 2-glycoprotein I only after a conformational change
Bas de Laat,
Ronald H. W. M. Derksen,
Menno van Lummel,
Maarten T. T. Pennings, and
Philip G. de Groot
From the Department of Haematology and the Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
Recently, we published the existence of 2 populations of anti- 2-glycoprotein I (2-GPI) IgG antibodies. Type A antibodies recognize epitope G40-R43 in domain I of 2-GPI and are strongly associated with thrombosis. Type B antibodies recognize other parts of 2-GPI and are not associated with thrombosis. In this study we demonstrate that type A antibodies only recognize plasma-purified 2-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 2-GPI was independent of the charge of the surface to which 2-GPI was coated. Type A antibodies did not recognize plasma-purified 2-GPI in solution, whereas they did recognize recombinant 2-GPI both in solution and coated onto a neutrally charged plate. When the carbohydrate chains were removed from plasma-purified 2-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 2-GPI is caused by the difference in glycosylation and that epitope G40-R43 of plasma-purified 2-GPI is covered by a carbohydrate chain. Type A anti-2-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-2-GPI antibodies and the comprehension of the pathophysiology of the antiphospholipid syndrome.
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[Abstract]
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