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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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Submitted May 13, 2005
Accepted October 19, 2005
Pathogenic anti- 2-glycoprotein I antibodies recognize domain I of 2-glycoprotein I only after a conformational change
Bas de Laat, Ronald H Derksen, Menno van Lummel, Maarten T Pennings, and Philip G de Groot*
Departments of Haematology, University Medical Centre Utrecht, Utrecht, The Netherlands
Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
* Corresponding author; email: ph.g.degroot{at}azu.nl.
Recently, we published the existence of two 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 towards 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 due to 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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