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Departments of Medicine and of Immunology, Allergy, and Infectious Disease, University of New South Wales, St. George Hospital, Sydney, New South Wales, Australia
"Antiphospholipid" autoantibodies are associated with arterial and venous thrombosis, recurrent fetal loss, and thrombocytopenia. At present, the best-characterized antigenic target for these autoantibodies (or Abs) is the phospholipid-binding protein ß2-glycoprotein I (ß2GPI). These Abs bind ß2GPI only in the presence of negatively charged phospholipids or microtiter polystyrene plates that have been specially treated to give the surface a negative charge. To determine whether the binding of these Abs to ß2GPI on negatively charged surfaces is dependent on increased density or neo-epitopes formed as a consequence of a conformational change on ß2GPI, we generated mutants of ß2GPI by site-directed mutagenesis and assessed the binding characteristics of anti-ß2GPI Abs to these mutants. Our results demonstrate that mutant F307*, which spontaneously forms significant dimerization, is bound best by all the anti-ß2GPI Abs in an anti-ß2GPI ELISA using irradiated polystyrene microtiter plates. In addition, these Abs bound mutant F307* coated onto standard polystyrene microtiter wells in the absence of phospholipid, whereas there was minimal binding with wild-type and mutant F307*/C288A, which formed minimal dimerization. Affinity-purified anti-ß2GPI Abs from patients with the antiphospholipid syndrome demonstrated significantly higher binding affinity for mutant F307* in fluid phase than for wild-type or mutant F307*/C288A of ß2GPI. These results demonstrate that autoantibody binding to ß2GPI is intrinsically of low affinity and that the binding is dependent on the density of the Ag and not on neo-epitope formation.
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