ANTIPHOSPHOLIPID AUTOANTIBODIES BIND TO APOPTOTIC, BUT NOT VIABLE, THYMOCYTES IN A BETA(2)-GLYCOPROTEIN I-DEPENDENT MANNER

Anti-phospholipid autoantibodies (aPL) are associated with a clinical syndrome of hypercoagulability, thrombocytopenia, and fetal loss. Seve ral groups have shown that the in vitro target of many aPL is not a pu re phospholipid Ag, hut is either a complex between anionic phospholip id and the plasma protein beta(2)-glycoprotein I (beta 2GPI) or the pr otein beta 2GPI alone. Anionic phospholipids are normally absent from the extracellular surface of cell membranes but redistribute from the inner to the outer leaflet during apoptosis. We show that aPL bind spe cifically to apoptotic, but not viable, thymocytes, and that binding i s dependent upon the presence of beta 2GPI. Moreover, we shaw that bet a 2GPI binds selectively to the surface of apoptotic thymocytes to gen erate an epitope for antiphospholipid autoantibodies. These findings s uggest that apoptotic cells may be the natural immunogen and/or target for aPL. Moreover, we propose that the interaction of circulating bet a 2GPI with redistributed anionic phospholipid may itself generate a n ovel ligand by which apoptotic cells are recognized directly for phago cytic clearance.