Abstract

SY67 New insights into mechanisms of antiphospholipid syndrome Hall 3 09:30 18th July, 2003 Session Type: Symposium Subject area: Invited Speaker Session title: Antiphospholipid syndrome Abstract: SY67 Authors: S. Krilis St. Georges Hospital, Australia The antiphospholipid syndrome is characterized by thrombosis, recurrent miscarriage, thrombocytopenia and the presence of antiphospholipid antibodies. There has been an explosion of interest in this disorder over the last 10 years since beta-2-glycoprotein I (B2GPI) was identified as the major antigenic target for antiphospholipid antibodies. B2GPI is a phospholipid binding plasma protein which has been thought to act as a natural inhibitor of the blood coagulation pathway. However, the biological function of B2GPI in vivo remains unclear. Both passive and active immunization of human aPL from patients with APS have been demonstrated to exacerbate thrombosis in mice and activate endothelium. However, the precise mechanism of how these antibodies induce clinical disease is still unknown. B2GPI contains 326 amino acids and consists of five domains arranged in a J as confirmed by crystallography with the fifth domain predicted to bind to anionic phospholipid. The aPL antibodies have been demonstrated to bind a charged surface patch defined by residues 40-43 on domain I of B2GPI. B2GPI will bind to many negatively charged macromolecules including heparin. Heparin is regularly used in the treatment of APS patients both in acute therapy and prophylaxis. B2GPI appears to bind heparin via the 5th domain and in the presence of plasmin heparin potentiates the plasmin mediated inactivation of B2GPI at the carboxy-terminus of the molecule. This leads to diminished ability of B2GPI to bind phospholipids and thus decrease the prothrombotic activity of the endogenous circulating anti-B2GPI antibodies in patients with APS. The generation of B2GPI knockout mice has allowed us the opportunity to examine the role of B2GPI in vivo. The B2GPI knockout mice were used to investigate the physiological requirement for B2GPI in pregnancy and to examine the effects of passive transfer of antiphospholipid antibodies on pregnancy outcome in the presence and absence of endogenous functional B2GPI. Using a panel of human and murine antibodies to B2GPI, we explored the effect of these antibodies on pregnancy. B2GPI null mice were refractory to antibody induced pregnancy failure indicating that antiphospholipid antibodies require the presence of endogenous B2GPI to exert maximal pregnancy pathology. These findings support a mechanism in antiphospholipid syndrome involving antibody triggered signaling as opposed to neutralization of B2GPI function as previously thought. file:////ddn-453/d/ML3G-Data/JTH-Abstract-2003/HTML/Friday/Abstract%20SY67.html (1 of 2) [1/27/2014 4:25:29 PM]