ANTICARDIOLIPIN ANTIBODIES, BETA 2GI AND THROMBOSIS

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Lupus anticoagulants (LACs) and anticardiolipin antibodies (ACAs) are defined as immunoglobulins reactive directly against anionic phospholipids, or having a requirement for anionic phospholipids for their reactivity. LACs are recognized by their prolongation of phospholipid- dependent coagulation tests, while ACAs are generally measured in ELISA assays. Although LACs and ACAs are related phenomena, there is reason to believe that these two activities frequently reside in separate immunoglobulin subpopulations. Nevertheless, the presence of either phenomenon is associated with an increased risk of thrombosis, spontaneous abortion (in women of child-bearing age), thrombocytopenia, as well as several other manifestations that have sometimes been referred to collectively as the "antiphospholipid antibody syndrome". Since the discovery that beta2-glycoprotein l (beta2Gl) is a necessary component in the reactivity of the majority of ACAs and, possibly, LACs, the nature of the interaction of these antibodies with beta2Gl, with phospholipid, and with the beta2Gl-phospholipid complex has assumed major importance. The aims of this proposal are: 1) To identify the specific areas and critical amino acid residues in beta2Gl involved in binding of cardiolipin (CL) and other anionic phospholipids. 2) To identify the epitopes in beta2Gl, CL, and the beta2Gl-CL complex to which LACs/ACAs bind. 3) To study the functional characteristics of epitope-specific LAC/ACA subpopulations, and to correlate epitope-specificities with the risk of thrombosis. These studies will make use of expression mutants of beta2Gl, monoclonal antibodies to beta2Gl, synthetic peptides mimicking surface characteristics of the beta2Gl molecule, and an animal thrombosis model in which to test the thrombogenic potential of antibody subpopulations. We believe that an understanding of the assembly of the beta2Gl-CL complex and the isolation and determination of the functional characteristics of epitope-specific subpopulations of LACs/ACAs will lead to a better understanding of the mechanisms giving rise to the thromboembolic risk and other clinical manifestations associated with the presence of these antibodies.