LIS

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In systemic lupus erythematosus (SLE), antiphospholipid antibodies (APA), detected either by ELISA (anticardiolipin antibodies, A C A) or by an inhibitory effect on phospholipid-dependent in vitro blood coagulation (lupus anticoagulant, LAC), are strongly associated with recurrent thrombosis, fetal loss, thrombocytopenia and neurological pathology (the "antiphospholipid syndrome" APS). When acquired coagulation abnormalities of APS occur in the absence of SLE, it is referred to as primary APS. To date, the role of APA in immunopathogenesis of APS remains unclear. Analyses of APA indicate that they are composed of immunologically and functionally distinct antibody species. Considering that some individuals with persistently elevated serum ACA and LAC do not experience thrombotic problems, we hypothesize that only certain APA in APS patients may cause thrombosis, and that such thrombogenic APA is necessary, but not sufficient for, induction of pathologic thrombosis. The potentially thrombogenic antibodies may possess unique binding specificity and affinity to phospholipid and/or cofactor(s), not appreciated with present analyses of polyclonal heterogeneous APA in plasma samples. To test these hypotheses, we plan to: 1 Generate monoclonal IgG APA from APS patients with high titers of serum APA and recurrent thrombosis, and characterize the binding specificities and affinities of the monoclonal APA; 2) Determine the functional properties of monospecific APA by in vitro blood clotting assays and an in vivo thrombosis model in mice; 3) Study the mechanisms by which thrombogenic and anticoagulant APA exert their effects; The results from these studies will help to define various subsets of APA in APS patients with recurrent thrombosis, and to advance our understanding about the role of APA in thrombosis associated with APS. If some thrombogenic APA are found, their immunological characteristics and pathogenic mechanisms will be revealed.