Antibody populations in the antiphospholipid syndrome

Abstract

Of immunoglobulins directed against self-antigens which arise in autoimmune disorders such as systemic lupus erythematosis (SLE), the antiphospholipid (aPL) antibodies are of major interest to haematologists not only because the lupus anticoagulant (LA) causes an inhibition of in vitro blood coagulation, but also because the presence of certain aPL antibodies confers a risk of thrombosis. The inhibition of jn vitro phospholipid-dependent coagulation (LA) is thought to be due to the binding of LA to procoagulant phospholipid surfaces, thus impeding the clotting process. It is likely that LA interacts with lipid structures formed in the presence of hexagonal phase phosphatidyl-ethanolamine and thus that the antibody is directed against a complex phospholipid epitope. Another class of aPL are those originally described to be directed against negatively charged phospholipids, in particular cardiolipin. We have recently shown that ACL antibodies are usually directed against a complex antigen consisting of negatively charged phospholipid and a plasma protein, β 2 -glycoprotein-I (β 2 -GPI) (McNeil et al, Proc. Natl. Acad. Sci. 87:4120, 1990). Further, we have found a major degree of antibody heterogeneity even within individual patients so that ACL and LA are separable using physicochemical techniques such as ion exchange chromatography and chromatofocusing. Using such techniques we have enriched Ig fractions for LA and ACA. The majority of Ig with LA activity had a PI of 7.3-7.4 whereas ACA had a PI of 5-5.3. Using these enriched fractions labelled with 125 I-iodine we have shown that LA binds to platelets in a specific and saturable manner. Binding is dependent on thrombin activation. 125 I-ACA behaves differently. Like LA-IgG, binding is specific and dependent on thrombin activation but in this case requires the presence of β 2 -GPI. In neither case does LA or ACA have an effect on thrombin-induced release of 5-HT or β-thromboglobulin nor do they affect platelet aggregation induced by a number of agonists. This antibody binding may play an aetiological role in thrombocytopenia associated with aPL, but does not explain thrombosis.