Conformationally altered β2-glycoprotein I is the antigen for anti-cardiolipin autoantibodies

Anti-cardiolipin autoantibodies (aCL) induce thrombosis and recurrent fetal death. These antibodies require a ‘cofactor’, identified as β2-glycoprotein I (β2-GPI), to bind phospholipids. We show here that aCL can bind β2-GPI in the absence of phospholipid. Binding of aCL to β2-GPI is dependent upon the β2-GPI being immobilized on an appropriate surface including cardiolipin, irradiated polystyrene and nitrocellulose membrane. This effect cannot be explained by increased antigen density of β2-GPI immobilized on these surfaces. Rather, conformational changes that occur following the interaction of β2-GPI with phospholipid render this protein antigenic to aCL. Liquid-phase β2-GPI was not antigenic for aCL. Thus, aCL cannot bind circulating β2-GPI. These findings may explain why patients with aCL can remain healthy for many years but then undergo episodes of thrombosis or fetal loss without changes in their circulating aCL profile, as the triggering event for these pathologies can be predicted to be one that renders β2-GPI antigenic for aCL