Conformationally altered beta(2)-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 beta(2)-glycop rotein I (beta(2)-GPI), to bind phospholipids. We show here that aCL can bi nd beta(2)-GPI in the absence of phospholipid. Binding of aCL to beta(2)-GP I is dependent upon the beta(2)-GPI being immobilized on an appropriate sur face including cardiolipin, irradiated polystyrene and nitrocellulose membr ane. This effect cannot be explained by increased antigen density of beta(2 )-GPI immobilized on these surfaces. Rather, conformational changes that oc cur following the interaction of beta(2)-GPI with phospholipid render this protein antigenic to aCL. Liquid-phase beta(2)-GPI was not antigenic for aC L. Thus, aCL cannot bind circulating beta(2)-GPI. These findings may explai n why patients with aCL can remain healthy for many years but then undergo episodes of thrombosis or fetal loss without changes in their circulating a CL profile, as the triggering event for these pathologies can be predicted to be one that renders beta(2)-GPI antigenic for aCL.