The presence of autoantibodies against a cryptic epitope in domain I of β2-glycoprotein I (β2GPI) is strongly associated with thrombotic events in patients with the antiphospholipid syndrome. We hypothesized that a conformational change could be a trigger for the formation of antibodies against domain I of β2GPI. Therefore, we investigated whether immune responses against β2GPI are related to its conformation.


Conformational changes in β2GPI were studied using various techniques, either upon binding to cardiolipin or after disruption of the internal disulfide bonds. The immunogenicity of β2GPI in different conformations as well as the individual domains of β2GPI were studied in vivo by monitoring the generation of antibodies after intravenous administration of β2GPI to mice. Furthermore, plasma samples from these mice were assessed for lupus anticoagulant activity and thrombin–antithrombin complex levels.


We observed that the interaction of β2GPI with cardiolipin induced a conformational change in β2GPI: electron microscopy revealed that β2GPI assembled into polymeric meshworks. We next investigated the immunogenicity of both human and murine β2GPI in mice. Both human and murine β2GPI combined with cardiolipin and misfolded β2GPI triggered antibody formation against the native protein as well as against domain I of β2GPI, while native β2GPI was not immunogenic. In addition, we observed that anti–domain I antibodies developed in mice injected with domain I of β2GPI, and that antibodies did not develop in mice injected with domains II–V. The induced anti–domain I antibodies prolonged the dilute Russell's viper venom plasma clotting time. The plasma of mice with anti–domain I antibodies had increased levels of circulating thrombin–antithrombin complexes.


The results of our studies indicate that the exposure of cryptic epitopes due to conformational changes in β2GPI can induce autoantibody formation.