Modification of β2glycoprotein I by Glutardialdehyde: Conformational Changes and Aggregation Accompany Exposure of the Cryptic Autoepitope

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Abstract
Autoantibodies from patients with antiphospholipid syndrome (APS) recognize an epitope on β2glycoprotein I (β2GPI) only when native β2GPI is adsorbed on surfaces composed of anionic phospholipids or oxidized polystyrene, β2GPI was modified with the crosslinking agent, glutardialdehyde (GDA), which induced exposure of the anti-β2GPI epitope at GDA: β2GPI mol ratios in the range of 500–2000. A second crosslinking agent, dimethyl-suberimidate (DMS), did not expose the epitope, which may be a consequence of its having less tendency than GDA to form intermolecular links. SDS-PAGE experiments demonstrate that GDA does promote extensive intermolecular crosslinking of β2GPI, and DMS does not. Formaldehyde also reacts with the lysine residues of β2GPI, but does not expose the epitope. The circular dichroism spectra of native and modified β2GPI confirm that GDA induces changes in conformation that are qualitatively different from those caused by formaldehyde. These data provide evidence that binding of lysine residues is not a sufficient condition for exposure of the autoepitope, and also support the likelihood that β2GPI antibodies bind only to aggregates of the protein. Thus, by synthesizing an active holoantigen of β2GPI, conditions were defined that are necessary for binding of human autoantibodies. The authors also suggest that treatment of phospholipid-binding proteins with chemical agents might provide a strategy to modify their structure and permit exposure of epitopes, resulting in synthetic antigens for therapeutic and diagnostic use.

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