What is the antigenic determinant for anti β2GPI antibodies? What is the proposed pathogenesis of APS
The primary target of aPLabs is β2GPI (apolipoprotein H). This is a phospholipid-binding glycoprotein that exists in the blood in a circular conformation. It contains five domains (sushi domains) and belongs to the complement control protein superfamily. It binds through its fifth domain to anionic phospholipid membranes and receptors. After binding, it undergoes a conformational change to an open “hockey stick” conformation. With this change, it becomes antigenic by exposing hidden epitopes in the first domain. In addition, the clustering of these molecules provides a high antigenic density. The pathogenic anti-β2GPI antibodies bind to an epitope (D8, D9, R39, G40, R43) in the first domain of the β2GPI molecule.
In vivo , β2GPI binds avidly to anionic phospholipid surfaces (especially phosphatidylserine) on activated or apoptotic cell membranes. The anti-β2GPI antibodies then bind to the first domain of the uncoiled β2GPI dimers on the cell surface. This binding results in a proinflammatory and prothrombotic state:
- • Cell activation: upregulates the expression of prothrombotic endothelial cell adhesion molecules (e.g., E-selectin, tissue factor), inhibits nitric oxide synthetase production, and activates the mTOR pathway leading to endothelial cell proliferation. Neutrophil activation with the release of tissue factor and neutrophil extracellular traps. Monocyte activation with the release of microparticles containing tissue factor. Platelet activation causing secretion of the platelet factor-4 (procoagulant) and thromboxane A2 (increases platelet aggregation).
- • Promotion of coagulation: increases expression of glycoprotein IIb/IIIa (fibrinogen receptor) on platelets and interferes with binding of other phospholipid-binding proteins (e.g., thrombomodulin, annexins, others) with anticoagulant activity, resulting in the suppression of tissue factor pathway inhibitor activity, decrease in activated protein C activity, and less fibrinolysis.
- • Complement activation: anti-β2GPI binding can lead to complement activation with C5a release leading to recruitment and activation of neutrophils, monocytes, and platelets. This is particularly important in pregnancy complications where trophoblasts bind β2GPI, followed by binding of anti-β2GPI antibodies resulting in complement activation, cellular recruitment, tissue factor expression, and coagulation cascade activation leading to thrombosis and placental insufficiency.
- • Other receptors have been identified that can bind β2GPI or the β2GPI–anti-β2GPI complexes leading to cellular activation, adhesion molecule upregulation, and tissue factor release causing a prothrombotic state. Putative receptors are toll-like receptors (TLR2, TLR4 important during times of infection), annexin A2 (tissue plasminogen activator receptor), GPIbα, and low-density lipoprotein receptors (apoER2, LRP8). Therefore, the inciting prothrombotic stimulus and cells involved may differ between episodes of thrombosis.