The interactions among B2-glycoprotein I, natural anticoagulants, and complement : significance for the antiphospholipid syndrome

• Main Author: Sim, Derek Shu Kay
• Language: English
• Published: 2009
• Online Access: http://hdl.handle.net/2429/10912

Antiphospholipid syndrome (APS) patients are predisposed to recurrent thrombosis and miscarriages. Elevated levels of complement activation have also been demonstrated. A major antigenic target of antiphospholipid autoantibodies (aPL) is β2- glycoprotein I (β2GPI). Impairments of anticoagulation by aPL have been demonstrated; however, the mechanism is unclear. Also, the in vivo functions o f β2GPI in the coagulation and complement systems remain to be established. Therefore, the effects of aPL on the interactions among β2GPI, anticoagulation, and complement system were studied. β2GPI interacted with two anticoagulant proteins, activated protein C (APC) and protein S. β2GPI inhibited total APC activity by competing with APC for the phospholipids. However, β2GPI potentiated APC specific activity on phosphatidylethanolamine and phosphatidylserine. Therefore, β2GPI appeared to inhibit as well as to enhance APC. β2GPI also interacted with protein S and C4b-binding protein (C4BP), a complement regulator. C4BP and protein S circulate as a complex in blood. Analyses of the interactions among β2GPI, protein S, and C4BP showed that oxidized surface-bound β2GPI prevented protein S binding to C4BP by competing for the β-chain on C4BP. Also, β2GPI interacted with protein S when β2GPI was not occupied by C4BP. Thus, β2GPI may have a role in maintaining the free protein S level. Besides C4BP, β2GPI also interacted with another complement protein, mannose-binding lectin (MBL). MBL is a complement activator. Their interactions led to weak in vitro complement activation. Interactions of oxidized surface-bound β2GPI with APC and protein S were inhibited by aPL. Also, aPL inhibited the total APC activity on a phosphatidylserine surface by increasing β2GPI deposition. However, this was accompanied by an increase in APC specific activity. Therefore, aPL appeared to inhibit as well as enhance anticoagulation activity. Antiphospholipid antibodies inhibited C4BP and enhanced MBL binding to β2GPI. These observations suggest that aPL can promote complement activation. This possibility was further supported by the observation of in vitro complement activation by a PL in patients' plasma. Therefore, β2GPI may normally interact with APC, protein S, C4BP, and MBL to regulate anticoagulation and complement activation. However, aPL may interfere with these protein interactions, and thereby disrupt the anticoagulation mechanism and elevate complement activation.