| Summary: | 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.
|
|---|
