科研之友
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摘要
Background: beta 2GPI is a major antigen for autoantibodies associated with antiphospholipid syndrome (APS), an autoimmune disease characterized by thrombosis and recurrent pregnancy loss. Only the dimeric form of beta 2GPI generated by anti-beta 2GPI antibodies is pathologically important, in contrast to monomeric beta 2GPI which is abundant in plasma.
Principal Findings: We created a dimeric inhibitor, A1-A1, to selectively target beta 2GPI in beta 2GPI/ antibody complexes. To make this inhibitor, we isolated the first ligand-binding module from ApoER2 (A1) and connected two A1 modules with a flexible linker. A1-A1 interferes with two pathologically important interactions in APS, the binding of beta 2GPI/ antibody complexes with anionic phospholipids and ApoER2. We compared the efficiency of A1-A1 to monomeric A1 for inhibition of the binding of beta 2GPI/ antibody complexes to anionic phospholipids. We tested the inhibition of beta 2GPI present in human serum, beta 2GPI purified from human plasma and the individual domain V of beta 2GPI. We demonstrated that when beta 2GPI/ antibody complexes are formed, A1-A1 is much more effective than A1 in inhibition of the binding of beta 2GPI to cardiolipin, regardless of the source of beta 2GPI. Similarly, A1-A1 strongly inhibits the binding of dimerized domain V of beta 2GPI to cardiolipin compared to the monomeric A1 inhibitor. In the absence of anti-beta 2GPI antibodies, both A1-A1 and A1 only weakly inhibit the binding of pathologically inactive monomeric beta 2GPI to cardiolipin.
Conclusions: Our results suggest that the approach of using a dimeric inhibitor to block beta 2GPI in the pathological multivalent beta 2GPI/ antibody complexes holds significant promise. The novel inhibitor A1-A1 may be a starting point in the development of an effective therapeutic for antiphospholipid syndrome.
- 出版日期2010-12-15
