3op8

Publication Abstract from PubMed

BACKGROUND: beta2GPI 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 beta2GPI generated by anti-beta2GPI antibodies is pathologically important, in contrast to monomeric beta2GPI which is abundant in plasma. PRINCIPAL FINDINGS: We created a dimeric inhibitor, A1-A1, to selectively target beta2GPI in beta2GPI/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 beta2GPI/antibody complexes with anionic phospholipids and ApoER2. We compared the efficiency of A1-A1 to monomeric A1 for inhibition of the binding of beta2GPI/antibody complexes to anionic phospholipids. We tested the inhibition of beta2GPI present in human serum, beta2GPI purified from human plasma and the individual domain V of beta2GPI. We demonstrated that when beta2GPI/antibody complexes are formed, A1-A1 is much more effective than A1 in inhibition of the binding of beta2GPI to cardiolipin, regardless of the source of beta2GPI. Similarly, A1-A1 strongly inhibits the binding of dimerized domain V of beta2GPI to cardiolipin compared to the monomeric A1 inhibitor. In the absence of anti-beta2GPI antibodies, both A1-A1 and A1 only weakly inhibit the binding of pathologically inactive monomeric beta2GPI to cardiolipin. CONCLUSIONS: Our results suggest that the approach of using a dimeric inhibitor to block beta2GPI in the pathological multivalent beta2GPI/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.

A Novel Dimeric Inhibitor Targeting Beta2GPI in Beta2GPI/Antibody Complexes Implicated in Antiphospholipid Syndrome.,Kolyada A, Lee CJ, De Biasio A, Beglova N PLoS One. 2010 Dec 15;5(12):e15345. PMID:21179511^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.