A novel dimeric inhibitor targeting Beta2GPI in Beta2GPI/antibody complexes implicated in antiphospholipid syndrome.
PLoS One
; 5(12): e15345, 2010 Dec 15.
Article
em En
| MEDLINE
| ID: mdl-21179511
ABSTRACT
BACKGROUND:
ß2GPI 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 ß2GPI generated by anti-ß2GPI antibodies is pathologically important, in contrast to monomeric ß2GPI which is abundant in plasma. PRINCIPALFINDINGS:
We created a dimeric inhibitor, A1-A1, to selectively target ß2GPI in ß2GPI/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 ß2GPI/antibody complexes with anionic phospholipids and ApoER2. We compared the efficiency of A1-A1 to monomeric A1 for inhibition of the binding of ß2GPI/antibody complexes to anionic phospholipids. We tested the inhibition of ß2GPI present in human serum, ß2GPI purified from human plasma and the individual domain V of ß2GPI. We demonstrated that when ß2GPI/antibody complexes are formed, A1-A1 is much more effective than A1 in inhibition of the binding of ß2GPI to cardiolipin, regardless of the source of ß2GPI. Similarly, A1-A1 strongly inhibits the binding of dimerized domain V of ß2GPI to cardiolipin compared to the monomeric A1 inhibitor. In the absence of anti-ß2GPI antibodies, both A1-A1 and A1 only weakly inhibit the binding of pathologically inactive monomeric ß2GPI to cardiolipin.CONCLUSIONS:
Our results suggest that the approach of using a dimeric inhibitor to block ß2GPI in the pathological multivalent ß2GPI/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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Aborto Habitual
/
Síndrome Antifosfolipídica
/
Beta 2-Glicoproteína I
Limite:
Animals
/
Female
/
Humans
/
Pregnancy
Idioma:
En
Revista:
PLoS One
Assunto da revista:
CIENCIA
/
MEDICINA
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Estados Unidos