Anti-beta2-glycoprotein I (beta2GPI) monoclonal antibodies with lupus anticoagulant-like activity enhance the beta2GPI binding to phospholipids.

Takeya, Hiroyuki; Mori, Terumi; Gabazza, Esteban C.; Kuroda, Kenji; Deguchi, Hiroshi; Matsuura, Eiji; Ichikawa, Kenji; Koike, Takao; Suzuki, Koji

doi:10.1172/jci119401

Cited by 125 publications

(49 citation statements)

References 63 publications

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“…54 When an antibody links 2 ␤ 2 -glycoprotein I molecules, the membranebinding affinity is increased, and ␤ 2 -glycoprotein becomes a more potent in vitro anticoagulant. 55 Whether ␤ 2 -glycoprotein I has a physiologic function influencing procoagulant or anticoagulant membrane interactions remains unknown. 56 The physiologic relationship of these proteins and lactadherin to blood coagulation is a likely field for speculation and further investigation.…”

Section: Discussionmentioning

confidence: 99%

Lactadherin inhibits enzyme complexes of blood coagulation by competing for phospholipid-binding sites

Shi

Gilbert

2003

Blood

160

149

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Lactadherin, a glycoprotein of the milk-fat globule membrane, contains tandem C domains with homology to discoidin-type lectins and to membrane-binding domains of blood-clotting factors V and VIII. We asked whether the structural homology confers the capacity to compete for the membrane-binding sites of factor VIII and factor V and to function as an anticoagulant. Our results indicate that lactadherin competes efficiently with factor VIII and factor V for binding sites on synthetic phosphatidylserine-containing membranes with half-maximal displacement at lactadherin concentrations of 1 to 4 nM. Binding competition correlated to functional inhibition of factor VIIIa-factor IXa (factor Xase) enzyme complex. In contrast to annexin V, lactadherin was an efficient inhibitor of the prothrombinase and the factor Xase complexes regardless of the degree of membrane curvature and the phosphatidylserine content. Lactadherin also inhibited the factor VIIa-tissue factor complex efficiently whereas annexin V was less effective. Because the inhibitory concentration of lactadherin was proportional to the phospholipid concentration, and because lactadherin was not an efficient inhibitor in the absence of phospholipid, the major inhibitory effect of lactadherin relates to blocking phospholipid sites rather than forming inhibitory protein-protein complexes. Lactadherin was also an effective inhibitor of a modified whole blood prothrombin time assay in which clotting was initiated by dilute tissue factor; 60 nM lactadherin prolonged the prothrombin time 150% IntroductionLactadherin is a 47 000-Da molecular weight (MW) glycoprotein of milk-fat globules. It has also been known as PAS-6/7, indicating the 2 glycosylation variants, 1 bovine-associated mucoprotein, BA-46, P47, and MFG-E8. 2 Lactadherin has a domain structure of EGF1-EGF2-C1-C2 in which EGF indicates epidermal growth factor homology domains, and the C domains share homology with the discoidin family, including the lipid-binding C domains of blood coagulation factor VIII and factor V. 2 The second EGF domain displays an Arg-Gly-Asp motif, 3 which binds to the ␣ v ␤ 3 and ␣ v ␤ 5 integrins. 1,[4][5][6] The second C domain binds to phospholipids. 6 In milk-fat globules, lactadherin lines the surface of the phospholipid bilayer that surrounds the central triglyceride droplet, apparently stabilizing the bilayer. 7 Lactadherin decreases the symptoms of rotavirus infection in infants, possibly by binding to rotavirus particles via carbohydrate moieties. 8 In tissue sections, lactadherin is found localized on the apical portion of secretory epithelium in the breast. 7 Abundant expression by breast carcinoma tissue makes lactadherin a potential target for antigen-guided radiation therapy. 9 Lactadherin is also found on the apical surface of epithelia in the biliary tree, the pancreas, and sweat glands 7 and is synthesized by aortic medial smooth muscle cells. 10 Function in these tissues remains unknown. Lactadherin has been identified as a zona pellucida-binding protein on the a...

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Section: Discussionmentioning

confidence: 99%

Lactadherin inhibits enzyme complexes of blood coagulation by competing for phospholipid-binding sites

Shi

Gilbert

2003

Blood

160

149

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“…Recent reports indicated that the presence of LA activity is the strongest risk factor for thromboembolic events in patients with SLE (33,34 ). However, LA activity detected by a PL-dependent coagulation assay is heterogeneous, and some investigations showed that LA activity depends on the ability of autoantibodies to bind to PL-bound PT or ␤2-GPI (1,25,27,35,36 ). We therefore used specific ELISAs to examine the concentrations of anti-CL/␤2-GPI and anti-PS/PT antibodies in 87 SLE patients with or without VTE.…”

Section: Discussionmentioning

confidence: 99%

“…These findings suggest that acquired APC-R in SLE patients is attributable to functional interference of the protein C pathway by anti-CL/␤2-GPI or anti-PS/PT antibodies. Several recent studies showed that anti-CL/␤2-GPI/anti-PS/PT antibodies enhance the binding of ␤2-GPI/PT to negatively charged PL in the prothrombinase reaction (35,(45)(46)(47)(48). It is possible that these antibodies could indirectly inhibit the PL-dependent reactions of the APC pathway.…”

Section: Discussionmentioning

confidence: 99%

Acquired Activated Protein C Resistance Associated with IgG Antibodies against β2-Glycoprotein I and Prothrombin as a Strong Risk Factor for Venous Thromboembolism

et al. 2005

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Background:Venous thromboembolic events such as deep vein thrombosis and pulmonary embolism are common manifestations of antiphospholipid syndrome. Our aim was to clarify the roles of anti-phospholipid (aPL) antibodies in the pathogenesis of venous thromboembolism (VTE) in patients with systemic lupus erythematosus (SLE). Methods and Results:We examined anti-cardiolipin/ ␤ 2 -glycoprotein I (anti-CL/␤2-GPI) antibody concentrations, anti-phosphatidylserine/prothrombin (anti-PS/ PT) antibody concentrations, and lupus anticoagulant (LA) activity in 87 patients with SLE (21 with VTE and 66 without thrombosis). Both anti-CL/␤2-GPI and anti-PS/PT antibodies strongly correlated with LA activity. Multivariate logistic analysis confirmed that both anti-CL/␤2-GPI and anti-PS/PT antibodies were significant independent risk factors for VTE (odds ratios ‫؍‬ 4.98 and 7.54, respectively; 95% confidence intervals, 1.51-16.4 and 2.30 -24.7, respectively). We therefore studied the in vitro effects of IgG fractions containing anti-CL/␤2-GPI or anti-PS/PT antibodies on the anticoagulant activity of activated protein C (APC) and found that purified IgG containing anti-CL/␤2-GPI or anti-PS/PT antibodies significantly hampered the anticoagulant activity of APC.

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“…The Fab of the anticardiolipin Abs have no appreciable effect on ␤ 2 -GP1 binding. Takeya et al (26) showed that anti-␤ 2 -GP1 mAbs directed against the third and fourth domains of ␤ 2 -GP1 enhance binding of ␤ 2 -GP1 to plastic-adsorbed phospholipid and phospholipid vesicles. The Fab of the mAbs were without effect.…”

Section: Discussionmentioning

confidence: 99%

Lupus Antibody Bivalency Is Required to Enhance Prothrombin Binding to Phospholipid

Field

Chesterman

Dai

et al. 2001

The Journal of Immunology

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Lupus anticoagulants (LA) are a family of autoantibodies that are associated with in vitro anticoagulant activity but a strong predisposition to in vivo thrombosis. They are directed against plasma phospholipid-binding proteins including prothrombin. We have proposed that LA propagates coagulation in flowing blood by facilitating prothrombin interaction with the damaged blood vessel wall. A murine monoclonal anti-prothrombin Ab and three of three LA IgGs enhanced prothrombin binding to 75:25 phosphatidyl choline:phosphatidyl serine vesicles measured by either ultracentrifugation or right-angle light scattering. The assembly of prothrombin and LA IgG on phospholipid vesicles was estimated by surface plasmon resonance. The on rates for prothrombin and LA IgG were approximately the same as the on rate for prothrombin alone. In contrast, the off rates for prothrombin and LA IgG were 2- to 3-fold slower than the off rate for prothrombin. LA IgG bivalency was required for enhanced prothrombin binding to phospholipid vesicles, as Fab of the LA IgGs did not influence prothrombin binding at concentrations up to 40 μM. Modeling of the interactions of prothrombin, LA IgG and phospholipid vesicles indicated that augmentation of prothrombin binding to phospholipid vesicles by LA IgG could be accounted for by the bivalency of the LA IgG and the elevated microenvironmental concentration of prothrombin on the surface of phospholipid vesicles.

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Anti-beta2-glycoprotein I (beta2GPI) monoclonal antibodies with lupus anticoagulant-like activity enhance the beta2GPI binding to phospholipids.

Cited by 125 publications

References 63 publications

Lactadherin inhibits enzyme complexes of blood coagulation by competing for phospholipid-binding sites

Lactadherin inhibits enzyme complexes of blood coagulation by competing for phospholipid-binding sites

Acquired Activated Protein C Resistance Associated with IgG Antibodies against β2-Glycoprotein I and Prothrombin as a Strong Risk Factor for Venous Thromboembolism

Lupus Antibody Bivalency Is Required to Enhance Prothrombin Binding to Phospholipid

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