Inhibition of thrombotic properties of persistent autoimmune anti-β2GPI antibodies in the mouse model of antiphospholipid syndrome

Kolyada, Alexey; Porter, A.J.; Beglova, Natalia

doi:10.1182/blood-2013-08-520882

Cited by 33 publications

(33 citation statements)

References 56 publications

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“…A1–A1 not only interferes with the binding of β2GPI/antibody complexes to ApoER2, but also prevents their association with anionic phospholipids, therefore inhibiting two potentially harmful activities of β2GPI/antibody complexes . Most importantly, we demonstrated that infusion of A1–A1 in mice abrogated the increase in thrombus size caused by the presence of β2GPI/antibody complexes .…”

Section: Introductionmentioning

confidence: 68%

“…β2GPI/antibody complexes are prothrombotic in APS patients and in mice . Disruption of a protective shield formed by annexin V on anionic phospholipids by β2GPI/antibody complexes is one of the thrombogenic mechanisms in APS .…”

Section: Resultsmentioning

confidence: 99%

“…Inhibition of the binding of human and mouse b2GPI to anionic phospholipids assessed by cardiolipin ELISA b2GPI/antibody complexes are prothrombotic in APS patients and in mice [7,8,33]. Disruption of a protective shield formed by annexin V on anionic phospholipids by b2GPI/antibody complexes is one of the thrombogenic mechanisms in APS [21,37].…”

Section: Binding Of A1 Variants To Domain V Of Human B2gpimentioning

confidence: 99%

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An A1–A1 mutant with improved binding and inhibition of β2GPI/antibody complexes in antiphospholipid syndrome

et al. 2015

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Beta2-glycoprotein I (β2GPI) is the most common antigen for autoimmune antibodies in antiphospholipid syndrome (APS). Thrombosis is a clinical feature of APS. We made a molecule (A1-A1) that consists of two identical β2GPI-binding modules from ApoE receptor 2. A1-A1 binds to β2GPI/anti-β2GPI antibody complexes preventing their association with ApoER2 and anionic phospholipids, and reducing thrombus size in the mouse model of APS. Here, we describe a mutant of A1-A1 (mA1-A1ND) with improved affinity for β2GPI. mA1-A1ND inhibits the binding of β2GPI to cardiolipin in the presence of anti-β2GPI antibodies and inhibits β2GPI/antibody complexes in plasma samples of APS patients affecting the clotting time. Inhibition of the clotting time demonstrates the presence of soluble β2GPI/anti-β2GPI antibody complexes in patients’ plasma. These complexes either already exist in patients’ plasma or form rapidly in the vicinity of phospholipids. All members of the LDL receptor family can bind β2GPI. Modelling studies of A1 in a complex with domain V of β2GPI (β2GPI-DV) revealed two possible orientations of a ligand-binding module from lipoprotein receptors on β2GPI-DV. In both orientations, the ligand-binding module interferes with the binding of β2GPI to anionic phospholipids, however it interacts with two different though overlapping sets of lysine residues in β2GPI-DV, depending on the orientation.

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Section: Introductionmentioning

confidence: 68%

Section: Resultsmentioning

confidence: 99%

Section: Binding Of A1 Variants To Domain V Of Human B2gpimentioning

confidence: 99%

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An A1–A1 mutant with improved binding and inhibition of β2GPI/antibody complexes in antiphospholipid syndrome

et al. 2015

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“…The binding of the anti-b2GP1 antibody/b2GP1 complex to cell receptors 19,36,[39][40][41] has been studied, and receptors have been proposed to be involved in thrombus enhancement. The inhibition of enhancement of thrombus formation in the absence of specific receptors [20][21][22]42 or in the presence of inhibitors of receptors 43 suggest that some receptors may not be directly involved in the pathway initiated by the anti-b2GP1 autoantibody/b2GP1 complex. Therefore, we visualized both cell binding and cell activation induced by the anti-b2GP1 autoantibody/b2GP1 complex in vivo.…”

Section: Discussionmentioning

confidence: 99%

Platelets are required for enhanced activation of the endothelium and fibrinogen in a mouse thrombosis model of APS

Proulle

Furie

Merrill-Skoloff

et al. 2014

Blood

104

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• The anti-b2GP1 autoantibody/ b2GP1 complex binds to the platelet thrombus, amplifying platelet activation.• Platelets are required for enhanced activation of the endothelium and fibrin generation by the anti-b2GP1 autoantibody/b2GP1 complex.Antiphospholipid syndrome (APS) is defined by thrombosis, fetal loss, and the presence of antiphospholipid antibodies, including anti-b2-glycoprotein-1 autoantibodies (antib2GP1) that have a direct role in the pathogenesis of thrombosis in vivo. The cellular targets of the anti-b2GP1 autoantibody/b2GP1 complex in vivo were studied using a laserinduced thrombosis model of APS in a live mouse and human anti-b2GP1 autoantibodies affinity-purified from APS patients. Cell binding of fluorescently labeled b2GP1 and antib2GP1 autoantibodies revealed their colocalization on the platelet thrombus but not the endothelium. Anti-b2GP1 autoantibodies enhanced platelet activation, monitored by calcium mobilization, and endothelial activation, monitored by intercellular adhesion molecule-1 expression. When eptifibatide was infused to block platelet thrombus formation, enhanced fibrin generation and endothelial cell activation were eliminated. Thus, the anti-b2GP1 autoantibody/b2GP1 complex binds to the thrombus, enhancing platelet activation, and platelet secretion leads to enhanced endothelium activation and fibrin generation. These results lead to a paradigm shift away from the concept that binding of the anti-b2GP1 autoantibody/b2GP1 complex activates both endothelial cells and platelets toward one in which activation of platelets in response to anti-b2GP1 autoantibody/b2GP1 complex binding leads to subsequent enhanced endothelium activation and fibrin generation. (Blood. 2014;124(4):611-622) IntroductionAntiphospholipid syndrome (APS) is characterized by venous or arterial thrombosis and/or pregnancy morbidity and is associated with circulating antiphospholipid (aPL) autoantibodies.1-3 These antibodies, including anti-b2-glycoprotein-1 (anti-b2GP1) autoantibodies, recognize plasma proteins that bind to anionic phospholipids, among which b2GP1 is the major target. 4 Antibodies directed against b2GPI 5,6 are associated with thrombotic events in APS. Antib2GP1 autoantibodies from patients with APS and thrombosis enhance arterial thrombus formation after injury in a mouse model of APS, 7 with dramatic increases in platelet thrombus size and fibrin generation.The mechanisms leading to thrombosis in APS are unresolved. In vitro and in vivo studies using animal models demonstrated that aPL antibodies interact with endothelial cells and monocytes to increase tissue factor expression and complement activation and proinflammatory cytokines. 8,9 In vitro, platelet activation occurs after the binding of complexes of anti-b2GP1 antibodies and dimerized b2GP1 to GPIba and ApoER2. [10][11][12] Furthermore, APS patients exhibit markers of platelet activation. 13 The conventional understanding is that the antib2GP1/b2GP1 complex binds to receptors on both the endothelial cell and the platelet, lea...

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“…Previously, we have shown that A1‐A1 preferentially binds to β2GPI when it is dimerized by anti‐β2GPI antibody, compared with β2GPI alone . A1‐A1 inhibited the anti‐β2GPI‐dependent increase of thrombus size in laser‐induced thrombosis in BALB/c mice infused with anti‐β2GPI antibodies isolated from a patient with APS and in (NZWxBXSB)F1 male mice with spontaneous anti‐β2GPI antibodies .…”

Section: Introductionmentioning

confidence: 93%

Soluble analog of ApoER2 targeting beta2‐glycoprotein I in immune complexes counteracts hypertension in lupus‐prone mice with spontaneous antiphospholipid syndrome

Kolyada

Karageorgos

et al. 2016

Journal of Thrombosis and Haemostasis

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To cite this article: Kolyada A, Ke Q, Karageorgos I, Mahlawat P, Barrios DA, Kang PM, Beglova N. Soluble analog of ApoER2 targeting beta2-glycoprotein I in immune complexes counteracts hypertension in lupus-prone mice with spontaneous antiphospholipid syndrome.J Thromb Haemost 2016; 14: 1298-307. Essentials(NZWxBXSB)F1 male mice develop antibodies beta2-glycoprotein I (b2GPI) and hypertension. A1-A1 is a soluble analogue of ApoE receptor 2 with a high affinity for b2GPI/antibody complexes. A1-A1 improved blood pressure and arterial elastance in (NZWxBXSB)F1 male mice. A1-A1 had no adverse effects on the hemodynamics of healthy mice.Summary. Background: Antiphospholipid syndrome (APS) is diagnosed based on the presence of antiphospholipid antibodies and clinical thrombosis or fetal loss during pregnancy. Lupus-prone (NZWxBXSB)F1 male mice are the mouse model of spontaneous APS. They develop antib2GPI antibodies, microinfarcts and hypertension. ApoER2 is a receptor that contributes to anti-b2GPI-dependent thrombosis in APS by down-regulating endothelial nitric oxide synthase activation. Objectives: A1-A1 is a small protein constructed from two identical ligand-binding modules from ApoER2, containing the binding site for b2GPI. We studied how treatment with A1-A1 affects the development of hypertension in (NZWxBXSB)F1 male mice. Methods: We treated (NZWxBXSB)F1 male mice with A1-A1 for up to 4 weeks and examined changes in hemodynamics by left ventricular pressure-volume loop measurements. Results: We observed improvements in blood pressure in the A1-A1 treated mice. A1-A1 prevented the deterioration of arterial elastance by decreasing systemic resistance and improving vessel compliance. We did not detect any adverse effects of the treatment in either male mice or in apparently healthy female (NZWxBXSB)F1 mice. Conclusions: We demonstrated that A1-A1, which is a soluble analog of ApoER2 that binds pathological b2GPI/anti-b2GPI complexes, has a positive impact on hemodynamics in lupus-prone mice with spontaneous anti-b2GPI antibodies and hypertension.

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Inhibition of thrombotic properties of persistent autoimmune anti-β2GPI antibodies in the mouse model of antiphospholipid syndrome

Cited by 33 publications

References 56 publications

An A1–A1 mutant with improved binding and inhibition of β2GPI/antibody complexes in antiphospholipid syndrome

An A1–A1 mutant with improved binding and inhibition of β2GPI/antibody complexes in antiphospholipid syndrome

Platelets are required for enhanced activation of the endothelium and fibrinogen in a mouse thrombosis model of APS

Soluble analog of ApoER2 targeting beta2‐glycoprotein I in immune complexes counteracts hypertension in lupus‐prone mice with spontaneous antiphospholipid syndrome

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