A peptide that mimics the Vth region of β2glycoprotein I reverses antiphospholipid-mediated thrombosis in mice

Abstract

Antiphospholipid (aPL) antibodies bind to beta2glycoprotein I (beta2GPI) and cause endothelial cell (EC) activation and thrombosis in mice. beta2GPI binds to EC through its Vth domain and induces their activation. TIFI is a 20 amino acid synthetic peptide that shares similarity with the Vth domain of beta2GPI. Our objectives were to examine the ability of TIFI to affect aPL-mediated thrombosis in mice and the interactions of TIFI, beta2GPI with phospholipid surfaces and target cells. CD1 mice were injected with IgG from a patient with antiphospholipid syndrome (IgG-APS) or with control IgG-NHS and with either TIFI or with control peptide (VITT). Size of induced thrombi was determined. Inhibition and competition studies were done using aPL antibodies, cardiolipin (CL) liposomes in the presence of varying amounts of TIFI and beta2GPI. Binding of fluorescinated beta2GPI to human ECs and to murine macrophages in the presence or absence of TIFI, was also examined. TIFI significantly decreased thrombus size in mice injected with IgG-APS. TIFI reverted the beta2GPI-dependent binding of aPL antibodies to CL liposomes in a dose-dependent fashion. This effect was abrogated by addition of beta2GPI, suggesting that TIFI displaces the binding of beta2GPI to phospholipids. TIFI inhibited the binding of fluorescinated beta2GPI to human EC and to murine macrophages. The data indicate that TIFI abrogates thrombogenic properties of aPL in mice by competing with beta2GPI and preventing its binding to target cells. This may be important in designing new modalities for the treatment of thrombosis in APS.

A non–complement-fixing antibody to β2 glycoprotein I as a novel therapy for antiphospholipid syndrome

“…A synthetic peptide derived from cytomegalovirus, which mimics the V domain of b2GPI and competes with this molecule for binding to target cells, was shown to reduce the size of For personal use only. on May 10, 2018. by guest www.bloodjournal.org From thrombi 38,39 and the incidence of fetal loss in mice treated with IgGaPL. 40 Although the ability of the peptide to displace bound b2GPI has not been investigated, the removal of cell-bound molecules should be considered with caution because this may affect fetal development and pregnancy outcomes, as suggested by the defect in embryo implantation and placental morphogenesis observed in b2GPI 2/2 mice.…”

The significance of autoantibodies against β2-glycoprotein I

“…This peptide, referred to as TIFI, effectively competes with ␤ 2 GPI-antibody complexes for binding sites on cellular surfaces. 107 Coinjection of TIFI and antiphospholipid antibodies prevents excessive thrombus formation on a mechanical vascular injury, 108 and TIFI-treatment of pregnant mice that were injected with human antiphospholipid antibodies significantly reduces fetal resorption rates. 107 It should be noted, however, that immunization of mice with TIFI induces the generation of prothrombotic antiphospholipid antibodies, 41 which precludes its applicability as a therapeutic agent in the syndrome.…”

Nuevas estrategias en el tratamiento del síndrome antifosfolípido

“…Además, en pacientes con SAF la prevalencia de polimorfismos protectores (con mutación de TLR) fue menor que en controles 42 . Un péptido sintético de 20 aminoácidos que comparte similitudes con el dominio V de B2G-PI, TIFI, mostró inhibir el estado protrombótico inducido por aPL en ratones, al competir con B2GPI para unirse a la membrana fosfolipídica de la célula blanco 43 . Distintos péptidos similares han sido evaluados en modelos animales demostrando disminución del daño 44 .…”