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A peptide that mimics the Vth region of ß2glycoprotein I reverses antiphospholipid-mediated thrombosis in mice

Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA, USA

X Liu

Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA, USA

V Henderson

Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA, USA

S S Pierangeli

Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA, USA, pierans{at}msm.edu

Antiphospholipid (aPL) antibodies bind to 2glycoprotein I (2GPI) and cause endothelial cell (EC) activation and thrombosis in mice. 2GPI 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 2GPI. Our objectives were to examine the ability of TIFI to affect aPL-mediated thrombosis in mice and the interactions of TIFI, 2GPI with phospholipid surfaces and target cells. CD1 mice were injected with IgG from a patient with antiphospholipid syndrome (IgG-APS) or with control IgGNHS 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 2GPI. Binding of fluorescinated 2GPI 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 2GPI-dependent binding of aPL antibodies to CL liposomes in a dose-dependent fashion. This effect was abrogated by addition of 2GPI, suggesting that TIFI displaces the binding of 2GPI to phospholipids. TIFI inhibited the binding of fluorescinated 2GPI to human EC and to murine macrophages. The data indicate that TIFI abrogates thrombogenic properties of aPL in mice by competing with 2GPI and preventing its binding to target cells. This may be important in designing new modalities for the treatment of thrombosis in APS.

Key Words: antiphospholipid antibodies • ß2GPI • thrombosis • viral peptides

Lupus, Vol. 15, No. 6, 358-365 (2006)
DOI: 10.1191/0961203306lu2315oa


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