A peptide that mimics the Vth region of beta-2-glycoprotein I reverses antiphospholipid-mediated thrombosis in mice.
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.
Ostertag
M Vega
MV
Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA 30310-1495, USA.
Liu
X
X
Henderson
V
V
Pierangeli
S S
SS
D000595:Amino Acid Sequence; D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000097:blood / Q000276:immunology / Q000633:toxicity; D016736:Antiphospholipid Syndrome / Q000097:blood / Q000276:immunology*; D001667:Binding, Competitive; D002308:Cardiolipins / Q000276:immunology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D004797:Enzyme-Linked Immunosorbent Assay; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000627:therapeutic use*; D006801:Humans; D007074:Immunoglobulin G / Q000633:toxicity; D008081:Liposomes; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D013927:Thrombosis / Q000209:etiology / Q000517:prevention & control*; D053482:beta 2-Glycoprotein I / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism
D017152:Antibodies, Antiphospholipid; D002308:Cardiolipins; D005343:Fibrinolytic Agents; D007074:Immunoglobulin G; D008081:Liposomes; D010455:Peptides; C516775:TIFI peptide; D053482:beta 2-Glycoprotein I