title: Anti-apolipoprotein A-1 auto-antibodies as active modulators of atherothrombosis.
abstract: Humoral autoimmune-mediated inflammation plays a role in atherogenesis, and potentially in arterial thrombosis. Anti-apolipoprotein A-1 (apoA-1) IgG have been reported to represent emergent mediators of atherogenesis through Toll-like receptors (TLR) 2, 4 and CD14 signalling. We investigated the role of anti-apoA-1 IgG on tissue factor (TF) expression and activation, a key coagulation regulator underlying atherothrombosis. Atherothrombosis features were determined by immunohistochemical TF staining of human carotid biopsies derived from patients with severe carotid stenosis undergoing elective surgery (n=176), and on aortic roots of different genetic backgrounds mice (ApoE-/-; TLR2-/-ApoE-/- and TLR4-/-ApoE-/-) exposed to passive immunisation with anti-apoA-1 IgG. Human serum levels of anti-apoA-1 IgG were measured by ELISA. In vitro, on human-monocyte-derived-macrophages (HMDM) the anti-apoA-1 IgG increased TF expression and activity were analysed by FACS and chromogenic assays in presence of different pharmacological inhibitors. Human serum anti-apoA-1 IgG levels significantly correlated to intraplaque TF expression in carotid biopsies (r=0.31, p<0.001), which was predictive of clinically symptomatic lesions. On HMDM, anti-apoA-1 IgG induced a TLR2, 4 and CD14-dependent increase in TF expression and activity, involving NF-kappaB and a c-Jun N-terminal kinase-dependent AP-1 transcription factors. In ApoE-/- mice, anti-apoA-1 IgG passive immunisation significantly enhanced intraplaque TF expression when compared to control IgG. This effect was lost in both TLR2-/-ApoE-/- and TLR4-/-ApoE-/- mice. These results demonstrate that anti-apoA-1 IgG are associated with TF expression in human atherosclerotic plaques, induce TF expression in vitro and in vivo through TLR2 and 4 signalling, supporting a possible causal relationship between anti-apoA-1 IgG and atherothrombosis.
authors.affiliation: Sabrina Pagano, PhD, Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, 4 rue Gabrielle Perret-Gentil, 1205 Geneva, Switzerland, Tel.: +41 22 37 95 321, Fax: +41 22 3795502, E-mail: Sabrina.Pagano@hcuge.ch.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pagano
authors.forename: Federico
authors.initials: F
authors.lastname: Carbone
authors.forename: Fabienne
authors.initials: F
authors.lastname: Burger
authors.forename: Aline
authors.initials: A
authors.lastname: Roth
authors.forename: Maria
authors.initials: M
authors.lastname: Bertolotto
authors.forename: Bianca
authors.initials: B
authors.lastname: Pane
authors.forename: Giovanni
authors.initials: G
authors.lastname: Spinella
authors.forename: Domenico
authors.initials: D
authors.lastname: Palombo
authors.forename: Aldo
authors.initials: A
authors.lastname: Pende
authors.forename: Franco
authors.initials: F
authors.lastname: Dallegri
authors.forename: Nathalie
authors.initials: N
authors.lastname: Satta
authors.forename: Julien
authors.initials: J
authors.lastname: Virzi
authors.forename: Pierre
authors.initials: P
authors.lastname: Fontana
authors.forename: François
authors.initials: F
authors.lastname: Mach
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Montecucco
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vuilleumier
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016632:Apolipoprotein A-I / Q000037:antagonists & inhibitors* / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood*; D016893:Carotid Stenosis / Q000097:blood / Q000209:etiology / Q000276:immunology; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000074085:Mice, Knockout, ApoE; D058226:Plaque, Atherosclerotic / Q000097:blood / Q000209:etiology / Q000276:immunology; D011446:Prospective Studies; D013925:Thromboplastin / Q000378:metabolism; D013927:Thrombosis / Q000097:blood / Q000209:etiology* / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics
chemical_list: D016632:Apolipoprotein A-I; D001323:Autoantibodies; D007074:Immunoglobulin G; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D013925:Thromboplastin
keywords: Anti-apoA-1 IgG; atherothrombosis; macrophages; tissue factor; toll-like receptors