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Thromb Haemost 2016; 116(03): 554-564
DOI: 10.1160/TH16-03-0229
Atherosclerosis and Ischaemic Disease
Schattauer GmbH

Anti-apolipoprotein A-1 auto-antibodies as active modulators of atherothrombosis

Sabrina Pagano
1   Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland
2   Department of Human Protein Sciences, Geneva, Switzerland
,
Federico Carbone
3   Division of Cardiology, Geneva University Hospitals, Faculty of Medicine, Foundation for Medical Researches, Geneva, Switzerland
,
Fabienne Burger
3   Division of Cardiology, Geneva University Hospitals, Faculty of Medicine, Foundation for Medical Researches, Geneva, Switzerland
,
Aline Roth
3   Division of Cardiology, Geneva University Hospitals, Faculty of Medicine, Foundation for Medical Researches, Geneva, Switzerland
,
Maria Bertolotto
4   First Medical Clinic, Laboratory of Phagocyte Physiopathology and Inflammation, Department of Internal Medicine, University of Genoa, Genoa, Italy
,
Bianca Pane
5   Vascular and Endovascular Surgery Unit, Department of Surgery, San Martino Hospital, Genoa, Italy
,
Giovanni Spinella
5   Vascular and Endovascular Surgery Unit, Department of Surgery, San Martino Hospital, Genoa, Italy
,
Domenico Palombo
5   Vascular and Endovascular Surgery Unit, Department of Surgery, San Martino Hospital, Genoa, Italy
,
Aldo Pende
4   First Medical Clinic, Laboratory of Phagocyte Physiopathology and Inflammation, Department of Internal Medicine, University of Genoa, Genoa, Italy
,
Franco Dallegri
4   First Medical Clinic, Laboratory of Phagocyte Physiopathology and Inflammation, Department of Internal Medicine, University of Genoa, Genoa, Italy
,
Nathalie Satta
1   Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland
2   Department of Human Protein Sciences, Geneva, Switzerland
,
Julien Virzi
1   Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland
2   Department of Human Protein Sciences, Geneva, Switzerland
,
Pierre Fontana
1   Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland
2   Department of Human Protein Sciences, Geneva, Switzerland
6   Division of Angiology and Haemostasis, Geneva University Hospitals, Geneva, Switzerland
,
François Mach
3   Division of Cardiology, Geneva University Hospitals, Faculty of Medicine, Foundation for Medical Researches, Geneva, Switzerland
,
Fabrizio Montecucco
3   Division of Cardiology, Geneva University Hospitals, Faculty of Medicine, Foundation for Medical Researches, Geneva, Switzerland
4   First Medical Clinic, Laboratory of Phagocyte Physiopathology and Inflammation, Department of Internal Medicine, University of Genoa, Genoa, Italy
,
Nicolas Vuilleumier
1   Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland
2   Department of Human Protein Sciences, Geneva, Switzerland
› Author Affiliations Financial support: This study was supported by European Commission (FP7-INNOVATION I HEALTH-F2–2013–602114; Athero-B-Cell: Targeting and exploiting B cell function for treatment in cardiovascular disease). This work was supported by Swiss National Science Foundation Grants to Prof. F. Montecucco (#310030_152639/1), to Prof. F. Mach (#310030_152912/1) and to Prof. N. Vuilleumier (#310030_163335). This study was supported by a grant from the Leenaards Foundation to Dr. F. Montecucco and Prof. N. Vuilleumier (#3698).
Further Information

Publication History

Received: 21 March 2016

Accepted after major revision: 25 May 2016

Publication Date:
29 November 2017 (online)

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Summary

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.

Keywords

Anti-apoA-1 IgG - tissue factor - atherothrombosis - macrophages - toll-like receptors
 

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