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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
› Institutsangaben 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).
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Publikationsverlauf

Received: 21. März 2016

Accepted after major revision: 25. Mai 2016

Publikationsdatum:
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
 

  • References

  • 1 Burke AP, Farb A, Malcom GT. et al. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med 1997; 336: 1276-1282.
    CrossrefPubMedSuche in Google Scholar
  • 2 Laufer EM, Winkens MH, Narula J. et al. Molecular imaging of macrophage cell death for the assessment of plaque vulnerability. Arterioscler Thromb Vasc Biol 2009; 29: 1031-1038.
    CrossrefPubMedSuche in Google Scholar
  • 3 Steffel J, Luscher TF, Tanner FC.. Tissue factor in cardiovascular diseases: molecular mechanisms and clinical implications. Circulation 2006; 113: 722-731.
    CrossrefPubMedSuche in Google Scholar
  • 4 Mackman N. Triggers, targets and treatments for thrombosis. Nature 2008; 451: 914-918.
    CrossrefPubMedSuche in Google Scholar
  • 5 Darbousset R, Thomas GM, Mezouar S. et al. Tissue factor-positive neutrophils bind to injured endothelial wall and initiate thrombus formation. Blood 2012; 120: 2133-2143.
    CrossrefPubMedSuche in Google Scholar
  • 6 Libby P, Tabas I, Fredman G. et al. Inflammation and its resolution as determinants of acute coronary syndromes. Circ Res 2014; 114: 1867-1879.
    CrossrefPubMedSuche in Google Scholar
  • 7 Luyendyk JP, Schabbauer GA, Tencati M. et al. Genetic analysis of the role of the PI3K–Akt pathway in lipopolysaccharide-induced cytokine and tissue factor gene expression in monocytes/macrophages. J Immunol 2008; 180: 4218-4226.
    CrossrefPubMedSuche in Google Scholar
  • 8 Mach F, Schonbeck U, Bonnefoy JY. et al. Activation of monocyte/macrophage functions related to acute atheroma complication by ligation of CD40: induction of collagenase, stromelysin, and tissue factor. Circulation 1997; 96: 396-399.
    CrossrefPubMedSuche in Google Scholar
  • 9 Hansson GK, Nilsson J.. Introduction: atherosclerosis as inflammation: a controversial concept becomes accepted. J Intern Med 2008; 263: 462-463.
    CrossrefPubMedSuche in Google Scholar
  • 10 Mullick AE, Tobias PS, Curtiss LK.. Modulation of atherosclerosis in mice by Toll-like receptor 2. J Clin Invest 2005; 115: 3149-3156.
    CrossrefPubMedSuche in Google Scholar
  • 11 Boles J, Mackman N.. Role of tissue factor in thrombosis in antiphospholipid antibody syndrome. Lupus 2010; 19: 370-378.
    CrossrefPubMedSuche in Google Scholar
  • 12 Pierangeli SS, Vega-Ostertag ME, Raschi E. et al. Toll-like receptor and anti-phospholipid mediated thrombosis: in vivo studies. Ann Rheum Dis 2007; 66: 1327-1333.
    CrossrefPubMedSuche in Google Scholar
  • 13 Batuca JR, Ames PR, Isenberg DA. et al. Antibodies toward high-density lipoprotein components inhibit paraoxonase activity in patients with systemic lupus erythematosus. Ann NY Acad Sci 2007; 1108: 137-146.
    CrossrefPubMedSuche in Google Scholar
  • 14 Croca S, Bassett P, Chambers S. et al. IgG anti-apolipoprotein A-1 antibodies in patients with systemic lupus erythematosus are associated with disease activity and corticosteroid therapy: an observational study. Arthritis Res Ther 2015; 17: 26.
    CrossrefPubMedSuche in Google Scholar
  • 15 Dinu AR, Merrill JT, Shen C. et al. Frequency of antibodies to the cholesterol transport protein apolipoprotein A1 in patients with SLE. Lupus 1998; 7: 355-360.
    CrossrefPubMedSuche in Google Scholar
  • 16 Ames PR, Matsuura E, Batuca JR. et al. High-density lipoprotein inversely relates to its specific autoantibody favoring oxidation in thrombotic primary anti-phospholipid syndrome. Lupus 2010; 19: 711-716.
    CrossrefPubMedSuche in Google Scholar
  • 17 Keller PF, Pagano S, Roux-Lombard P. et al. Autoantibodies against apolipoprotein A-1 and phosphorylcholine for diagnosis of non-ST-segment elevation myocardial infarction. J Intern Med 2012; 271: 451-462.
    CrossrefPubMedSuche in Google Scholar
  • 18 Rubini Gimenez M, Pagano S, Virzi J. et al. Diagnostic and prognostic value of autoantibodies anti-apolipoprotein A-1 and anti-phosphorylcholine in acute non-ST elevation myocardial infarction. Eur J Clin Invest 2015; 45: 369-379.
    CrossrefPubMedSuche in Google Scholar
  • 19 Vuilleumier N, Reber G, James R. et al. Presence of autoantibodies to apolipoprotein A-1 in patients with acute coronary syndrome further links autoimmunity to cardiovascular disease. J Autoimmun 2004; 23: 353-360.
    CrossrefPubMedSuche in Google Scholar
  • 20 Vuilleumier N, Rossier MF, Pagano S. et al. Anti-apolipoprotein A-1 IgG as an independent cardiovascular prognostic marker affecting basal heart rate in myocardial infarction. Eur Heart J 2010; 31: 815-823.
    CrossrefPubMedSuche in Google Scholar
  • 21 Montecucco F, Vuilleumier N, Pagano S. et al. Anti-Apolipoprotein A-1 auto-antibodies are active mediators of atherosclerotic plaque vulnerability. Eur Heart J 2011; 32: 412-421.
    CrossrefPubMedSuche in Google Scholar
  • 22 Vuilleumier N, Montecucco F, Spinella G. et al. Serum levels of anti-apolipoprotein A-1 auto-antibodies and myeloperoxidase as predictors of major adverse cardiovascular events after carotid endarterectomy. Thromb Haemost 2013; 109: 706-715.
    Thieme ConnectPubMedSuche in Google Scholar
  • 23 Pruijm M, Schmidtko J, Aho A. et al. High prevalence of anti-apolipoprotein/A-1 autoantibodies in maintenance hemodialysis and association with dialysis vintage. Ther Apher Dial 2012; 16: 588-594.
    CrossrefPubMedSuche in Google Scholar
  • 24 Vuilleumier N, Bas S, Pagano S. et al. Anti-apolipoprotein A-1 IgG predicts major cardiovascular events in patients with rheumatoid arthritis. Arthritis Rheum 2010; 62: 2640-2650.
    CrossrefPubMedSuche in Google Scholar
  • 25 Vuilleumier N, Bratt J, Alizadeh R. et al. Anti-apoA-1 IgG and oxidized LDL are raised in rheumatoid arthritis (RA): potential associations with cardiovascular disease and RA disease activity. Scand J Rheumatol 2010; 39: 447-453.
    CrossrefPubMedSuche in Google Scholar
  • 26 Pagano S, Satta N, Werling D. et al. Anti-apolipoprotein A-1 IgG in patients with myocardial infarction promotes inflammation through TLR2/CD14 complex. J Intern Med 2012; 272: 344-357.
    CrossrefPubMedSuche in Google Scholar
  • 27 Montecucco F, Braunersreuther V, Burger F. et al. Anti-apoA-1 auto-antibodies increase mouse atherosclerotic plaque vulnerability, myocardial necrosis and mortality triggering TLR2 and TLR4. Thromb Haemost 2015; 114: 410-422.
    Thieme ConnectPubMedSuche in Google Scholar
  • 28 DiDonato JA, Huang Y, Aulak KS. et al. Function and distribution of apolipoprotein A1 in the artery wall are markedly distinct from those in plasma. Circulation 2013; 128: 1644-1655.
    CrossrefPubMedSuche in Google Scholar
  • 29 Fernandez-Lizarbe S, Montesinos J, Guerri C. Ethanol induces TLR4/TLR2 association, triggering an inflammatory response in microglial cells. J Neurochem 2013; 126: 261-273.
    CrossrefPubMedSuche in Google Scholar
  • 30 Mackman N, Brand K, Edgington TS.. Lipopolysaccharide-mediated transcriptional activation of the human tissue factor gene in THP-1 monocytic cells requires both activator protein 1 and nuclear factor kappa B binding sites. J Exp Med 1991; 174: 1517-1526.
    CrossrefPubMedSuche in Google Scholar
  • 31 Frantz S, Kelly RA, Bourcier T.. Role of TLR-2 in the activation of nuclear factor kappaB by oxidative stress in cardiac myocytes. J Biol Chem 2001; 276: 5197-5203.
    CrossrefPubMedSuche in Google Scholar
  • 32 Kawai T, Akira S.. TLR signalling. Cell Death Differ 2006; 13: 816-825.
    CrossrefPubMedSuche in Google Scholar
  • 33 Meana C, Pena L, Lorden G. et al. Lipin-1 integrates lipid synthesis with proinflammatory responses during TLR activation in macrophages. J Immunol 2014; 193: 4614-4622.
    CrossrefPubMedSuche in Google Scholar
  • 34 Tang SC, Arumugam TV, Xu X. et al. Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits. Proc Natl Acad Sci USA 2007; 104: 13798-13803.
    CrossrefPubMedSuche in Google Scholar
  • 35 Stampfuss JJ, Censarek P, Fischer JW. et al. Rapid release of active tissue factor from human arterial smooth muscle cells under flow conditions. Arterioscler Thromb Vasc Biol 2006; 26: e34-37.
    CrossrefPubMedSuche in Google Scholar
  • 36 Tedgui A, Mallat Z.. Apoptosis as a determinant of atherothrombosis. Thromb Haemost 2001; 86: 420-426.
    Thieme ConnectPubMedSuche in Google Scholar
  • 37 Pagano S, Gaertner H, Cerini F. et al. The Human Autoantibody Response to Apolipoprotein A-I Is Focused on the C-Terminal Helix: A New Rationale for Diagnosis and Treatment of Cardiovascular Disease?. PLoS One 2015; 10: e0132780.
    CrossrefPubMedSuche in Google Scholar