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Role of anti-apolipoprotein A-1 auto-antibodies in atherogenesis-related complications: from bench to bedside

English title Role of anti-apolipoprotein A-1 auto-antibodies in atherogenesis-related complications: from bench to bedside
Applicant Vuilleumier Nicolas
Number 140736
Funding scheme Project funding (Div. I-III)
Research institution Département de médecine génétique et de laboratoire (DMGL) Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Cardiovascular Research
Start/End 01.04.2012 - 31.03.2015
Approved amount 289'536.00
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All Disciplines (2)

Discipline
Cardiovascular Research
Immunology, Immunopathology

Keywords (4)

inflammation; anti-apolipoprotein A-1 autoantibodies; cardiovascular disease; atherogenesis

Lay Summary (English)

Lead
Lay summary

« Role of anti-apolipoprotein A-1 auto-antibodies in atherogenesis-related complications: from bench to bedside

 

                                    SNF grant 310030_140736

 

Background

Cardiovascular diseases (CVD) is the leading cause of morbidity and mortality in Western countries, and are often clinically manifest as acute coronary syndromes (ACS), including myocardial infarction (MI). The underlying mechanism of ACS is atherosclerotic plaque rupture, in which vascular immune-mediated inflammation has been recognized of major importance, and atherosclerosis-related inflammation even fulfils the required “Koch’s postulates” to be considered as an autoimmune disease. Consistent with this hypothesis, there is a growing body of biological evidences demonstrating that auto-antibodies could modulate inflammation through innate immune receptors (mostly Toll-like receptors) signaling which can either stimulate or inhibit atherogenesis-related processes. Accordingly, different clinical trials have demonstrated that high levels of anti-cardiolipin, anti-β2 glycoprotein-I (anti-β2 GPI), anti-heat shock protein 60 (anti-HSP-60), anti-apolipoproteinA-1 (apoA-1) auto-antibodies were associated with an increased CV risk, whereas other studies demonstrated that high levels of autoantibodies of IgM subtype against phosphorylcholine (anti-PC IgM), the immunodominant epitope of oxidised Low-Density Lipoprotein (oxLDL), protected against CVD. Given their relative independence toward classical cardiovascular risk factors, those autoantibodies have been proposed as emergent tools for cardiovascular risk stratification. Our work in the field is focused on anti-apolipoprotein A-1 (anti-apoA-1) IgG. ApoA-1 is the major protein fraction of high-density lipoproteins (HDL), conferring to the latter most of its atheroprotective role. So far, we demonstrated that anti-apoA-1 IgG is an independent prognostic marker of major cardiovascular events after a MI and in Rheumatoid arthritis (RA). In RA, anti-apoA-1 IgG was shown to be the only biomarker providing significant incremental prognostic information to FRS, according to reclassification statistics, and in acute chest pain patients those auto-antibodies were shown to display a significant diagnostic accuracy for non ST elevation (MI), and subsequent troponin I elevation with a high negative predictive value, especially when combined to NSTEMI-TIMI score. In patients with carotid atherosclerosis, high circulating levels of those auto-antibodies were associated with increased vulnerable plaques, and anti-apoA-1 IgG passive immunization in apoE double knock-out mice increased atherogenesis as well as atherosclerotic plaque vulnerability. From a pathophysiological point of view, those autoantibodies have been shown in vitro to promote sterile inflammation by stimulating Toll-Like receptor (TLR)2/CD14 complex, to increase neutrophil chemotaxis, and to interfere with basal heart rate regulation through L-type calcium channels activation. Those results indicate that anti-apoA-1 IgG are more than just marker of CV risk, but represent active modulators of atherogenesis and atherosclerotic plaque stability.

Hypotheses

Anti-apoA-1 IgG may represent a new modifiable cardiovascular risk factor promoting plaque rupture, and atherothrombosis.

Methods

To achieve this goal we choose a translational research approach combining in vivo, in vitro and clinical studies in a collaboration project between Geneva and Basel University hospitals.

 

a) Specific aims:

1. To confirm in vitro that the complex CD14/TLR2 is required for anti-apoA-1 IgG their pro-inflammatory and chronotropic effects

2. To determine the effect of anti-apoA-1 IgG passive immunization in apoE-/- mice mutated for TLR2 and 4 on: i) atherogenesis, ii) on mice survival and malignant arythmia occurrence.

3. To evaluate the incremental diagnostic value of anti-apoA-1 in acute chest pain patients for rapid myocardial infarction exclusion on APACE cohort (NCT00470587) cohort.

b) Experimental Design and Methods: Pro-inflammatory and pro-arythmogenic properties of anti-apoA-1 IgG will be tested in vitro on human macrophages, HEKblue2 and 4 cells, and neonatal rat cardiomyocytes, respectively. Passive immunisation protocol with anti-apoA-1 IgG in apoE-/-, apoE/TLR2 -/- and apoE/TLR4 -/- mice equipped with telemetry allowing continuous electrocardiographic (ECG) recordings during one month will be performed. Readout systems will include ELISA, FACS analysis, immunohistochemistry and confocal microscope for in vitro experiments, and ECG mortality rate monitoring for mice studies. The diagnostic and prognostic value of anti-apoA-1 IgG for MI will be assessed on APACE (NCT00470587) multicentre cohort including 1250 patients, allowing determining whether the assessment of those autoantibodies can provide incremental information to bench mark biomarkers such as high sensitive troponins, and natriuretic peptides.

 

Expected Relevance

This collaborative translational research project between Geneva and Basel University hospitals combining in vitro, in vivo and clinical studies will generate benchmark high quality data allowing to answer the debated question concerning the clinical relevance of those autoantibodies in cardiovascular–related complication in humans.  Because actual preventive and therapeutic strategies in CVD management have stemmed from our knowledge of the so-called “traditional” (Framingham) cardiovascular risk factors”,  present  approximately in only 20% of patients with patent CVD, identifying new and reversible emergent cardiovascular factors is of utmost clinical relevance. Because antibody-mediated diseases and some cardiovascular conditions can be treated by specific immunologic therapeutic strategies, such as passive immunization, our results could be of valuable help to better identify cardiovascular patients that could benefit from this kind of therapy in the future, and substantially contribute to personalized medicine in the field of cardiovascular disease.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Infection-Induced Humoral Autoimmunity: A Missing Link in the Interplay Between Pathogens, Dyslipidemia, and Innate Immunity?
Antiochos P et al. (2018), Infection-Induced Humoral Autoimmunity: A Missing Link in the Interplay Between Pathogens, Dyslipidemia, and Innate Immunity?, in J Am Coll Cardiol. 2018 Aug 21;72(8):955-956, 955.
ANTI-APOLIPOPROTEIN A1 (APOA1) AUTOANTIBODIES DISRUPT THE CHOLESTEROL PATHWAY VIA SREBP-2 AND DECREASE CIRCULATING MIR-33A IN HYPERCHOLESTEROLAEMIC CHILDREN
PaganoS et al. (2018), ANTI-APOLIPOPROTEIN A1 (APOA1) AUTOANTIBODIES DISRUPT THE CHOLESTEROL PATHWAY VIA SREBP-2 AND DECREASE CIRCULATING MIR-33A IN HYPERCHOLESTEROLAEMIC CHILDREN, in Atherosclerosis, e42.
AUTOANTIBODIES TO APOLIPOPROTEIN A-I AS INDEPENDENT PREDICTORS OF CARDIOVASCULAR MORTALITY IN RENAL TRANSPLANT RECIPIENTS
VuilleumierN (2018), AUTOANTIBODIES TO APOLIPOPROTEIN A-I AS INDEPENDENT PREDICTORS OF CARDIOVASCULAR MORTALITY IN RENAL TRANSPLANT RECIPIENTS, in Atherosclerosis, e97.
Anti-apolipoprotein A-1 autoantibodies are associated with immunodeficiency and systemic inflammation in HIV patients.
SattaN et al. (2018), Anti-apolipoprotein A-1 autoantibodies are associated with immunodeficiency and systemic inflammation in HIV patients., in J Infect. 2018 Feb;76(2):186-195., 186.
Pharmacological Intervention to Modulate HDL: What Do We Target?
Woudberg MJ et al. (2018), Pharmacological Intervention to Modulate HDL: What Do We Target?, in Front Pharmacol. 2018 Jan 22;8:989, 989.
Autoantibody to apolipoprotein A-1 in hepatitis C virus infection: a role in atherosclerosis?
Bridge SH et al. (2018), Autoantibody to apolipoprotein A-1 in hepatitis C virus infection: a role in atherosclerosis?, in Hepatol Int. 2018 Jan;12(1):17-25., 17.
Impact of CD14 Polymorphisms on Anti-Apolipoprotein A-1 IgG-Related Coronary Artery Disease Prediction in the General Population.
Antiochos P et al. (2017), Impact of CD14 Polymorphisms on Anti-Apolipoprotein A-1 IgG-Related Coronary Artery Disease Prediction in the General Population., in Arterioscler Thromb Vasc Biol. 2017 Dec;37(12):2342-2349., 2342.
Anti-Apolipoprotein A-1 IgG Predict All-Cause Mortality and Are Associated with Fc Receptor-Like 3 Polymorphisms.
AntiochosP et al. (2017), Anti-Apolipoprotein A-1 IgG Predict All-Cause Mortality and Are Associated with Fc Receptor-Like 3 Polymorphisms., in Front Immunol. 2017 Apr 18;8:437. , 437.
Vitamin D receptor is expressed within human carotid plaques and correlates with pro-inflammatory M1 macrophages.
Carbone F et al. (2016), Vitamin D receptor is expressed within human carotid plaques and correlates with pro-inflammatory M1 macrophages., in Vascul Pharmacol. 2016 Oct;85:57-65., 57.
Association between anti-apolipoprotein A-1 antibodies and cardiovascular disease in the general population. Results from the CoLaus study.
AntiochosP et al. (2016), Association between anti-apolipoprotein A-1 antibodies and cardiovascular disease in the general population. Results from the CoLaus study., in Thromb Haemost. 2016 Sep 27;116(4):764-71., 764.
Anti-ApoA-1 IgG serum levels predict worse poststroke outcomes.
CarboneF et al. (2016), Anti-ApoA-1 IgG serum levels predict worse poststroke outcomes., in Eur J Clin Invest. 2016 Sep;46(9):805-17, 805.
Anti-apolipoprotein A-1 auto-antibodies as active modulators of atherothrombosis.
Pagano S et al. (2016), Anti-apolipoprotein A-1 auto-antibodies as active modulators of atherothrombosis., in Thromb Haemost. 2016 Aug 30;116(3):554-64., 554.
Anti-apoA-1 auto-antibodies increase mouse atherosclerotic plaque vulnerability, myocardial necrosis and mortality triggering TLR2 and TLR4.
MontecuccoF et al. (2015), Anti-apoA-1 auto-antibodies increase mouse atherosclerotic plaque vulnerability, myocardial necrosis and mortality triggering TLR2 and TLR4., in Thromb Haemost. 2015 Aug;114(2):410-22., 410.
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?
Pagano S et al. (2015), 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?, in PLoS One. 2015 Jul 15;10(7):e0132780., e0132780.
Diagnostic and prognostic value of autoantibodies anti-apolipoprotein A-1 and anti-phosphorylcholine in acute non-ST elevation myocardial infarction.
Rubini Gimenez M et al. (2015), Diagnostic and prognostic value of autoantibodies anti-apolipoprotein A-1 and anti-phosphorylcholine in acute non-ST elevation myocardial infarction., in Eur J Clin Invest. 2015 Apr;45(4):369-79., 369.
Improving reconstituted HDL composition for efficient post-ischemic reduction of ischemia reperfusion injury.
Brulhart-MeynetMC et al. (2015), Improving reconstituted HDL composition for efficient post-ischemic reduction of ischemia reperfusion injury., in PLoS One. 2015 Mar 17;10(3):e0119664, e0119664.
Biomarkers for cardiovascular risk assessment in autoimmune diseases.
Teixeira PC Ferber P Vuilleumier N Cutler P. (2015), Biomarkers for cardiovascular risk assessment in autoimmune diseases., in Proteomics Clin Appl., 9(1-2), 48-57.
CD14 as a Mediator of the Mineralocorticoid Receptor-Dependent Anti-apolipoprotein A-1 IgG Chronotropic Effect on Cardiomyocytes.
MannicT (2015), CD14 as a Mediator of the Mineralocorticoid Receptor-Dependent Anti-apolipoprotein A-1 IgG Chronotropic Effect on Cardiomyocytes., in Endocrinology. 2015 Dec;156(12):4707-19., 4707.
Impact of Systemic Inflammation and Autoimmune Diseases on apoA-I and HDL Plasma Levels and Functions.
Montecucco F Favari E Norata GD Ronda N Nofer JR Vuilleumier N. (2015), Impact of Systemic Inflammation and Autoimmune Diseases on apoA-I and HDL Plasma Levels and Functions., in Handb Exp Pharmacol., 224, 455-482.
Treatment with recombinant tissue plasminogen activator (r-TPA) induces neutrophil degranulation in vitro via defined pathways.
Carbone F Vuilleumier N Bertolotto M Burger F Galan K Roversi G Tamborino C Casetta I Serace (2015), Treatment with recombinant tissue plasminogen activator (r-TPA) induces neutrophil degranulation in vitro via defined pathways., in Vascul Pharmacol., 64, 16-27.
Autoantibodies to apolipoprotein A-1 as a biomarker of cardiovascular autoimmunity.
Vuilleumier N Montecucco F Hartley O. (2014), Autoantibodies to apolipoprotein A-1 as a biomarker of cardiovascular autoimmunity., in World J Cardiol. , 6(5), 260-276.
Cannabinoid receptor type 2 activation in atherosclerosis and acute cardiovascular diseases.
Carbone F Mach F Vuilleumier N Montecucco F. (2014), Cannabinoid receptor type 2 activation in atherosclerosis and acute cardiovascular diseases., in Curr Med Chem., 21(35), 4046-4058.
Definition of human apolipoprotein A-I epitopes recognized by autoantibodies present in patients with cardiovascular diseases.
Teixeira PC Ducret A Ferber P Gaertner H Hartley O Pagano S Butterfield M Langen H Vuilleumi (2014), Definition of human apolipoprotein A-I epitopes recognized by autoantibodies present in patients with cardiovascular diseases., in J Biol Chem., 289(41), 28249-2859.
Inferior vena cava parameters predict re-admission in ischaemic heart failure.
Carbone F Bovio M Rosa GM Ferrando F Scarrone A Murialdo G Quercioli A Vuilleumier N Mach F (2014), Inferior vena cava parameters predict re-admission in ischaemic heart failure., in Eur J Clin Invest., 44(4), 341-349.
Nicotinamide phosphoribosyltransferase inhibition reduces intraplaque CXCL1 production and associated neutrophil infiltration in atherosclerotic mice.
Nencioni A da Silva RF Fraga-Silva RA Steffens S Fabre M Bauer I Caffa I Magnone M Sociali G (2014), Nicotinamide phosphoribosyltransferase inhibition reduces intraplaque CXCL1 production and associated neutrophil infiltration in atherosclerotic mice., in Thromb Haemost. , 111(2), 308-322.
Potential pathophysiological role for the vitamin D deficiency in essential hypertension.
Carbone F Mach F Vuilleumier N Montecucco F. (2014), Potential pathophysiological role for the vitamin D deficiency in essential hypertension., in World J Cardiol, 6(5), 260-276.
Update on selective treatments targeting neutrophilic inflammation in atherogenesis and atherothrombosis.
Gomes Quinderé AL Benevides NM Carbone F Mach F Vuilleumier N Montecucco F. (2014), Update on selective treatments targeting neutrophilic inflammation in atherogenesis and atherothrombosis., in Thromb Haemost., 111(4), 634-646.
Anti-apolipoprotein A-1 autoantibodies as biomarker for atherosclerosis burden in patients with periodontitis.
Wick PA Mombelli A Pagano S Moren X Giannopoulou C Mach F Roux-Lombard P Vuilleumier N. (2013), Anti-apolipoprotein A-1 autoantibodies as biomarker for atherosclerosis burden in patients with periodontitis., in J Periodontal Res, 48(3), 350-356.
Evidence on the pathogenic role of auto-antibodies in acute cardiovascular diseases.
Carbone F Nencioni A Mach F Vuilleumier N Montecucco F (2013), Evidence on the pathogenic role of auto-antibodies in acute cardiovascular diseases., in Thromb Haemost. , 109(4), 854-868.
Pathophysiological role of neutrophils in acute myocardial infarction.
Carbone F Nencioni A Mach F Vuilleumier N Montecucco F. (2013), Pathophysiological role of neutrophils in acute myocardial infarction., in Thromb Haemost. , 110(3), 501-514.
Pro- or anti-inflammatory role of apolipoprotein A-1 in high-density lipoproteins?
Vuilleumier N Dayer JM von Eckardstein A Roux-Lombard P. (2013), Pro- or anti-inflammatory role of apolipoprotein A-1 in high-density lipoproteins?, in Swiss Med Wkly., 143, 13781.
Serum levels of anti-apolipoprotein A-1 auto-antibodies and myeloperoxidase as predictors of major adverse cardiovascular events after carotid endarterectomy.
Vuilleumier N Montecucco F Spinella G Pagano S Bertolotto M Pane B Pende A Galan K Roux-Lomb (2013), Serum levels of anti-apolipoprotein A-1 auto-antibodies and myeloperoxidase as predictors of major adverse cardiovascular events after carotid endarterectomy., in Thromb Haemost. , 109(4), 706-715.
The vulnerable coronary plaque: update on imaging technologies.
Rosa GM Bauckneht M Masoero G Mach F Quercioli A Seitun S Balbi M Brunelli C Parodi A Nenci (2013), The vulnerable coronary plaque: update on imaging technologies., in Thromb Haemost. , 110(4), 706-722.
Treatment with the CC chemokine-binding protein Evasin-4 improves post-infarction myocardial injury and survival in mice.
Braunersreuther V Montecucco F Pelli G Galan K Proudfoot AE Belin A Vuilleumier N Burger F L (2013), Treatment with the CC chemokine-binding protein Evasin-4 improves post-infarction myocardial injury and survival in mice., in Thromb Haemost., 110(4), 807-825.
Anti-apolipoprotein A-1 IgG levels predict coronary artery calcification in obese but otherwise healthy individuals.
Quercioli A Montecucco F Galan K Ratib O Roux-Lombard P Pagano S Mach F Schindler TH Vuilleu (2012), Anti-apolipoprotein A-1 IgG levels predict coronary artery calcification in obese but otherwise healthy individuals., in Mediators Inflamm. , 868251.
Autoantibodies to apolipoprotein A-1 in cardiovascular diseases: current perspectives.
Teixeira PC Cutler P Vuilleumier N. (2012), Autoantibodies to apolipoprotein A-1 in cardiovascular diseases: current perspectives., in Clin Dev Immunol., 868251.
High prevalence of anti-apolipoprotein/A-1 autoantibodies in maintenance hemodialysis and association with dialysis vintage.
Pruijm M Schmidtko J Aho A Pagano S Roux-Lombard P Teta D Burnier M Vuilleumier N. (2012), High prevalence of anti-apolipoprotein/A-1 autoantibodies in maintenance hemodialysis and association with dialysis vintage., in Ther Apher Dial. , 16(6), 588-594.
Inflammatory cardiovascular risk biomarkers: update on novelties and limitations.
Montecucco F Mach F Pende A Schindler TH da Silva RF Vuilleumier N. (2012), Inflammatory cardiovascular risk biomarkers: update on novelties and limitations., in Mediators Inflamm, 515692..
Auto-antibodies as possible markers and mediators of ischemic, dilated, and rhythmic cardiopathies.
Satta N Vuilleumier N., Auto-antibodies as possible markers and mediators of ischemic, dilated, and rhythmic cardiopathies., in Curr Drug Targets. .
Pathophysiology and Treatments of Oxidative Injury in Ischemic Stroke: Focus on the Phagocytic NADPH Oxidase 2.
Carbone F Camillo Teixeira P Braunersreuther V Mach F Vuilleumier N Montecucco F., Pathophysiology and Treatments of Oxidative Injury in Ischemic Stroke: Focus on the Phagocytic NADPH Oxidase 2., in Antioxid Redox Signal. .

Collaboration

Group / person Country
Types of collaboration
Prof. P.Kalra; Manchester Universty Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. O. Hartley; Geneva University Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof Chrisitian Mueller, Basel University Hospital Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. P.Vollenweider; CHUV Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Francois Mach Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
- Exchange of personnel
Roche Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
- Industry/business/other use-inspired collaboration
Roland Klingenberg, Zurich University Hospital, Suisse Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
European Atheroslcerosis society Talk given at a conference CD14 as a potential receptor and key regulator of anti-apoA-1 IgG-mediated positive chronotropic effect on cardiac cells 22.03.2015 Glasgow, Great Britain and Northern Ireland Vuilleumier Nicolas; Pagano Sabrina;
European Atherosclerosis Society Talk given at a conference Anti-apoliporpotein A-1 autoantibodies induce tissue factor activity ans expression: a role in atherothrombosis 22.03.2015 Glasgow, Great Britain and Northern Ireland Virzi Julien; Pagano Sabrina; Vuilleumier Nicolas;
European Atherosclerosis Society Talk given at a conference Anti-apoA-1 IgG induce atherosclerotic plaque vulnerability, myocardial necrosis and death in apoE-/-mice 22.03.2015 Glasgow, Great Britain and Northern Ireland Vuilleumier Nicolas; Pagano Sabrina;
Assemblée annuelle commune de la Societé Suisse de Cardiologie, Chirurgie Thoracique et Cardiovasculaire Talk given at a conference Anti-ApoA-1 auto-antibodies increase cardiovascular mortality in atherosclerosis mice. 11.06.2014 Interlaken, Switzerland Vuilleumier Nicolas; Pagano Sabrina;
Joint Annual Meeting of the Swiss Society of Cardiology (SSC) Talk given at a conference Apolipoprotein A-1 autoantibodies induce Tissue factor Activity and Expression: a role in Atherothrombosis. 11.06.2014 Interlaken, Switzerland Pagano Sabrina;
European Society of Clinical Investigation (ESCI) Meeting Talk given at a conference Anti-ApoA-1 auto-antibodies increase cardiovascular mortality in atherosclerosis mice 30.04.2014 Utrecht, Netherlands Pagano Sabrina; Vuilleumier Nicolas;
International Autoimmunity Congress Talk given at a conference CD14 as a potential receptor and key regulator of anti-apolipoproteinA-1 IgG-mediated positive chronotropic effect on cardiac cells 26.03.2014 Nice, France Pagano Sabrina; Vuilleumier Nicolas;
9°International Congress on Autoimmunity. Talk given at a conference The C-terminal part of apolipoprotein A-1 as one cardiovascular-relevant epitope of anti-ApoA-1 auto-antibodies 26.03.2014 Nice, France Pagano Sabrina;
International congress of autoimmunity Talk given at a conference Anti-ApoA-1 auto-antibodies increase cardiovascular mortality in atherosclerotic mice. 26.03.2014 Nice, France Pagano Sabrina;
9°International Congress on Autoimmunity Talk given at a conference Anti-Apolipoprotein A-1 autoantibodies induce Tissue factor Activity and Expression: a role in Atherothrombosis 26.03.2014 Nice, France Pagano Sabrina;
AGLA Poster Anti-Apolipoprotein A-1 autoantibodies induce Tissue factor Activity and Expression: a role in Atherothrombosis. 16.01.2014 Fribourg, Switzerland Pagano Sabrina;
AGLA Poster CD14 as a receptor and key regulator of anti-apolipoproteinA-1 IgG-mediated positive chronotropic effect 16.01.2014 Fribourg, Switzerland Pagano Sabrina;
AGLA Poster Anti-apolipoprotein A-1 autoantibodies as biomarker for atherosclerosis burden in patients with periodontitis 10.01.2013 Bern, Switzerland Pagano Sabrina;
8°International Congress on Autoimmunity Talk given at a conference Anti-apolipoprotein A-1 IgG in myocardial infarction promote inflammation through TLR2/CD14 complex 09.05.2012 Grenada, Spain Pagano Sabrina;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Journée de l'innovation Talk 30.10.2014 Genève, Switzerland Vuilleumier Nicolas;


Communication with the public

Communication Title Media Place Year
Media relations: radio, television CQFD TSR Western Switzerland 2014
Media relations: radio, television La Fondation Leenaards récompense deux projets de recherche biomédicale Western Switzerland 2014
Media relations: print media, online media Piste prometteuse pour la prévention et le traitement des maladies cardiovasculaires planète santé Western Switzerland 2014
Media relations: print media, online media Recherches contre le cancer et l’athérosclérose primées le temps Western Switzerland 2014

Awards

Title Year
Bizot price for the best PD thesis 2014
Leenaards Price 2014 for translational medical research 2014

Patents

Title Date Number Inventor Owner
Detecting cardiovascular disease in human, comprises measuring level of endogenous antibodies recognizing dermcidin in sample of serum or plasma from human subject, and comparing measured level with control level 25.07.2013 WO2015011073-A1
New mimetic peptide of an epitope of Apolipoprotein A-I is anti-apolipoprotein A-I inhibitor, useful for detecting and preventing a cardiovascular disease in a subject 06.11.2012 WO2014072916-A1

Associated projects

Number Title Start Funding scheme
163335 Human autoantibody response to the C-terminal helix of apolipoprotein A-1 as new rationale for prognosis and treatment of cardiovascular disease 01.01.2016 Project funding (Div. I-III)

Abstract

Background: Immune-mediated inflammation plays a major role in atherosclerosis and atherothrombosis, two essential features for cardiovascular disease (CVD) development, currently considered as the leading cause of death in the Western world. There is accumulating evidence showing that humoral autoimmunity might play an important role in CVD, and that some auto-antibodies could represent emerging cardiovascular risk factors. We demonstrated that IgG auto-antibodies against apolipoprotein A-1 (apoA-1), the major proteic fraction of high-density lipoprotein (HDL), were present at high titres in a significant subset of patients suffering from myocardial infarction (MI) (10-20%) and rheumatoid arthritis (RA) (17%), were associated to more vulnerable carotid atherosclerotic plaques in humans and independently predicted cardiovascular complications. In those clinical studies we demonstrated significant associations between high levels of those antibodies and some pro-inflammatory cytokines considered as possible systemic marker of atherosclerotic plaque instability (TNF-a; IL-6; IL-8, MMP-9, and oxidised low-density lipoprotein). Concomitantly, our data from in vitro studies suggest that anti-apoA-1 IgG i) directly induces the production TNF-a, IL-6, IL-8, and MMP-9 by human macrophages, possibly trough the engagement of Toll-like receptor (TLR)-2/CD14 complex, ii) directly affects basal heart rate by an unknown but aldosterone-specific and dependent mechanism in vitro, that can by prevented by specific therapeutic interventions in vitro. Finally, we demonstrated that passive immunization with anti-apoA-1 IgG in apoE -/- mice increased atherogenesis and atherosclerotic plaque vulnerability.Hypotheses: Anti-apoA-1 IgG may represent a new modifiable cardiovascular risk factor promotingatherogenesis , and atherothrombosis. Specific aims:1. To confirm in vitro that the complex CD14/TLR2 is required for anti-apoA-1 IgG their pro-inflammatory and chronotropic effects2. To determine the effect of anti-apoA-1 IgG passive immunization in apoE-/- mice mutated for TLR2 and 4 on: i) atherogenesis, ii) on mice survival and malignant arythmia occurrence.3. To evaluate the incremental diagnostic and prognostic value of anti-apoA-1 in acute chest pain patients for rapid myocardial infarction exclusion on the complete APACE multicentre cohort, including 1600 patients.Experimental Design and Methods: Pro-inflammatory and pro-arythmogenic properties of anti-apoA-1 IgG will be tested in vitro on human macrophages, HEKblue2 and 4 cells, and neonatal rat cardiomyocytes, respectively. Passive immunisation protocol with anti-apoA-1 IgG in apoE-/-, apoE/TLR2 -/- and apoE/TLR4 -/- mice equipped with telemetry allowing continuous electrocardiographic (ECG) recordings during one month will be performed. Readout systems will include ELISA, FACS analysis, immunohistochemistry and confocal microscope for in vitro experiments, and ECG mortality rate monitoring for mice studies. The diagnostic and prognostic values of anti-apoA-1 IgG for MI will be assessed on APACE (NCT00470587) cohort.Expected Relevance: This collaborative translational research project between Geneva and Basel University Hospitals combining in vitro, in vivo and clinical studies will generate benchmark high quality data allowing to answer the debated question concerning the clinical relevance of those autoantibodies in cardiovascular-related complication in humans.
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