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Anti-ApoA-1 auto-antibodies: biomarkers and Anti-ApoA-1 auto-antibodies: biomarkers and mediators of cardiovascular riskmediators of cardiovascular risk
Fabrizio Montecucco, MD, PhDFabrizio Montecucco, MD, PhD
Division of Laboratory Medicine, HUG, SwitzerlandDivision of Laboratory Medicine, HUG, SwitzerlandDivision of Cardiology, University of Geneva, SwitzerlandDivision of Cardiology, University of Geneva, Switzerland
Email: [email protected]: [email protected]
Geneva, October 30th 2014
2014 view 2014 view of inflammation in plaque rupture and of inflammation in plaque rupture and thrombosisthrombosis
Libby P et al. Circulation Research. 2014;114:1867.
Liao Y et al., Int J Cardiol 2006; 21-26
=> CV risk increased of 2-3 times
Due to which auto-antibodies ?
Edward CJ, et al. Heart 2007; 93:1263-67.
SLE Rheumatoid arthritisAnti-phospholipid
syndrome
Skaggs BJ ; Nat Rev Reumatol 2012 ; 8:214-23
Autoimmunity as a CV risk condition?Autoimmunity as a CV risk condition?
Anti-ApoA-1 IgG positivity is associated with Anti-ApoA-1 IgG positivity is associated with increased cardiovascular mortalityincreased cardiovascular mortality
Vuilleumier N, et al. Eur Heart J. 2010;31:815.Vuilleumier N, et al. Arthritis Rheum. 2010;62:2640.
Vuilleumier N, Montecucco F, et al. Thromb Haemost. 2013;109:706.
AMI patients (n=221) RA patients (n=133) Carotid stenosis patients (n=178)
Anti-ApoA-1 IgG might affect HDL function, but Anti-ApoA-1 IgG might affect HDL function, but also bind inflammatory cells via Toll-like receptor 2 also bind inflammatory cells via Toll-like receptor 2
Pagano S, et al. J Intern Med. 2012;272:344.Montecucco F, et al. Unpublished data.
NF-kB nuclear translocation in human macrophagesApoA-1 TLR2
ApoE-/- MΦ ApoE-/- TLR2-/- MΦ
Anti-ApoA-1 IgG
CTL IgG
Anti-ApoA-1 IgG
CTL IgG
Passive immunization with anti-ApoA-1 IgG in Passive immunization with anti-ApoA-1 IgG in TLR2-/- ApoE-/- and TLR4-/- ApoE-/- mice TLR2-/- ApoE-/- and TLR4-/- ApoE-/- mice
0 16
TLR2-/-ApoE-/-TLR4-/-ApoE-/-ApoE -/- mice (aged 11 weeks)
-Isotype IgG (50 microg every two weeks)-Anti-ApoA1 IgG (50 microg every two weeks)
Normal diet
weekssacrifice
I.v. injection
Montecucco F, et al. Unpublished data
Follow-up (days)
Cu
mu
lati
ve
su
rviv
al p
rop
ort
ion
(%
)
ApoE -/- mouse survival
0 40 80 12020 10060
IgG CTL (n=33)
anti-ApoA-1 IgG (n=39)
p=0.04 (LogRank)
20
40
60
80
100
0
Passive immunization with anti-ApoA-1 IgG Passive immunization with anti-ApoA-1 IgG increase mouse mortalityincrease mouse mortality
Montecucco F, et al. Unpublished data
Follow-up (days)
0 40 80 12020 10060
Cu
mu
lati
ve
surv
ival
pro
po
rtio
n (
%)
Survival after treatment with anti-ApoA-1 IgG
TLR4-/-ApoE-/- (n=14)
ApoE-/-(n=39)
TLR2-/-ApoE-/- (n=19)
20
40
60
80
100
0
TLR4-/-ApoE-/- vs. ApoE-/- p=0.17 (LogRank)
TLR2-/-ApoE-/- vs. ApoE-/- p=0.26 (LogRank)
Anti-ApoA-1 IgG-induced mortality is abrogated by Anti-ApoA-1 IgG-induced mortality is abrogated by TLR2 and TLR4 deficienciesTLR2 and TLR4 deficiencies
Montecucco F, et al. Unpublished data
TLR4-/-ApoE-/-
CTL IgG anti-ApoA-1 IgG
TLR2-/-ApoE-/-
anti-ApoA-1 IgGCTL IgG
CTL IgG
anti-ApoA-1 IgG
CTL IgG anti-ApoA-1 IgG
p=0.005p=0.763
p=0.094
p=0.129
p=0.508
p=0.144
p=0.501
ApoE-/- TLR2-/-ApoE-/- TLR4-/-ApoE-/-
ApoE-/-
ApoE-/- TLR2-/-ApoE-/- TLR4-/-ApoE-/-
p=0.001p=0.581
p=0.329
p=0.412
p=0.001
p<0.0010.
p=0.043
TLR4-/-ApoE-/-
CTL IgG anti-ApoA-1 IgG
TLR2-/-ApoE-/-
CTL IgG anti-ApoA-1 IgG
ApoE-/-
CTL IgG anti-ApoA-1 IgG
Anti-ApoA-1 IgG-induced intraplaque effects are Anti-ApoA-1 IgG-induced intraplaque effects are abrogated by TLR2 and TLR4 deficienciesabrogated by TLR2 and TLR4 deficiencies
Telemetry device implantation in ApoE-/- miceTelemetry device implantation in ApoE-/- mice
0 16
ApoE -/- mice (aged 11 weeks)
-Isotype IgG (50 microg every two weeks)-Anti-ApoA1 IgG (50 microg every two weeks)
Normal diet
weekssacrifice
I.v. injection
12
TELEMETRY
Montecucco F, et al. Unpublished data
Anti-ApoA-1 IgG induce ST segment depression Anti-ApoA-1 IgG induce ST segment depression and increase Troponin I levels in ApoE-/- miceand increase Troponin I levels in ApoE-/- mice
STEMI at 04.00 pmNormal EKG at 12.00 am Asystolia at 16.30 pm
ApoE-/- Tlr2-/-ApoE-/- Tlr4-/-ApoE-/-
p=0.001 p=0.350 p=0.571
p<0.001p=0.001
p=0.477p=0.0.653
Tro
po
nin
I (
ng
/ml)
p<0.001 p<0.001 p<0.001 p<0.001 p<0.001 p<0.001 p<0.001 p<0.001S
T (
mV
)
Week 13
day night
Week 15
day night
Week 14
day night
Week 16
day night
CTL IgG
anti-apoA-1 IgG
Montecucco F, et al. Unpublished data
Conclusion: Conclusion: anti-ApoA-1 IgG are active anti-ApoA-1 IgG are active cardiovascular risk factors in micecardiovascular risk factors in mice
Adapted from Libby P et al. Circulation Research. 2014;114:1867.
Anti-ApoA-1 IgG
+
Teixeira PC et al, JBC 2014, in press
Patent PCT 059948, 6.10.2013
Therapeutic perspectives: human anti-ApoA-1 IgG Therapeutic perspectives: human anti-ApoA-1 IgG bind the C-terminal portion of ApoA-1 bind the C-terminal portion of ApoA-1
Impact on chronotropic response, n=8
CTRL Anti -apoA-1 IgG40ug/ml
+F3L1p=0.004
SPp=0.45
Impact on lnflammation, n=9
IgG
F3L1 SP
Patent PCT 059948, 6.10.2013
A modified peptide impacts anti-ApoA-1 IgG-A modified peptide impacts anti-ApoA-1 IgG-mediated activities mediated activities in vitroin vitro
Group:Nicolas Vuilleumier
Sabrina PaganoPriscilla Teixeira
Julien VirziThiphaine Mannic
Nathalie SattaFondations:
LeenaardsTélémaque De Reuters
Gustave Simone PrévostSchmidheiny
Swiss Heart FoundationGerbex-Bourget
Funding:
Collaborators:Dick JamesCem Gabay
Michel RossierPascale Roux-Lombard
Denis HochstrasserOliver HartleyFrançois Mach
Acknowledgements
