title: Anti-apolipoprotein A-1 IgG in patients with myocardial infarction promotes inflammation through TLR2/CD14 complex.
abstract: OBJECTIVE
  Toll-like receptor (TLR)-mediated vascular inflammation, inducible by - amongst other factors - auto-antibodies, is increasingly recognized as a potential mediator of cardiovascular disease. We investigated whether anti-apolipoprotein (Apo)A-1 IgG was associated with a pro-inflammatory cytokine profile in myocardial infarction (MI) patients and whether anti-ApoA-1 IgG elicited a pro-inflammatory response by activating TLRs.
  
  
  METHODS
  As surrogate markers of atherosclerotic plaque vulnerability, interleukin (IL)-6, tumour necrosis factor (TNF)-α, matrix metalloproteinase (MMP)-9 and MMP-3 levels were assessed in 221 consecutive MI patients. Using human monocyte-derived macrophages (HMDMs) we investigated (i) the anti-ApoA-1 IgG interaction with TLRs using proximity ligation assay and (ii) anti-ApoA-1 IgG-dependent IL-6/TNF-α production. TLR involvement was further confirmed using HEK293-Blue TLR-2/-4 cells and by computational docking simulations.
  
  
  RESULTS
  In MI patients, anti-ApoA-1 IgG positivity was associated with higher levels of IL-6, TNF-α and MMP-9, but lower MMP-3 levels. In in vitro experiments, anti-ApoA-1 antibodies bound to HDMDs in a TLR2-dependent manner, resulting in nuclear translocation of NFκB and a significant increase in TNF-α and IL-6 production. Subsequent functional studies highlighted the importance of CD14 as co-receptor in the anti-ApoA-1 IgG-TLR2-induced cytokine production. Additional bioinformatic studies identified structural homologies between TLR2 and ApoA-1, which may explain the observed cross-reactivity between antibodies against these two molecules.
  
  
  CONCLUSIONS
  Anti-ApoA-1 IgG positivity in MI is associated with a high-risk cytokine profile. These auto-antibodies promote inflammation by stimulating the TLR2/CD14 receptor complex, probably because of molecular mimicry, which may contribute to atherosclerosis-related complications in patients.
authors.affiliation: Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospital, Geneva, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Pagano
authors.forename: N
authors.initials: N
authors.lastname: Satta
authors.forename: D
authors.initials: D
authors.lastname: Werling
authors.forename: V
authors.initials: V
authors.lastname: Offord
authors.forename: P
authors.initials: P
authors.lastname: de Moerloose
authors.forename: E
authors.initials: E
authors.lastname: Charbonney
authors.forename: D
authors.initials: D
authors.lastname: Hochstrasser
authors.forename: P
authors.initials: P
authors.lastname: Roux-Lombard
authors.forename: N
authors.initials: N
authors.lastname: Vuilleumier
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016632:Apolipoprotein A-I / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D018950:Lipopolysaccharide Receptors / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000150:complications / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000276:immunology*
chemical_list: D016632:Apolipoprotein A-I; D001323:Autoantibodies; D007074:Immunoglobulin G; D018950:Lipopolysaccharide Receptors; D051195:Toll-Like Receptor 2