title: Systemic sclerosis immunoglobulin induces growth and a pro-fibrotic state in vascular smooth muscle cells through the epidermal growth factor receptor.
abstract: OBJECTIVE
  It has been suggested that autoantibodies in systemic sclerosis (SSc) may induce the differentiation of cultured fibroblasts into myofibroblasts through platelet-derived growth factor receptor (PDGFR) activation. The present study aims to characterize the effects of SSc IgG on vascular smooth muscle cells (VSMCs) and to determine if stimulatory autoantibodies directed to the PDGFR can be detected, and whether they induce a profibrotic response in primary cultured VSMCs.
  
  
  METHODS
  Cultured VSMCs were exposed to IgG fractions purified from SSc-patient or control sera. VSMC responses were then analyzed for ERK1/2 and Akt phosphorylation, PDGFR immunoprecipitation, cellular proliferation, protein synthesis, and pro-fibrotic changes in mRNA expression.
  
  
  RESULTS
  Stimulatory activity in IgG fractions was more prevalent and intense in the SSc samples. SSc IgG immunoprecipitated the PDGFR with greater avidity than control IgG. Interestingly, activation of downstream signaling events (e.g. Akt, ERK1/2) was independent of PDGFR activity, but required functional EGFR. We also detected increased protein synthesis in response to SSc IgG (p<0.001) and pro-fibrotic changes in gene expression (Tgfb1 +200%; Tgfb2 -23%; p<0.001)) in VSMCs treated with SSc IgG.
  
  
  CONCLUSIONS
  When compared to control IgG, SSc IgG have a higher stimulation index in VSMCs. Although SSc IgG interact with the PDGFR, the observed remodeling signaling events occur through the EGFR in VSMC. Our data thus favour a model of transactivation of the EGFR by SSc-derived PDGFR autoantibodies and suggest the use of EGFR inhibitors in future target identification studies in the field of SSc.
authors.affiliation: Université de Montréal, Faculté de Pharmacie, Montreal, Quebec, Canada; McGill University, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Monique R
authors.initials: MR
authors.lastname: Arts
authors.affiliation: McGill University, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Murray
authors.initials: M
authors.lastname: Baron
authors.affiliation: Université de Montréal, Faculté de Pharmacie, Montreal, Quebec, Canada.
authors.forename: Nidaa
authors.initials: N
authors.lastname: Chokr
authors.affiliation: Department of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Marvin J
authors.initials: MJ
authors.lastname: Fritzler
authors.affiliation: Université de Montréal, Faculté de Pharmacie, Montreal, Quebec, Canada.
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Servant
mesh_terms: D000328:Adult; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000502:physiology*; D005260:Female; D005355:Fibrosis / Q000139:chemically induced; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D012595:Scleroderma, Systemic / Q000276:immunology* / Q000473:pathology
chemical_list: D007074:Immunoglobulin G; D066246:ErbB Receptors