title: Involvement of functional autoantibodies against vascular receptors in systemic sclerosis.
abstract: BACKGROUND
  Systemic sclerosis (SSc) features autoimmunity, vasculopathy and tissue fibrosis. The renin-angiotensin and endothelin systems have been implicated in vasculopathy and fibrosis. A role for autoantibody-mediated receptor stimulation is hypothesised, linking three major pathophysiological features consistent with SSc.
  
  
  METHODS
  Serum samples from 478 patients with SSc (298 in the study cohort and 180 from two further independent cohorts), 372 healthy subjects and 311 control-disease subjects were tested for antibodies against angiotensin II type 1 receptor (AT(1)R) and endothelin-1 type A receptor (ET(A)R) by solid phase assay. Binding specificities were tested by immunoprecipitation. The biological effects of autoantibodies in microvascular endothelial cells in vitro were also determined, as well as the quantitative differences in autoantibody levels on specific organ involvements and their predictive value for SSc-related mortality.
  
  
  RESULTS
  Anti-AT(1)R and anti-ET(A)R autoantibodies were detected in most patients with SSc. Autoantibodies specifically bound to respective receptors on endothelial cells. Higher levels of both autoantibodies were associated with more severe disease manifestations and predicted SSc-related mortality. Both autoantibodies exert biological effects as they induced extracellular signal-regulated kinase 1/2 phosphorylation and increased transforming growth factor β gene expression in endothelial cells which could be blocked with specific receptor antagonists.
  
  
  CONCLUSIONS
  Functional autoimmunity directed at AT(1)R and ET(A)R is common in patients with SSc. AT(1)R and ET(A)R autoantibodies could contribute to disease pathogenesis and may serve as biomarkers for risk assessment of disease progression.
authors.affiliation: Department of Nephrology and Intensive Care Medicine, Charité University Hospital Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Riemekasten
authors.forename: Aurélie
authors.initials: A
authors.lastname: Philippe
authors.forename: Melanie
authors.initials: M
authors.lastname: Näther
authors.forename: Torsten
authors.initials: T
authors.lastname: Slowinski
authors.forename: Dominik N
authors.initials: DN
authors.lastname: Müller
authors.forename: Harald
authors.initials: H
authors.lastname: Heidecke
authors.forename: Marco
authors.initials: M
authors.lastname: Matucci-Cerinic
authors.forename: László
authors.initials: L
authors.lastname: Czirják
authors.forename: Ivo
authors.initials: I
authors.lastname: Lukitsch
authors.forename: Mike
authors.initials: M
authors.lastname: Becker
authors.forename: Angela
authors.initials: A
authors.lastname: Kill
authors.forename: Jacob M
authors.initials: JM
authors.lastname: van Laar
authors.forename: Rusan
authors.initials: R
authors.lastname: Catar
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.forename: Gerd R
authors.initials: GR
authors.lastname: Burmester
authors.forename: Björn
authors.initials: B
authors.lastname: Hegner
authors.forename: Duska
authors.initials: D
authors.lastname: Dragun
mesh_terms: D000293:Adolescent; D000328:Adult; D000918:Antibody Specificity; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D015415:Biomarkers / Q000097:blood; D004730:Endothelium, Vascular / Q000276:immunology; D004812:Epidemiologic Methods; D005260:Female; D006801:Humans; D008297:Male; D008833:Microcirculation / Q000276:immunology; D008875:Middle Aged; D011379:Prognosis; D044140:Receptor, Angiotensin, Type 1 / Q000276:immunology*; D044022:Receptor, Endothelin A / Q000276:immunology*; D012595:Scleroderma, Systemic / Q000276:immunology*; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D044140:Receptor, Angiotensin, Type 1; D044022:Receptor, Endothelin A