title: Vascular receptor autoantibodies in pulmonary arterial hypertension associated with systemic sclerosis.
abstract: BACKGROUND
  Systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) portends worse outcome than other forms of PAH. Vasoconstrictive and vascular remodeling actions of endothelin (ET) 1 and angiotensin (Ang) II via endothelin receptor type A (ETAR) and Ang receptor type-1 (AT1R) activation are implicated in PAH pathogenesis.
  
  
  OBJECTIVE
  We hypothesized that stimulating autoantibodies (Abs) targeting and activating AT1R and ETAR may contribute to SSc-PAH pathogenesis, and tested their functional and biomarker relevance.
  
  
  METHODS
  Anti-AT1R and -ETAR Abs were detected by ELISA in different cohorts of patients and tested in vitro and in an animal model for their pathophysiological effects.
  
  
  RESULTS
  The Abs were significantly higher and more prevalent in patients with SSc-PAH (n = 81) and connective tissue disease-associated PAH (n = 110) compared with other forms of PAH/pulmonary hypertension (n = 106). High anti-AT1R and anti-ETAR Abs predicted development of SSc-PAH and SSc-PAH-related mortality in a prospective analysis. Both Abs increased endothelial cytosolic Ca(2+) concentrations in isolated perfused rat lungs, which could be blocked by respective specific receptor antagonists. Ab-mediated stimulation of intralobar pulmonary rat artery ring segments increased vasoconstrictive responses to Ang II and ET-1, and implicated cross-talk between both pathways demonstrated by reciprocal blockade with respective antagonists. Transfer of SSc-IgG containing both autoantibodies into healthy C57BL/6J mice led to more abundant vascular and airway α-smooth muscle actin expression and inflammatory pulmonary vasculopathy.
  
  
  CONCLUSIONS
  Anti-AT1R and -ETAR Abs are more frequent in SSc-PAH/connective tissue disease-PAH compared with other forms of pulmonary hypertension, and serve as predictive and prognostic biomarkers in SSc-PAH. Both antibodies may contribute to SSc-PAH via increased vascular endothelial reactivity and induction of pulmonary vasculopathy.
authors.affiliation: 1 Department of Rheumatology and Clinical Immunology.
authors.forename: Mike O
authors.initials: MO
authors.lastname: Becker
authors.forename: Angela
authors.initials: A
authors.lastname: Kill
authors.forename: Marissa
authors.initials: M
authors.lastname: Kutsche
authors.forename: Jeannine
authors.initials: J
authors.lastname: Guenther
authors.forename: Angelika
authors.initials: A
authors.lastname: Rose
authors.forename: Christoph
authors.initials: C
authors.lastname: Tabeling
authors.forename: Martin
authors.initials: M
authors.lastname: Witzenrath
authors.forename: Anja A
authors.initials: AA
authors.lastname: Kühl
authors.forename: Harald
authors.initials: H
authors.lastname: Heidecke
authors.forename: Hossein A
authors.initials: HA
authors.lastname: Ghofrani
authors.forename: Henning
authors.initials: H
authors.lastname: Tiede
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Schermuly
authors.forename: Nils
authors.initials: N
authors.lastname: Nickel
authors.forename: Marius M
authors.initials: MM
authors.lastname: Hoeper
authors.forename: Ivo
authors.initials: I
authors.lastname: Lukitsch
authors.forename: Maik
authors.initials: M
authors.lastname: Gollasch
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Kuebler
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bock
authors.forename: Gerd R
authors.initials: GR
authors.lastname: Burmester
authors.forename: Duska
authors.initials: D
authors.lastname: Dragun
authors.forename: Gabriela
authors.initials: G
authors.lastname: Riemekasten
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D015415:Biomarkers / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000150:complications / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009213:Myography / Q000379:methods; D011446:Prospective Studies; D011651:Pulmonary Artery / Q000276:immunology* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012595:Scleroderma, Systemic / Q000097:blood / Q000150:complications / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D015415:Biomarkers
keywords: angiotensin receptor type-1; autoantibodies; endothelin receptor type A; pulmonary arterial hypertension; systemic sclerosis