title: Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis.
abstract: BACKGROUND
  Systemic sclerosis (scleroderma) is characterized by immunologic abnormalities, injury of endothelial cells, and tissue fibrosis. Abnormal oxidative stress has been documented in scleroderma and linked to fibroblast activation. Since platelet-derived growth factor (PDGF) stimulates the production of reactive oxygen species (ROS) and since IgG from patients with scleroderma reacts with human fibroblasts, we tested the hypothesis that patients with scleroderma have serum autoantibodies that stimulate the PDGF receptor (PDGFR), activating collagen-gene expression.
  
  
  METHODS
  We analyzed serum from 46 patients with scleroderma and 75 controls, including patients with other autoimmune diseases, for stimulatory autoantibodies to PDGFR by measuring the production of ROS produced by the incubation of purified IgG with mouse-embryo fibroblasts carrying inactive copies of PDGFR alpha or beta chains or the same cells expressing PDGFR alpha or beta. Generation of ROS was assayed with and without specific PDGFR inhibitors. Antibodies were characterized by immunoprecipitation, immunoblotting, and absorption experiments.
  
  
  RESULTS
  Stimulatory antibodies to the PDGFR were found in all the patients with scleroderma. The antibodies recognized native PDGFR, inducing tyrosine phosphorylation and ROS accumulation. Autoantibody activity was abolished by preincubation with cells expressing the PDGFR alpha chain or with recombinant PDGFR or by PDGFR tyrosine kinase inhibitors. Stimulatory PDGFR antibodies selectively induced the Ha-Ras-ERK1/2 and ROS cascades and stimulated type I collagen-gene expression and myofibroblast phenotype conversion in normal human primary fibroblasts.
  
  
  CONCLUSIONS
  Stimulatory autoantibodies against PDGFR appear to be a specific hallmark of scleroderma. Their biologic activity on fibroblasts strongly suggests that they have a causal role in the pathogenesis of the disease.
authors.affiliation: Dipartimento di Scienze Mediche e Chirurgiche, Sezione di Clinica Medica, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Silvia Svegliati
authors.initials: SS
authors.lastname: Baroni
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Santillo
authors.forename: Federica
authors.initials: F
authors.lastname: Bevilacqua
authors.forename: Michele
authors.initials: M
authors.lastname: Luchetti
authors.forename: Tatiana
authors.initials: T
authors.lastname: Spadoni
authors.forename: Matteo
authors.initials: M
authors.lastname: Mancini
authors.forename: Paolo
authors.initials: P
authors.lastname: Fraticelli
authors.forename: Paola
authors.initials: P
authors.lastname: Sambo
authors.forename: Ada
authors.initials: A
authors.lastname: Funaro
authors.forename: Andrius
authors.initials: A
authors.lastname: Kazlauskas
authors.forename: Enrico V
authors.initials: EV
authors.lastname: Avvedimento
authors.forename: Armando
authors.initials: A
authors.lastname: Gabrielli
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001323:Autoantibodies / Q000097:blood*; D001327:Autoimmune Diseases / Q000276:immunology*; D001681:Biological Assay; D016022:Case-Control Studies; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D011905:Genes, ras / Q000502:physiology; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000276:immunology*; D012595:Scleroderma, Systemic / Q000276:immunology*; D015398:Signal Transduction; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D017382:Reactive Oxygen Species; D020032:Tyrphostins; C106250:6,7-dimethoxy-3-phenylquinoxaline; D003094:Collagen; D017479:Receptors, Platelet-Derived Growth Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3