Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis

N Engl J Med. 2006 Jun 22;354(25):2667-76. doi: 10.1056/NEJMoa052955.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Autoantibodies / blood*
  • Autoimmune Diseases / immunology*
  • Biological Assay
  • Case-Control Studies
  • Cells, Cultured
  • Collagen / genetics
  • Collagen / metabolism
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gene Expression
  • Genes, ras / physiology
  • Humans
  • Immunoglobulin G / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Reactive Oxygen Species / metabolism*
  • Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors
  • Receptors, Platelet-Derived Growth Factor / immunology*
  • Scleroderma, Systemic / immunology*
  • Signal Transduction
  • Tyrphostins / pharmacology


  • Autoantibodies
  • Immunoglobulin G
  • Reactive Oxygen Species
  • Tyrphostins
  • 6,7-dimethoxy-3-phenylquinoxaline
  • Collagen
  • Receptors, Platelet-Derived Growth Factor
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3