Lack of evidence of stimulatory autoantibodies to platelet‐derived growth factor receptor in patients with systemic sclerosis

Abstract

Objective. Systemic sclerosis (SSc) is a severe connective tissue disease of unknown etiology, characterized by fibrosis of the skin and multiple internal organs. Recent findings suggested that the disease is driven by stimulatory autoantibodies to platelet-derived growth factor receptor (PDGFR), which stimulate the production of reactive oxygen species (ROS) and collagen by fibroblasts. These results opened novel avenues of research into the diagnosis and treatment of SSc. The present study was undertaken to confirm the presence of anti-PDGFR antibodies in patients with SSc.Methods. Immunoglobulins from 37 patients with SSc were purified by protein A/G chromatography. PDGFR activation was tested using 4 different sensitive bioassays, i.e., cell proliferation, ROS production, signal transduction, and receptor phosphorylation; the latter was also tested in a separate population of 7 patients with SSc from a different research center.Results. Purified IgG samples from patients with SSc were positive when tested for antinuclear autoantibodies, but did not specifically activate PDGFR␣ or PDGFR␤ in any of the tests. Cell stimulation with PDGF itself consistently produced a strong signal.Conclusion. The present results raise questions regarding the existence of agonistic autoantibodies to PDGFR in SSc.

Epitope Specificity Determines Pathogenicity and Detectability of Anti–Platelet‐Derived Growth Factor Receptor α Autoantibodies in Systemic Sclerosis

“…Finally, direct and competitive ELISAs were performed with serum samples from 29 consecutive patients with SLE (SLE Disease Activity Index range [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. The distribution of PDGFRa binding in SLE serum was comparable to that in healthy control serum, as determined by direct ELISA with PDGFRa-His.…”

Role of Growth Factors in the Pathogenesis of Tissue Fibrosis in Systemic Sclerosis

“…In one study, immunoglobulins (IgGs) from 37 patients with SSc were purified and PDGFR activation tested using 4 different bioassays. Purified IgG samples from patients with SSc were positive when tested for antinuclear autoantibodies, but failed to specifically activate PDGFRα or PDGFRβ in any of the tests [127]. Another study employed an electrochemiluminescence binding assay for detection of serum autoantibodies to PDGFRα, PDGFRβ, epidermal growth factor receptor (EGFR), and colony-stimulating factor receptor 1 (CSFR1), and the level of receptor phosphorylation induced by pure Ig was determined by enzyme-linked immunoassay, Western blot, and functional agonist activity mitogenic assay.…”

Tyrosine Kinase Inhibitors in the Treatment of Systemic Sclerosis: From Animal Models to Clinical Trials

“…A recent study showed that SSc patients have autoantibodies against PDGFR, which stimulate the production of reactive oxygen species and expression of typeＩcollagen (2). Because these findings could not be reproduced in other studies (3,4), more work is necessary to identify the role of PDGFR stimulating autoantibodies (5). However, the importance of PDGF/PDGFR in the pathogenesis of SSc is further underlined by their upregulation and activation in skin and bronchoalveolar lavage fluids (5)(6)(7).…”