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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
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
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.
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chains or the same cells expressing PDGFR or . Generation of ROS was assayed with and without specific PDGFR inhibitors. Antibodies were characterized by immunoprecipitation, immunoblotting, and absorption experiments. 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.
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From the Dipartimento di Scienze Mediche e Chirurgiche, Sezione di Clinica Medica, Università Politecnica delle Marche, Ancona (S.S.B., F.B., M.L., T.S., M.M., P.F., P.S., A.G.); the Sezione di Fisiologia (M.S.) and the Dipartimento di Biologia e Patologia Molecolare e Cellulare, Centro di Endocrinologia ed Oncologia Sperimentale del CNR (E.V.A.), Università Federico II, Naples; the Dipartimento di Genetica, Biologia e Biochimica and the Research Center for Experimental Medicine, Università di Torino, Turin (A.F.) — all in Italy; and Schepens Eye Research Institute, Harvard Medical School, Boston (A.K.).
Address reprint requests to Dr. Gabrielli at the Dipartimento di Scienze Mediche e Chirurgiche–Università Politecnica delle Marche, Polo Didattico, Via Tronto 10, 60020 Ancona, Italy, or at a.gabrielli{at}univpm.it, or to Dr. Avvedimento at the Dipartimento di Biologia e Patologia Molecolare e Cellulare, Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Università Federico II, Via Pansini 5, 80131 Napoli, Italy, or at avvedim{at}unina.it.
Related Letters:
Stimulatory Autoantibodies to the PDGF Receptor in Scleroderma
Okamoto H., Lozano E., Segarra M., Cid M. C., Gabrielli A., Baroni S. S., Avvedimento E. V., Tan F. K.
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N Engl J Med 2006;
355:1278-1280, Sep 21, 2006.
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