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Autoantibodies to Fibrillin-1 Activate Normal Human Fibroblasts in Culture through the TGF- Pathway to Recapitulate the "Scleroderma Phenotype"¹

Xiaodong Zhou^2,*, Filemon K. Tan^*, Dianna M. Milewicz, Xinjian Guo^*, Constantin A. Bona and Frank C. Arnett^*

^* Division of Rheumatology and Clinical Immunogenetics and Division of Medical Genetics, Department of Internal Medicine, University of Texas-Health Science Center, Houston, TX 77030; and Department of Microbiology, Mount Sinai Medical School, New York, NY 10029

Fibroblasts from patients with systemic sclerosis (SSc) are activated producing excessive amounts of extracellular matrix (ECM) components. Recently, we identified a new SSc-specific autoantibody against portions of fibrillin-1, a major component of ECM microfibrils and regulator of TGF-1 signaling. To examine a potential pathogenic role of anti-fibrillin-1 autoantibodies, normal human fibroblasts were treated with affinity-purified autoantibodies isolated from SSc sera and then examined for alterations in gene and protein expression levels using microarrays, quantitative RT-PCR, immunoblots, and immunofluorescence. Compared with fibroblasts cultured in normal medium or in medium containing normal human IgG, anti-fibrillin-1 autoantibody-treated normal dermal fibroblasts showed increased expression of COL and several other ECM components characteristically overexpressed in SSc fibroblasts. This was accompanied by phosphorylation and nuclear translocation of Smad3. Neutralization of TGF-1 with anti-TGF-1 Abs significantly diminished the activation of fibroblasts by anti-fibrillin-1 autoantibodies. These data indicate that anti-fibrillin-1 autoantibodies can induce the activation of normal dermal fibroblasts into a profibrotic phenotype resembling that of SSc by potentially causing the release of sequestered TGF-1 from fibrillin-1-containing microfibrils in the ECM.

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