title: Autoantibodies to fibrillin-1 activate normal human fibroblasts in culture through the TGF-beta pathway to recapitulate the "scleroderma phenotype".
abstract: 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-beta1 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-beta1 with anti-TGF-beta1 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-beta1 from fibrillin-1-containing microfibrils in the ECM.
authors.affiliation: Division of Rheumatology and Clinical Immunogenetics, Department of Internal Medicine, University of Texas-Health Science Center, Houston 77030, USA. Xiaodong.Zhou@uth.tmc.edu
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhou
authors.forename: Filemon K
authors.initials: FK
authors.lastname: Tan
authors.forename: Dianna M
authors.initials: DM
authors.lastname: Milewicz
authors.forename: Xinjian
authors.initials: X
authors.lastname: Guo
authors.forename: Constantin A
authors.initials: CA
authors.lastname: Bona
authors.forename: Frank C
authors.initials: FC
authors.lastname: Arnett
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000328:Adult; D001323:Autoantibodies / Q000097:blood*; D015415:Biomarkers; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics; D000071838:Fibrillin-1; D000071837:Fibrillins; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D008840:Microfilament Proteins / Q000276:immunology*; D008875:Middle Aged; D010766:Phosphorylation; D012595:Scleroderma, Systemic / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D054392:Adipokines
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D016326:Extracellular Matrix Proteins; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D016212:Transforming Growth Factor beta; C000605722:FBN1 protein, human; D054392:Adipokines