title: Frequency of circulating topoisomerase-I-specific CD4 T cells predicts presence and progression of interstitial lung disease in scleroderma.
abstract: Scleroderma is an antigen-driven T cell-mediated autoimmune disease. Presence of anti-topoisomerase-I antibodies is associated with pulmonary fibrosis and predicts increased mortality. Characterization of autoreactive T lymphocytes may shed light on disease pathogenesis and serve as a biomarker for disease activity. Here, we aimed to quantify and functionally characterize circulating topoisomerase I (topo-I)-specific CD4+ T cells and to define their association with presence and progression of interstitial lung disease (ILD) in patients with scleroderma.
  
  
  
  Using flow cytometry, circulating topo-I-reactive CD4+ T cells were identified by the expression of specific activation markers (CD154 and CD69) upon stimulation with purified topo-I and quantified in 27 SSc patients and 4 healthy donors (HD). Polarization of autoreactive T cells (Th1, Th2, Th17, Th1-17) was defined using surface expression of specific chemokine receptors. Presence and progression of ILD were determined using high-resolution chest CT and pulmonary function tests.
  
  
  
  Topo-I-reactive CD4+ T cells were found in all topo-I-positive patients compared to one topo-I-negative subject and no HD. Topo-I-specific CD4+ T cells exhibited a distinct Th17 polarized phenotype. Autoreactive T cells were significantly increased in subjects with evidence of ILD and were quantitatively associated with the decline of lung volumes.
  
  
  
  Topo-I-specific T cells can be reliably quantified in the peripheral blood of patients with scleroderma, exhibit a pro-inflammatory Th17 phenotype, and predict progression of ILD.
authors.affiliation: Department of Medicine, Division of Rheumatology, Johns Hopkins University School of Medicine, 5200 Eastern Avenue, MFL Building, Center Tower, Suite 4100, Baltimore, MD, 21224, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Fava
authors.affiliation: Department of Medicine, Division of Rheumatology, Johns Hopkins University School of Medicine, 5200 Eastern Avenue, MFL Building, Center Tower, Suite 4100, Baltimore, MD, 21224, USA.
authors.forename: Raffaello
authors.initials: R
authors.lastname: Cimbro
authors.affiliation: Department of Medicine, Division of Rheumatology, Johns Hopkins University School of Medicine, 5200 Eastern Avenue, MFL Building, Center Tower, Suite 4100, Baltimore, MD, 21224, USA.
authors.forename: Fredrick M
authors.initials: FM
authors.lastname: Wigley
authors.affiliation: Behavioral Neuroscience Research Branch, National Institute of Drug Abuse, National Institutes of Health, 251 Bayview Boulevard, Baltimore, Maryland, 21224, USA.
authors.forename: Qing-Rong
authors.initials: QR
authors.lastname: Liu
authors.affiliation: Department of Medicine, Division of Rheumatology, Johns Hopkins University School of Medicine, 5200 Eastern Avenue, MFL Building, Center Tower, Suite 4100, Baltimore, MD, 21224, USA.
authors.forename: Antony
authors.initials: A
authors.lastname: Rosen
authors.affiliation: Department of Medicine, Division of Rheumatology, University of California, San Francisco, 513 Parnassus Avenue, Med Sci, S-847, San Francisco, CA, 94143, USA. francesco.boin@ucsf.edu.
authors.forename: Francesco
authors.initials: F
authors.lastname: Boin
mesh_terms: D000328:Adult; D001324:Autoantigens / Q000276:immunology*; D015415:Biomarkers / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004264:DNA Topoisomerases, Type I / Q000276:immunology*; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D017563:Lung Diseases, Interstitial / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012595:Scleroderma, Systemic / Q000276:immunology*
chemical_list: D001324:Autoantigens; D015415:Biomarkers; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human
keywords: Autoantigen; Interstitial lung disease; Systemic sclerosis; T lymphocytes; Th17