title: Sarcoidosis activates diverse transcriptional programs in bronchoalveolar lavage cells.
abstract: Sarcoidosis is a multisystem immuno-inflammatory disorder of unknown etiology that most commonly involves the lungs. We hypothesized that an unbiased approach to identify pathways activated in bronchoalveolar lavage (BAL) cells can shed light on the pathogenesis of this complex disease.
  
  
  
  We recruited 15 patients with various stages of sarcoidosis and 12 healthy controls. All subjects underwent bronchoscopy with lavage. For each subject, total RNA was extracted from BAL cells and hybridized to an Affymetrix U133A microarray. Rigorous statistical methods were applied to identify differential gene expression between subjects with sarcoidosis vs.
  
  
  
  To better elucidate pathways differentially activated between these groups, we integrated network and gene set enrichment analyses of BAL cell transcriptional profiles.
  
  
  
  Sarcoidosis patients were either non-smokers or former smokers, all had lung involvement and only two were on systemic prednisone. Healthy controls were all non-smokers. Comparison of BAL cell gene expression between sarcoidosis and healthy subjects revealed over 1500 differentially expressed genes. Several previously described immune mediators, such as interferon gamma, were upregulated in the sarcoidosis subjects. Using an integrative computational approach we constructed a modular network of over 80 gene sets that were highly enriched in patients with sarcoidosis. Many of these pathways mapped to inflammatory and immune-related processes including adaptive immunity, T-cell signaling, graft vs. host disease, interleukin 12, 23 and 17 signaling. Additionally, we uncovered a close association between the proteasome machinery and adaptive immunity, highlighting a potentially important and targetable relationship in the pathobiology of sarcoidosis.
  
  
  
  BAL cells in sarcoidosis are characterized by enrichment of distinct transcriptional programs involved in immunity and proteasomal processes. Our findings add to the growing evidence implicating alveolar resident immune effector cells in the pathogenesis of sarcoidosis and identify specific pathways whose activation may modulate disease progression.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, Seattle, WA, USA. sagharib@u.washington.edu.|Computational Medicine Core, Center for Lung Biology, Department of Medicine, University of Washington, Seattle, WA, USA. sagharib@u.washington.edu.|, 850 Republican, Box 358052, Seattle, WA, 98109-4725, USA. sagharib@u.washington.edu.
authors.forename: Sina A
authors.initials: SA
authors.lastname: Gharib
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: Anagha
authors.initials: A
authors.lastname: Malur
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Texas Technical University Health Science Center, Lubbock, TX, USA.
authors.forename: Isham
authors.initials: I
authors.lastname: Huizar
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: Barbara P
authors.initials: BP
authors.lastname: Barna
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Thomas Jefferson University Hospital, Philadelphia, PA, USA.
authors.forename: Mani S
authors.initials: MS
authors.lastname: Kavuru
authors.affiliation: Pulmonary, Critical Care, Allergy and Sleep Medicine, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Schnapp
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: Mary Jane
authors.initials: MJ
authors.lastname: Thomassen
mesh_terms: D000328:Adult; D000368:Aged; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology*; D001999:Bronchoscopy; D002452:Cell Count; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D053263:Gene Regulatory Networks / Q000235:genetics; D006801:Humans; D007109:Immunity / Q000235:genetics; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D046988:Proteasome Endopeptidase Complex / Q000235:genetics; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D017565:Sarcoidosis, Pulmonary / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D012907:Smoking / Q000235:genetics
chemical_list: D016207:Cytokines; D012313:RNA; D046988:Proteasome Endopeptidase Complex
keywords: Microarray; Network analysis; Proteasome; Sarcoidosis