title: Increased expression of immunoreactive thymic stromal lymphopoietin in patients with severe asthma.
abstract: BACKGROUND
  Thymic stromal lymphopoietin (TSLP) is a cytokine implicated in the pathophysiology of asthma through 2 distinct pathways: a TSLP-OX40 ligand (OX40L)-T cell axis and a TSLP-mast cell axis. Whether these pathways are active in human asthma is unknown.
  
  
  OBJECTIVE
  We sought to investigate whether mucosal TSLP protein expression relates to asthma severity and distinct immunologic pathways.
  
  
  METHODS
  In healthy subjects and patients with mild-to-severe asthma, we immunostained bronchial biopsy specimens for TSLP, OX40, OX40L, T(H)2 cytokines, and inflammatory cell markers. We examined gene expression using RNA microarrays and quantitative RT-PCR.
  
  
  RESULTS
  There was considerable heterogeneity in the levels of TSLP, IL-13, and IL-4 immunostaining across the cohort of asthmatic patients examined. Overall, TSLP protein expression was significantly increased in airway epithelium and lamina propria of asthmatic patients, particularly in patients with severe asthma. TSLP immunostaining in both compartments correlated with the severity of airflow obstruction. The majority of leukocytes expressing IL-13 were possibly nuocytes. Accounting for intersubject variability, the 55% of asthmatic patients with increased IL-13 immunostaining in the lamina propria also had increased IL-4 and TSLP expression. This was further substantiated by significant correlations between TSLP gene expression, a T(H)2 gene expression signature, and eosinophilic inflammation in bronchial biopsy specimens. Immunostaining for OX40, OX40L, and CD83 was sparse, with no difference between asthmatic patients and healthy subjects.
  
  
  CONCLUSIONS
  TSLP expression is increased in a subset of patients with severe asthma in spite of high-dose inhaled or oral corticosteroid therapy. Targeting TSLP might only be efficacious in the subset of asthma characterized by increased TSLP expression and T(H)2 inflammation.
authors.affiliation: Institute for Lung Health, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom.
authors.forename: Aarti
authors.initials: A
authors.lastname: Shikotra
authors.forename: David F
authors.initials: DF
authors.lastname: Choy
authors.forename: Chandra M
authors.initials: CM
authors.lastname: Ohri
authors.forename: Emma
authors.initials: E
authors.lastname: Doran
authors.forename: Claire
authors.initials: C
authors.lastname: Butler
authors.forename: Beverley
authors.initials: B
authors.lastname: Hargadon
authors.forename: Maria
authors.initials: M
authors.lastname: Shelley
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Abbas
authors.forename: Cary D
authors.initials: CD
authors.lastname: Austin
authors.forename: Janet
authors.initials: J
authors.lastname: Jackman
authors.forename: Lawren C
authors.initials: LC
authors.lastname: Wu
authors.forename: Liam G
authors.initials: LG
authors.lastname: Heaney
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Arron
authors.forename: Peter
authors.initials: P
authors.lastname: Bradding
mesh_terms: D001249:Asthma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004802:Eosinophilia / Q000276:immunology / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism; D053278:OX40 Ligand / Q000378:metabolism; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D016207:Cytokines; D018793:Interleukin-13; D053278:OX40 Ligand; D015847:Interleukin-4; D000094632:Thymic Stromal Lymphopoietin