title: Identification of IL-17F/frequent exacerbator endotype in asthma.
abstract: BACKGROUND
  Severe asthma might be associated with overexpression of Th17 cytokines, which induce neutrophil recruitment via neutrophil-mobilizing cytokines in airways.
  
  
  OBJECTIVE
  To study IL-17-related cytokines in nasal/bronchial biopsies from controls and mild asthmatics (MAs) to severe asthmatics (SAs) in relation to exacerbation rate.
  
  
  METHODS
  Inflammatory cells and IL-17A+, IL-17F+, IL-21+, IL-22+, and IL-23+cells were examined by immunohistochemistry in cryostat sections of bronchial/nasal biopsies obtained from 33 SAs (21 frequent exacerbators [FEs]), 31 MAs (3 FEs), and 14 controls. IL-17F protein was also measured by ELISA in bronchial/nasal lysates and by immunohistochemistry in bronchial tissue obtained from subjects who died because of fatal asthma. Immunofluorescence/confocal microscopy was used for IL-17F colocalization.
  
  
  RESULTS
  Higher number (P < .05) of neutrophils, IL-17A+, IL-17F+, and IL-21+cells in bronchial biopsies and higher numbers (P < .01) of IL-17F+and IL-21+cells in nasal biopsies were observed in SAs compared with MAs. Bronchial IL-17F+cells correlated with bronchial neutrophils (r = 0.54), exacerbation rate (r = 0.41), and FEV1(r = -0.46). Nasal IL-17F+cells correlated with bronchial IL-17F (r = 0.35), exacerbation rate (r = 0.47), and FEV1(r = -0.61). FEs showed increased number of bronchial neutrophils/eosinophils/CD4+/CD8+cells and bronchial/nasal IL-17F+cells. Receiver operating characteristic curve analysis evidenced predictive cutoff values of bronchial neutrophils and nasal/bronchial IL-17F for discriminating between asthmatics and controls, between MAs and SAs and between FEs and non-FEs. IL-17F protein increased in bronchial/nasal lysates of SAs and FEs and in bronchial tissue of fatal asthma. IL-17F colocalized in CD4+/CD8+cells.
  
  
  CONCLUSIONS
  IL-17-related cytokines expression was amplified in bronchial/nasal mucosa of neutrophilic asthma prone to exacerbation, suggesting a pathogenic role of IL-17F in FEs.
authors.affiliation: Department of Clinical and Biological Sciences, Azienda Ospedaliera Universitaria (AOU) San Luigi Hospital, University of Torino, Torino, Italy. Electronic address: fabioluigimassimo.ricciardolo@unito.it.
authors.forename: Fabio L M
authors.initials: FLM
authors.lastname: Ricciardolo
authors.affiliation: Department of Clinical and Biological Sciences, Azienda Ospedaliera Universitaria (AOU) San Luigi Hospital, University of Torino, Torino, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Sorbello
authors.affiliation: Department of Clinical and Biological Sciences, Azienda Ospedaliera Universitaria (AOU) San Luigi Hospital, University of Torino, Torino, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Folino
authors.affiliation: Health Science Department, University of Genova, Genova, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Gallo
authors.affiliation: Division of Respiratory Disease, AOU San Luigi Hospital, Torino, Italy.
authors.forename: Gian Mario
authors.initials: GM
authors.lastname: Massaglia
authors.affiliation: Division of Ear, Nose, and Throat, AOU San Luigi Hospital, Torino, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Favatà
authors.affiliation: Division of Ear, Nose, and Throat, AOU San Luigi Hospital, Torino, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Conticello
authors.affiliation: Pulmonary Division, Fondazione S. Maugeri, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Novara, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Vallese
authors.affiliation: Division of Respiratory Disease, AOU San Luigi Hospital, Torino, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Gani
authors.affiliation: Department of Internal Medicine, University of Brescia, Brescia, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Malerba
authors.affiliation: Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Utrecht, The Netherlands.
authors.forename: Gert
authors.initials: G
authors.lastname: Folkerts
authors.affiliation: Allergologia ed Immunologia Clinica, Ospedale Ordine Mauriziano "Umberto I," University of Torino, Torino, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Rolla
authors.affiliation: Institute of Biomedicine and Molecular Immunology, Italian National Research Council, Palermo, Italy.
authors.forename: Mirella
authors.initials: M
authors.lastname: Profita
authors.affiliation: Department of Pathology, Sao Paulo University Medical School, São Paulo, Brazil.
authors.forename: Thais
authors.initials: T
authors.lastname: Mauad
authors.affiliation: Pulmonary Division, Fondazione S. Maugeri, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Novara, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Di Stefano
authors.affiliation: IRCCS-AOU San Martino, Genova, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Ciprandi
mesh_terms: D000328:Adult; D000368:Aged; D001249:Asthma / Q000276:immunology*; D001980:Bronchi / Q000166:cytology / Q000276:immunology; D016207:Cytokines / Q000276:immunology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology; D009666:Nose / Q000166:cytology / Q000276:immunology; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology*
chemical_list: D016207:Cytokines
keywords: IL-17F; Severe asthma; bronchial biopsy; endotype; frequent exacerbators; nasal biopsy; neutrophils; phenotype