Jörgen Östling1, Marleen van Geest1, James P R Schofield2, Zala Jevnikar1, Susan Wilson3, Jonathan Ward4, Rene Lutter5, Dominick E Shaw6, Per S Bakke7, Massimo Caruso8, Sven-Erik Dahlen9, Stephen J Fowler10, Ildikó Horváth11, Norbert Krug12, Paolo Montuschi13, Marek Sanak14, Thomas Sandström15, Kai Sun16, Ioannis Pandis16, Charles Auffray17, Ana R Sousa18, Yike Guo16, Ian M Adcock19, Peter Howarth4, Kian Fan Chung19, Jeanette Bigler20, Peter J Sterk21, Paul J Skipp2, Ratko Djukanović22, Outi Vaarala1. 1. Respiratory, Inflammation, Autoimmunity IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden. 2. Centre for Proteomic Research, University of Southampton, Southampton, United Kingdom; NIHR Southampton Biomedical Research Centre, Clinical and Experimental Sciences, Faculty of Research, University of Southampton, Southampton, United Kingdom. 3. NIHR Southampton Biomedical Research Centre, Clinical and Experimental Sciences, Faculty of Research, University of Southampton, Southampton, United Kingdom; Histochemistry Research Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. 4. NIHR Southampton Biomedical Research Centre, Clinical and Experimental Sciences, Faculty of Research, University of Southampton, Southampton, United Kingdom. 5. AUMC, Department of Experimental Immunology, University of Amsterdam, Amsterdam, The Netherlands; AUMC, Department of Respiratory Medicine, University of Amsterdam, Amsterdam, The Netherlands. 6. Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom. 7. Institute of Medicine, University of Bergen, Bergen, Norway. 8. Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy. 9. Centre for Allergy Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. 10. Respiratory and Allergy Research Group, University of Manchester, Manchester, United Kingdom. 11. Department of Pulmonology, Semmelweis University, Budapest, Hungary. 12. Fraunhofer Institute for Toxicology and Experimental Medicine Hannover, Hannover, Germany. 13. Faculty of Medicine, Catholic University of the Sacred Heart, Fondazione Policlinico Agostino Gemelli IRCCS, Rome, Italy. 14. Laboratory of Molecular Biology and Clinical Genetics, Medical College, Jagiellonian University, Krakow, Poland. 15. Department of Medicine, Department of Public Health and Clinical Medicine Respiratory Medicine Unit, Umeå University, Umeå, Sweden. 16. Data Science Institute, Imperial College, London, United Kingdom. 17. European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL-INSERM, Université de Lyon, Lyon, France. 18. Respiratory Therapeutic Unit, GlaxoSmithKline, Stockley Park, United Kingdom. 19. Experimental Studies, Airways Disease Section, National Heart & Lung institute, Imperial College London, London, United Kingdom. 20. Amgen, Thousand Oaks, Calif. 21. AUMC, Department of Respiratory Medicine, University of Amsterdam, Amsterdam, The Netherlands. 22. NIHR Southampton Biomedical Research Centre, Clinical and Experimental Sciences, Faculty of Research, University of Southampton, Southampton, United Kingdom. Electronic address: rd1@soton.ac.uk.
Abstract
BACKGROUND: The role of IL-17 immunity is well established in patients with inflammatory diseases, such as psoriasis and inflammatory bowel disease, but not in asthmatic patients, in whom further study is required. OBJECTIVE: We sought to undertake a deep phenotyping study of asthmatic patients with upregulated IL-17 immunity. METHODS: Whole-genome transcriptomic analysis was performed by using epithelial brushings, bronchial biopsy specimens (91 asthmatic patients and 46 healthy control subjects), and whole blood samples (n = 498) from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. Gene signatures induced in vitro by IL-17 and IL-13 in bronchial epithelial cells were used to identify patients with IL-17-high and IL-13-high asthma phenotypes. RESULTS: Twenty-two of 91 patients were identified with IL-17, and 9 patients were identified with IL-13 gene signatures. The patients with IL-17-high asthma were characterized by risk of frequent exacerbations, airway (sputum and mucosal) neutrophilia, decreased lung microbiota diversity, and urinary biomarker evidence of activation of the thromboxane B2 pathway. In pathway analysis the differentially expressed genes in patients with IL-17-high asthma were shared with those reported as altered in psoriasis lesions and included genes regulating epithelial barrier function and defense mechanisms, such as IL1B, IL6, IL8, and β-defensin. CONCLUSION: The IL-17-high asthma phenotype, characterized by bronchial epithelial dysfunction and upregulated antimicrobial and inflammatory response, resembles the immunophenotype of psoriasis, including activation of the thromboxane B2 pathway, which should be considered a biomarker for this phenotype in further studies, including clinical trials targeting IL-17.
BACKGROUND: The role of IL-17 immunity is well established in patients with inflammatory diseases, such as psoriasis and inflammatory bowel disease, but not in asthmatic patients, in whom further study is required. OBJECTIVE: We sought to undertake a deep phenotyping study of asthmatic patients with upregulated IL-17 immunity. METHODS: Whole-genome transcriptomic analysis was performed by using epithelial brushings, bronchial biopsy specimens (91 asthmatic patients and 46 healthy control subjects), and whole blood samples (n = 498) from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. Gene signatures induced in vitro by IL-17 and IL-13 in bronchial epithelial cells were used to identify patients with IL-17-high and IL-13-high asthma phenotypes. RESULTS: Twenty-two of 91 patients were identified with IL-17, and 9 patients were identified with IL-13 gene signatures. The patients with IL-17-high asthma were characterized by risk of frequent exacerbations, airway (sputum and mucosal) neutrophilia, decreased lung microbiota diversity, and urinary biomarker evidence of activation of the thromboxane B2 pathway. In pathway analysis the differentially expressed genes in patients with IL-17-high asthma were shared with those reported as altered in psoriasis lesions and included genes regulating epithelial barrier function and defense mechanisms, such as IL1B, IL6, IL8, and β-defensin. CONCLUSION: The IL-17-high asthma phenotype, characterized by bronchial epithelial dysfunction and upregulated antimicrobial and inflammatory response, resembles the immunophenotype of psoriasis, including activation of the thromboxane B2 pathway, which should be considered a biomarker for this phenotype in further studies, including clinical trials targeting IL-17.
Authors: Luke R Bonser; Walter L Eckalbar; Lauren Rodriguez; Jiangshan Shen; Kyung Duk Koh; Khadija Ghias; Lorna T Zlock; Stephanie Christenson; Prescott G Woodruff; Walter E Finkbeiner; David J Erle Journal: Am J Respir Cell Mol Biol Date: 2022-04 Impact factor: 6.914
Authors: Sophie Seité; Alyce Mei-Shiuan Kuo; Charles Taieb; Tamara Lazić Strugar; Peter Lio Journal: Int J Environ Res Public Health Date: 2020-05-12 Impact factor: 3.390
Authors: Lies Lahousse; Thomas Bahmer; Sara Cuevas-Ocaña; Pauline Flajolet; Alexander G Mathioudakis; Melissa McDonnell; Lena Uller; Florence Schleich; Sergio Dortas Junior; Marco Idzko; Dave Singh; Fabio L M Ricciardolo; Ian M Adcock; Omar Usmani; Antonio Spanevello; Sara J Bonvini Journal: ERJ Open Res Date: 2020-02-17
Authors: Elizabeth R Davies; Jeanne-Marie Perotin; Joanne F C Kelly; Ratko Djukanovic; Donna E Davies; Hans Michael Haitchi Journal: Clin Exp Allergy Date: 2020-03-09 Impact factor: 5.401