IL-17-high asthma with features of a psoriasis immunophenotype

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:144

Article

Oestling, Joergen¹  van Geest, Marleen¹  Schofield, James P. R.^2,3  Jevnikar, Zala¹  Wilson, Susan³  Ward, Jonathan³  Lutter, Rene^5,6  Shaw, Dominick E.^7,20  Bakke, Per S.⁸  Caruso, Massimo⁹  Dahlen, Sven-Erik¹⁰  Fowler, Stephen J.¹¹  Horvath, Ildiko¹²  Krug, Norbert¹³  Montuschi, Paolo¹⁴  Sanak, Marek¹⁵  Sandstrom, Thomas^16,17  Auffray, Charles¹⁹  Sousa, Ana R.²⁰  Adcock, Ian M.^21,23  Howarth, Peter³  Chung, Kian Fan²¹  Bigler, Jeanette²²  Sterk, Peter J.⁶  Skipp, Paul J.^2,3  Djukanovic, Ratko³  Vaarala, Outi¹  Ahmed, H.²⁴  Auffray, C.²⁴  Bakke, P.²⁵  Bansal, A. T.²⁶  Baribaud, F.²⁷  Bates, S.²⁸  Bel, E. H.²⁹  Bigler, J.²²  Bisgaard, H.^30,31  Boedigheimer, M. J.²²  Bonnelykke, K.^30,31  Brandsma, J.³²  Brinkman, P.²⁹  Bucchioni, E.³³  Burg, D.³⁴  Bush, A.^23,35  Caruso, M.⁹  Chaiboonchoe, A.²⁴  Chanez, P.³⁶  Chung, K. F.²³  Compton, C. H.²⁸  Corfield, J.³⁷  D'Amico, A.³⁸  De Meulder, B.²⁴  Djukanovic, R.⁴⁰  Erpenbeck, V. J.⁴¹  Fitch, N.⁴³  Fleming, L. J.^23,35  Formaggio, E.⁴⁴  Fowler, S. J.^45,46  Frey, U.⁴⁷  Gahlemann, M.⁴⁸  Geiser, T.⁴⁹  Guo, Y.¹⁸  Hashimoto, S.²⁹  Haughney, J.⁵⁰  Hedlin, G.⁵¹  Hekking, P. W.²⁹  Higenbottam, T.⁵²  Holweg, C.⁵⁴  Howarth, P.⁴⁰  Knowles, R.⁵⁶  Knox, A. J.⁷  Krug, N.⁵³  Lefaudeux, D.²⁴  Loza, M. J.²⁷  Lutter, R.²⁹  Manta, A.⁵⁷  Masefield, S.⁵⁸  Matthews, J. G.⁵⁴  Mazein, A.²⁴  Meiser, A.¹⁸  Miralpeix, M.⁵⁹  Montuschi, P.⁶⁰  Mores, N.⁶⁰  Murray, C. S.⁴⁵  Musial, J.⁶¹  Myles, D.²⁸  Pahus, L.³⁶  Pandis, I.¹⁸  Pavlidis, S.²³  Powell, P.⁵⁸  Pratico, G.⁴⁴  Valls, M. Puig⁶²  Rao, N.²⁷  Riley, J.²⁸  Roberts, A.⁶³  Roberts, G.⁴⁰  Rowe, A.⁶⁴  Sandstrom, T.⁶⁵  Selby, A.⁴⁰  Shaw, D. E.⁷  Sigmund, R.⁴²  Singer, F.⁶⁶  Skipp, P. J.³⁴  Sousa, A. R.²⁸  Sterk, P. J.²⁹  Sun, K.¹⁸  van Aalderen, W. M.²⁹  van Geest, M.⁶⁷  Vestbo, J.⁴⁵  Vissing, N. H.^30,31  Wagener, A. H.⁶⁸  Wagers, S. S.⁴³  Weiszhart, Z.⁵⁵  Wheelock, C. E.³⁹  Wilson, S. J.⁴ 

[1] AstraZeneca, Autoimmun IMED Biotech Unit, Inflammat, Resp, Gothenburg, Sweden

[2] Univ Southampton, Ctr Prote Res, Southampton, Hants, England

[3] Univ Southampton, NIHR Southampton Biomed Res Ctr Clin & Expt Sci, Fac Res, Southampton, Hants, England

[4] Univ Southampton, Fac Med, Histochem Res Unit, Southampton, Hants, England

[5] Univ Amsterdam, Dept Expt Immunol, AUMC, Amsterdam, Netherlands

[6] Univ Amsterdam, AUMC, Dept Resp Med, Amsterdam, Netherlands

[7] Univ Nottingham, Resp Res Unit, Nottingham, England

[8] Univ Bergen, Inst Med, Bergen, Norway

[9] Univ Catania, Dept Clin & Expt Med, Catania, Italy

[10] Karolinska Inst, Inst Environm Med, Ctr Allergy Res, Stockholm, Sweden

[11] Univ Manchester, Resp & Allergy Res Grp, Manchester, Lancs, England

[12] Semmelweis Univ, Dept Pulmonol, Budapest, Hungary

[13] Fraunhofer Inst Toxicol & Expt Med Hannover, Hannover, Germany

[14] Univ Cattolica Sacro Cuore, Fac Med, Fdn Policlin Agostino Gemelli IRCCS, Rome, Italy

[15] Jagiellonian Univ, Med Coll, Lab Mol Biol & Clin Genet, Krakow, Poland

[16] Umea Univ, Dept Publ Hlth, Dept Med, Umea, Sweden

[17] Umea Univ, Clin Med Resp Med Unit, Umea, Sweden

[18] Imperial Coll, Data Sci Inst, London, England

[19] Univ Lyon, European Inst Syst Biol & Med, INSERM, CNRS,ENS,UCBL, Lyon, France

[20] GlaxoSmithKline, Resp Therapeut Unit, Stockley Pk, England

[21] Imperial Coll London, Natl Heart & Lung Inst, Airways Dis Sect, Expt Studies, London, England

[22] Amgen Inc, Thousand Oaks, CA USA

[23] Imperial Coll, Natl Heart & Lung Inst, London, England

[24] UCBL, European Inst Syst Biol & Med, CNRS, ENS,INSERM, Lyon, France

[25] Univ Bergen, Dept Clin Sci, Bergen, Norway

[26] St Johns Innovat Ctr, Acclarogen, Cambridge, England

[27] Janssen R&D, Malvern, PA USA

[28] GlaxoSmithKline, Resp Therapeut Unit, London, England

[29] Univ Amsterdam, Acad Med Ctr, Amsterdam, Netherlands

[30] Copenhagen Prospect Studies Asthma Childhood, COPSAC, Herlev, Denmark

[31] Univ Copenhagen, Gentofte Hosp, Copenhagen, Denmark

[32] Univ Southampton, Southampton, Hants, England

[33] Chiesi Pharmaceut SPA, Parma, Italy

[34] Univ Southampton, Inst Life Sci, Ctr Prote Res, Southampton, Hants, England

[35] Royal Brompton & Harefield NHS Trust, London, England

[36] Aix Marseille Univ, Clin Bronches Allergies & Sommeil, AP HM, Marseille, France

[37] Areteva R&D, Nottingham, England

[38] Univ Roma Tor Vergata, Rome, Italy

[39] Karolinska Inst, Ctr Allergy Res, Stockholm, Sweden

[40] NIHR Southampton Resp Biomed Res Unit & Clin & Ex, Southampton, Hants, England

[41] Novartis Inst Biomed Res, Resp Profiling, Translat Med, Basel, Switzerland

[42] Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany

[43] BioSci Consulting, Maasmechelen, Belgium

[44] CROMSOURCE, Verona, Italy

[45] Univ Manchester, Inst Inflammat & Repair, Ctr Resp Med & Allergy, Manchester, Lancs, England

[46] Univ Hosp South Manchester, Acad Hlth Sci Ctr, Manchester, Lancs, England

[47] Univ Childrens Hosp, Basel, Switzerland

[48] Boehringer Ingelheim Schweiz GmbH, Basel, Switzerland

[49] Univ Hosp Bern, Dept Resp Med, Bern, Switzerland

[50] Int Primary Care Resp Grp, Aberdeen, Scotland

[51] Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden

[52] Allergy Therapeut, Worthing, W Sussex, England

[53] Fraunhofer Inst Toxicol & Expt Med, Hannover, Germany

[54] Genentech Inc, Resp & Allergy Dis, San Francisco, CA USA

[55] Semmelweis Univ, Budapest, Hungary

[56] Arachos Pharma, Stevenge, England

[57] Roche Diagnost GmbH, Mannheim, Germany

[58] European Lung Fdn, Sheffield, S Yorkshire, England

[59] Almirall, Barcelona, Spain

[60] Univ Cattolica Sacro Cuore, Milan, Italy

[61] Jagiellonian Univ, Med Coll, Dept Med, Krakow, Poland

[62] CROMSOURCE, Barcelona, Spain

[63] Asthma UK, London, England

[64] Janssen R&D UK, High Wycombe, Bucks, England

[65] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden

[66] Univ Childrens Hosp, Zurich, Switzerland

[67] AstraZeneca, Molndal, Sweden

[68] Acad Med Ctr Amsterdam, Amsterdam, Netherlands

关键词: IL-17;    asthma;    bronchial biopsies;    bronchial brushings;    biomarkers;    psoriasis;   

DOI  :  10.1016/j.jaci.2019.03.027

来源: Elsevier

【 摘 要 】

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 beta-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.

【 授权许可】

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