Intraepithelial neutrophils in pediatric severe asthma are associated with better lung function Cecilia K. Andersson, PhD, Alexandra Adams, MBBS, Prasad.

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Intraepithelial neutrophils in pediatric severe asthma are associated with better lung function Cecilia K. Andersson, PhD, Alexandra Adams, MBBS, Prasad Nagakumar, MBBS, Cara Bossley, MDRes, Atul Gupta, MDRes, Daphne De Vries, BSc, Afiqah Adnan, BSc, Andrew Bush, MD, Sejal Saglani, MD, Clare M. Lloyd, PhD Journal of Allergy and Clinical Immunology Volume 139, Issue 6, Pages 1819-1829.e11 (June 2017) DOI: 10.1016/j.jaci.2016.09.022 Copyright © 2016 The Authors Terms and Conditions

Fig 1 Eosinophils and neutrophils in different lung compartments. Eosinophil percentage in BAL (A) (controls n = 11, STRA n = 31), numbers per area of submucosa (B) (controls without asthma n = 7, STRA n = 20), and intraepithelial eosinophils per length of reticular basement membrane (C) (controls n = 7, STRA n = 20). Representative micrographs of Congo Red stain for eosinophils in controls without asthma (D) and patients with STRA (E). F, High magnification picture of epithelium with no eosinophils in patients with STRA. Neutrophil percentage in BAL (G) (controls without asthma n = 12, STRA n = 52), numbers per area of submucosa (H) (controls without asthma n = 10, STRA n = 28), and proportion of intraepithelial neutrophils (I) (controls without asthma n = 13, STRA n = 37). Representative micrographs of immunohistochemical stain for elastase in controls without asthma (J) and patients with STRA (K). L, High magnification picture of intraepithelial neutrophils in patients with STRA. Scale bar: 200 μm (Fig 1, D and J), 100 μm (Fig 1, E and K), 20 μm (Fig 1, F), and 10 μm (Fig 1, L). Statistical significance between controls without asthma and patients with STRA was tested using Mann-Whitney test. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2017 139, 1819-1829.e11DOI: (10.1016/j.jaci.2016.09.022) Copyright © 2016 The Authors Terms and Conditions

Fig 2 Sources and expression of IL-17A in children with STRA compared with controls without asthma. Representative micrograph of immunohistochemical stain for IL-17A in children with STRA (A). Scale bar: 100 μm. Quantification of the number of IL-17A–expressing cells per area in submucosa (B) (controls without asthma n = 6, STRA n = 39) and bronchial epithelium (C) (controls without asthma n = 6, STRA n = 32). BAL levels of IL-17A (D) (controls without asthma n = 11, STRA n = 23) and IL-22 (E) (controls without asthma n = 11, STRA n = 23) in controls without asthma and children with STRA. Percentages of IL-17A–expressing TH17 (F) (controls without asthma n = 10, STRA n = 13) and gamma delta (G) (controls without asthma n = 8, STRA n = 11) lymphocytes in children with STRA compared with controls without asthma. Statistical significance between controls without asthma and children with STRA was tested using Mann-Whitney test. NS, Not significant. Journal of Allergy and Clinical Immunology 2017 139, 1819-1829.e11DOI: (10.1016/j.jaci.2016.09.022) Copyright © 2016 The Authors Terms and Conditions

Fig 3 Representative micrographs of immunohistochemical stain for IL-17RA in controls without asthma and patients with STRA (A and B, respectively). Scare bar 100 μm (Fig 3, A) and 50 μm (Fig 3, B). Quantification of the expression (positive pixels per area) of IL-17RA in submucosa (controls without asthma n = 6, STRA n = 31) and epithelium (controls without asthma n = 6, STRA n = 24) (C and D, respectively). mRNA expression of IL-17RA and C in PBECs after stimulation with IL-17A and budesonide (Bud) (controls without asthma n = 3, STRA n = 3) (E and F, respectively). Correlations between ACT score and IL-17RA expression in epithelium (G) (n = 21). Statistical significance between controls without asthma and children with STRA was tested using Mann-Whitney test and correlation analysis was performed using Spearman rank test, where a P value of less than .05 was considered significant. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2017 139, 1819-1829.e11DOI: (10.1016/j.jaci.2016.09.022) Copyright © 2016 The Authors Terms and Conditions

Fig 4 Levels of IL-8 (A) (controls without asthma n = 9, STRA n = 24) and IL-6 (B) (controls without asthma n = 12, STRA n = 23) in BAL. Levels of IL-8 (C) and IL-6 (D) in culture supernatant from PBECs after stimulation with IL-17A, IL-22, and budesonide (controls n = 4, STRA n = 7). Differences in submucosal eosinophils (E) (Neuhi n = 10, Neulo n = 15), BAL eosinophils (F) (Neuhi n = 12, Neulo n = 20), total IgE (G) (Neuhi n = 10, Neulo n = 21), Feno (H) (Neuhi n = 11, Neulo n = 18), ACT score (I) (Neuhi n = 12, Neulo n = 20), dose of inhaled corticosteroids (J) (Neuhi n = 12, Neulo n = 21), and FEV1 % predicted (K) within the group of children with STRA based on the presence of intraepithelial neutrophils (Neuhi n = 13, Neulo n = 21). Correlations between FEV1 % predicted and proportion of intraepithelial neutrophils (L) (n = 36). Patients from the cohort previously published in Bossley et al5 are shown in gray. Statistical significance between controls and patients with STRA was tested using Mann-Whitney test and correlation analysis was performed using Spearman rank test, where a P value of less than .05 was considered significant. Feno, Fraction of exhaled nitric oxide. *P < .05. Journal of Allergy and Clinical Immunology 2017 139, 1819-1829.e11DOI: (10.1016/j.jaci.2016.09.022) Copyright © 2016 The Authors Terms and Conditions

Fig E1 Measurement of GRO in culture supernatants from PBECs after stimulation with IL-17A, IL-22, and budesonide (Bud) (Fig E1, A) (controls without asthma n = 4, STRA n = 4). Statistical significance between controls without asthma and STRA was tested using Mann-Whitney test, where a *P value of less than .05 was considered significant. Journal of Allergy and Clinical Immunology 2017 139, 1819-1829.e11DOI: (10.1016/j.jaci.2016.09.022) Copyright © 2016 The Authors Terms and Conditions

Fig E2 Tissue density of IL-17A in submucosa (A), IL-17RA in submucosa (B), and IL-17RA in epithelium (C) in bronchial biopsies from children with STRA divided into Neutrophilhigh vs Neutrophillow groups. Statistical significance was tested using Mann-Whitney test, where a P value of less than .05 was considered significant. Neu, Neutrophil. Journal of Allergy and Clinical Immunology 2017 139, 1819-1829.e11DOI: (10.1016/j.jaci.2016.09.022) Copyright © 2016 The Authors Terms and Conditions

Fig E3 Measurement of IL-6 (A), IL-8 (B), IL-13 (C), IP-10 (D), MCP-1 (E), MDC (F), FGF-2 (G), and IFN-γ (H) in culture supernatants from PBECs after stimulation with IL-17A, IL-22, and budesonide (Bud) (controls without asthma n = 4, STRA n = 4) using Milliplex assay. Statistical significance between controls without asthma and STRA was tested using Mann-Whitney test, where a *P value of less than .05 was considered significant. Journal of Allergy and Clinical Immunology 2017 139, 1819-1829.e11DOI: (10.1016/j.jaci.2016.09.022) Copyright © 2016 The Authors Terms and Conditions

Fig E4 Measurement of IL-6 (A) and IL-8 (B) in culture supernatants from 16HBEs after stimulation with IL-17A, IL-22, and budesonide (Bud) using ELISA. Journal of Allergy and Clinical Immunology 2017 139, 1819-1829.e11DOI: (10.1016/j.jaci.2016.09.022) Copyright © 2016 The Authors Terms and Conditions

Fig E5 The effect of IL-17A on airway remodeling parameters. Measurement of VEGF in culture supernatants from PBECs after stimulation with IL-17A, IL-22, and budesonide (A) (controls without asthma n = 4, STRA n = 4). mRNA expression in PBECs after stimulation with IL-17A, IL-22, and budesonide of fibronectin (B) and collagen I (C) (controls without asthma n = 3, STRA n = 3). RBM thickness in controls without asthma compared with STRA (D) (controls without asthma n = 7, STRA n = 21) and RBM thickness within the STRA group when divided into Neutrophilhigh subgroup vs Neutrophillow subgroup (E). Representative micrographs of bronchial biopsies stained with Masson's trichrome staining for collagen (blue) (F control and G STRA). Subepithelial collagen deposition (H) (nonasthmatic controls n = 7, STRA n = 9) in bronchial biopsies from controls without asthma and children with STRA expressed as positive pixels per area. Statistical significance between controls without asthma and STRA was tested using Mann-Whitney test, where a *P value of less than .05 was considered significant. Journal of Allergy and Clinical Immunology 2017 139, 1819-1829.e11DOI: (10.1016/j.jaci.2016.09.022) Copyright © 2016 The Authors Terms and Conditions

Fig E6 Immunohistochemical double staining of bronchial biopsies of IL-17A (red, AlexaF 555) and elastase (A) or CD3 (B) (green, AlexaF 488). Corresponding isotype controls are shown in C and D. Nuclei are stained blue with DAPI. DAPI, 4'-6-Diamidino-2-phenylindole, dihydrochloride; IHC, immunohistochemistry. Scale bar: 100 μm. Journal of Allergy and Clinical Immunology 2017 139, 1819-1829.e11DOI: (10.1016/j.jaci.2016.09.022) Copyright © 2016 The Authors Terms and Conditions