Brecht Steelant, PhD, Sven F

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Histamine and T helper cytokine–driven epithelial barrier dysfunction in allergic rhinitis Brecht Steelant, PhD, Sven F. Seys, PhD, Laura Van Gerven, MD, PhD, Matthias Van Woensel, PhD, Ricard Farré, PhD, Paulina Wawrzyniak, MSc, Inge Kortekaas Krohn, MSc, Dominique M. Bullens, MD, PhD, Karel Talavera, PhD, Ulrike Raap, MD, PhD, Louis Boon, PhD, Cezmi A. Akdis, PhD, Guy Boeckxstaens, MD, PhD, Jan L. Ceuppens, MD, PhD, Peter W. Hellings, MD, PhD Journal of Allergy and Clinical Immunology Volume 141, Issue 3, Pages 951-963.e8 (March 2018) DOI: 10.1016/j.jaci.2017.08.039 Copyright © 2017 The Authors Terms and Conditions

Journal of Allergy and Clinical Immunology 2018 141, 951-963 Journal of Allergy and Clinical Immunology 2018 141, 951-963.e8DOI: (10.1016/j.jaci.2017.08.039) Copyright © 2017 The Authors Terms and Conditions

Fig 1 Epithelial barrier function in patients with AR and IR. A, Transtissue resistance measured with Ussing chambers on nasal explants from AR and IR patients and control subjects. B, FD4 permeability. C, Visual analog scale (VAS) scores for major nasal symptom. D, Hematoxylin and eosin staining of nasal mucosal biopsies from healthy control subjects and patients with AR and IR. Bars = 100 μm. *P < .05 and ***P < .001. NS, Not significant. Journal of Allergy and Clinical Immunology 2018 141, 951-963.e8DOI: (10.1016/j.jaci.2017.08.039) Copyright © 2017 The Authors Terms and Conditions

Fig 2 Tight junction expression in mucosal biopsies from control subjects and AR and IR patients. A, mRNA expression of occludin, ZO-1, and claudin-1 and -4 in patients with AR and IR and control subjects. Relative mRNA expression versus the housekeeping genes encoding β-actin and β2 microglobulin is shown. B, Representative images of protein expression of occludin and ZO-1. Original magnification 40×. Data presented as medians and interquartile ranges. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2018 141, 951-963.e8DOI: (10.1016/j.jaci.2017.08.039) Copyright © 2017 The Authors Terms and Conditions

Fig 3 Effect of nasal fluid of AR patients on epithelial barrier function of Calu-3 cells. A, Effect of nasal fluid of healthy control subjects and AR and IR patients (n = 5/group). B, Histamine content measured in nasal fluid of healthy control subjects and patients with AR and IR. C and D, IL-4 and IL-13 concentration in nasal fluid. E, Substance P (SP) concentration in nasal fluid. F-H, Effect of histamine, IL-4 (10 ng/mL), IL-13 (10 ng/mL), and SP on Calu-3 epithelial cell integrity after 4-hour stimulation. I, Effect of 2-hour pretreatment with azelastine on the decrease of Calu-3 epithelial cell integrity induced by AR nasal secretions. *P < .05, **P < .01, and ***P < .001. M, Mol/L; SN, supernatant. Journal of Allergy and Clinical Immunology 2018 141, 951-963.e8DOI: (10.1016/j.jaci.2017.08.039) Copyright © 2017 The Authors Terms and Conditions

Fig 4 Effect of SN from activated immune cells on epithelial barrier function of Calu-3 cells and pNECs. A, Effect of SN from activated TH1 and TH2 cells. B, Effect of SN from IgE-activated mast cells. C, Effect of SN from capsaicin-activated murine TGNs. D, Effect of SN from C5a-activated eosinophils. n = 5 for all experiments. Data presented as medians and interquartile ranges. **P < .01 and ***P < .001. Journal of Allergy and Clinical Immunology 2018 141, 951-963.e8DOI: (10.1016/j.jaci.2017.08.039) Copyright © 2017 The Authors Terms and Conditions

Fig 5 Effect of TH1 and TH2 cytokines on epithelial barrier function of Calu-3 cells and pNECs. A and B, Calu-3 cells and pNECs were stimulated with SN of activated TH1 cells, TH1 cytokines, and their receptor antagonists for 72 hours. C and D, Calu-3 cells and pNECs were stimulated with SN of activated TH2 cells, TH2 cytokines, and their receptor antagonists for 72 hours. n = 5 for Calu-3 cells and n = 4 for pNECs. Data presented as means ± SD. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2018 141, 951-963.e8DOI: (10.1016/j.jaci.2017.08.039) Copyright © 2017 The Authors Terms and Conditions

Fig 6 Effect of IL-4, IFN-γ, and TNF-α on the mucosal barrier in naive BALB/c mice. A, Study protocol. On day 1, mice received 3 nasal instillations at 1-hour intervals with IL-4, IL-13, IFN-γ, TNF-α (all 250 ng), or sham. One day after the last instillation, 20 μL FD4 (50 mg/mL) was applied endonasally (en) for evaluation of mucosal permeability. One hour later, mice were sacrificed for further analysis with an intraperitoneal injection of Nembutal. B, Mucosal permeability for FD4. C, mRNA expression for occludin. D, mRNA expression for ZO-1. mRNA expression is relative to the housekeeping genes β-actin and β2 microglobulin. n = 5/group. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2018 141, 951-963.e8DOI: (10.1016/j.jaci.2017.08.039) Copyright © 2017 The Authors Terms and Conditions

Fig 7 Effect of anti-IL-4 in mouse model of HDM-induced allergic airway inflammation. A, Mouse model. Mice were sensitized with 1 μg HDM extract or saline control at day 1. One week later (days 7-11), mice were challenged endonasally (en) with 10 μg HDM extract or saline. One hour before each challenge, anti-IL-4 monoclonal antibody or vehicle was given intraperitoneally (ip). One hour after the last challenge, 20 μL FD4 (50 mg/mL) was applied, followed 1 hour later with the sacrifice of the mice. B, IL-4 levels in BAL fluid. C and D, Effect of anti-IL-4 treatment on FD4 permeability and albumin leakage in the lungs. E and F, mRNA expression of occludin and ZO-1. Relative expression versus the housekeeping β-actin and β2 microglobulin. n = 5/group. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2018 141, 951-963.e8DOI: (10.1016/j.jaci.2017.08.039) Copyright © 2017 The Authors Terms and Conditions

Fig E1 Effect of AR nasal secretions on TER of Calu-3 epithelial cell cultures at ALI. TER was measured of Calu-3 epithelial cell cultures after stimulation with nasal secretions from AR patients. n = 5. Paired t-test, *P < .05; **P < .01. Journal of Allergy and Clinical Immunology 2018 141, 951-963.e8DOI: (10.1016/j.jaci.2017.08.039) Copyright © 2017 The Authors Terms and Conditions

Fig E2 Histamine did not decrease TER after 24-hour stimulation of Calu-3 epithelial cell cultures at ALI. Data presented as means ± SDs. M, Mol/L. Journal of Allergy and Clinical Immunology 2018 141, 951-963.e8DOI: (10.1016/j.jaci.2017.08.039) Copyright © 2017 The Authors Terms and Conditions

Fig E3 Effect of pretreatment with anti-IL-4Rα monoclonal antibody on the decrease of Calu-3 epithelial cell integrity induced by AR nasal secretions. Calu-3 epithelial cell cultures were pretreated for 2 hours with 2 μg/mL anti-IL-4Rα monoclonal antibody before stimulation with nasal secretions of AR patients. n = 5/group. Data presented as means ± SDs. Two-way ANOVA with post-hoc analysis, ***P < .001. Journal of Allergy and Clinical Immunology 2018 141, 951-963.e8DOI: (10.1016/j.jaci.2017.08.039) Copyright © 2017 The Authors Terms and Conditions

Fig E4 Cytokines secretion by polarized TH1 and TH2 cell cultures in vitro. Naive CD4+ T cells were polarized in vitro for 3 weeks into TH1 or TH2 cells. T-cell cultures were stimulated for 6 hours with phorbol 12-myristate 13-acetate (25 ng/mL) and ionomycin (1 μg/mL). SN was collected and cytokine profile was measured with ELISA. Data are presented from 3 independent experiments, using cells from the same donor. Data are shown as means ± SEMs. Journal of Allergy and Clinical Immunology 2018 141, 951-963.e8DOI: (10.1016/j.jaci.2017.08.039) Copyright © 2017 The Authors Terms and Conditions

Fig E5 Effect of anti-TNF-α treatment in a mouse model of HDM-induced allergic airway inflammation. A, Mouse model. Mice were sensitized with 1 μg HDM extract or saline at day 1. One week later (days 7-11), mice were challenged endonasally with 10 μg HDM extract or saline. One hour before each challenge, anti-TNF-α monoclonal antibody or vehicle was given intraperitoneally. One hour after the last challenge, 20 μL FD4 (50 mg/mL) was applied followed 1 hour later with the sacrifice of the mice. B, TNF-α and IL-4 levels in BAL fluid. C and D, Effect of anti-TNF-α treatment on FD4 permeability and albumin leakage to BAL fluid in the lungs. E and F, mRNA expression of occludin and ZO-1 in nasal mucosa. Relative expression versus the housekeeping β-actin and β2 microglobulin. n = 5 mice/group. Data presented as medians and interquartile ranges. One-Way ANOVA with post-hoc analysis; *P < .05, **P < .01. Journal of Allergy and Clinical Immunology 2018 141, 951-963.e8DOI: (10.1016/j.jaci.2017.08.039) Copyright © 2017 The Authors Terms and Conditions