Mechanism of TH2/TH17-predominant and neutrophilic TH2/TH17-low subtypes of asthma Weimin Liu, PhD, Sucai Liu, PhD, Mukesh Verma, PhD, Iram Zafar, MS,

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Mechanism of TH2/TH17-predominant and neutrophilic TH2/TH17-low subtypes of asthma Weimin Liu, PhD, Sucai Liu, PhD, Mukesh Verma, PhD, Iram Zafar, MS, James T. Good, MD, Donald Rollins, MD, Stephen Groshong, MD, Magdalena M. Gorska, MD, PhD, Richard J. Martin, MD, Rafeul Alam, MD, PhD Journal of Allergy and Clinical Immunology Volume 139, Issue 5, Pages 1548-1558.e4 (May 2017) DOI: 10.1016/j.jaci.2016.08.032 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Journal of Allergy and Clinical Immunology 2017 139, 1548-1558 Journal of Allergy and Clinical Immunology 2017 139, 1548-1558.e4DOI: (10.1016/j.jaci.2016.08.032) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Expression of TH2/TH17-inducing cytokines in BAL fluid from patients with 3 immunophenotypes of asthma. BAL fluid from patients with TH2/-predominant (n = 22), TH2/TH17-predominant (n = 16), and TH2/TH17-low (n = 22) asthma were assayed for IL-1α (A), IL-1β (B), IL-6 (C), and IL-23 (D) by means of ELISA. Each symbol represents a single patient. P values are shown above the graphs. Journal of Allergy and Clinical Immunology 2017 139, 1548-1558.e4DOI: (10.1016/j.jaci.2016.08.032) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 DAMPs in 3 immunophenotypes of asthma. Levels of C3a (A), serum amyloid A (B), and uric acid (C) in BAL fluid were measured in patients with TH2-predominant (n = 22), TH2/TH17-predominant (n = 16), and TH2/TH17-low (n = 22) asthma. Each symbol represents a single patient. P values are shown above the graphs. Journal of Allergy and Clinical Immunology 2017 139, 1548-1558.e4DOI: (10.1016/j.jaci.2016.08.032) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 A, Correlation of cytokine and DAMP levels with TH2/TH17 cell counts. B, Correlation of IL-1β levels with TH2/TH17 cell counts. C, Correlation of IL-1β levels with C3a levels. D, Expression of IL1R and phospho-p38 MAPK in IL-4+ (TH2), IL-17+ (TH17), IL-4/IL-17+ (TH2/TH17), and total cells. BAL fluid cells from asthmatic patients were analyzed by using flow cytometry for expression of CD4 and intracellular IL-4, IL-17, IL-1R, and phospho-p38 MAPK. *P < .04 (n = 6). E, Inhibition of TH2/TH17 cells by using anakinra. BAL fluid cells were cultured with increasing concentrations of anakinra for 3 days and then analyzed for dual IL-4/IL-17+ CD4 T cells by using flow cytometry. Each symbol represents an asthmatic patient. P values (on the top of the graph) were calculated by using the Kruskal-Wallis test. F, Inhibition of phospho-p38 MAPK in BAL T cells by anakinra. BAL cells were cultured with anakinra for 24 hours and then examined for expression of phospho-p38 MAPK in CD4 T cells by using flow cytometry. Each symbol represents an asthmatic patient. P values were calculated by using the Kruskal-Wallis test. Journal of Allergy and Clinical Immunology 2017 139, 1548-1558.e4DOI: (10.1016/j.jaci.2016.08.032) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 BAL fluid neutrophils in various immunophenotypes of asthma. A, BAL fluid neutrophils in patients with TH2-predominant (n = 22), TH2/TH17-predominant (n = 16), and TH2/TH17-low (n = 22) asthma. Flow cytometric detection of IL-4+ and IL-4/IL-17 dual-positive BAL CD4 T cells was performed, and the immunophenotype was assigned, as reported in Irvin et al.11 B and C, BAL fluid myeloperoxidase (Fig 4, B) and IL-8 (Fig 4, C) levels in patients with TH2-predominant, TH2/TH17-predominant, and TH2/TH17-low asthma. D, Correlation of BAL fluid neutrophil counts and IL-8 levels in patients with TH2/TH17-low asthma. E, Effect of type 2 cytokines on IL-8 production. Airway epithelial BEAS-2B cells were cultured with increasing concentrations of IL-4 and IL-13 for 3 days, and the culture supernatant was assayed for IL-8 by using ELISA. **P < .05 (n = 4). F, Correlation between IL-4 and IL-8 levels in BAL fluid from all 3 study groups (n = 42). Journal of Allergy and Clinical Immunology 2017 139, 1548-1558.e4DOI: (10.1016/j.jaci.2016.08.032) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 A-C, Comparison of levels of IL-17A (Fig 5, A), GM-CSF (Fig 5, B), and G-CSF (Fig 5, C) in BAL fluid from patients with TH2-predominant, TH2/TH17-predominant, and TH2/TH17-low asthma. D, Effect of cytokines/mediators on epithelial IL-8 production. Freshly isolated human bronchial epithelial cells (HBE) and BEAS-2B cells were cultured with various cytokines/mediators (10 ng/mL) singly or in combination for 3 days. The BEAS-2B cell cultures were primed with a subthreshold dose of LPS (0.25 μg/mL). Culture supernatants were assayed for IL-8 by means of ELISA. *P < .05 (n = 4). E, Freshly isolated human bronchial epithelial cells were cultured with dimethyl sulfoxide (DMSO) or SB212190 (10 μmol/L) in the presence of IL-1α (10 ng/mL) for 3 days. Culture supernatant was assayed for IL-8 by using ELISA. *P < .05 (n = 3). Journal of Allergy and Clinical Immunology 2017 139, 1548-1558.e4DOI: (10.1016/j.jaci.2016.08.032) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Representative flow cytograms from patients with TH2-predominant, TH2/TH17-predominant, and TH2/TH17-low asthma. BAL cells were gated for CD4+ cells and analyzed for expression of IL-4 and IL-17. Journal of Allergy and Clinical Immunology 2017 139, 1548-1558.e4DOI: (10.1016/j.jaci.2016.08.032) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Distribution of immune endotypes and neutrophilic asthma in a cohort of 60 patients with refractory asthma. Journal of Allergy and Clinical Immunology 2017 139, 1548-1558.e4DOI: (10.1016/j.jaci.2016.08.032) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 The approximate relationship between immune endotypes and conventional phenotypes of asthma. Journal of Allergy and Clinical Immunology 2017 139, 1548-1558.e4DOI: (10.1016/j.jaci.2016.08.032) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions