Β-Glucan exacerbates allergic asthma independent of fungal sensitization and promotes steroid-resistant TH2/TH17 responses Zhonghua Zhang, MD, Jocelyn.

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β-Glucan exacerbates allergic asthma independent of fungal sensitization and promotes steroid-resistant TH2/TH17 responses Zhonghua Zhang, MD, Jocelyn M. Biagini Myers, PhD, Eric B. Brandt, PhD, Patrick H. Ryan, PhD, Mark Lindsey, BS, Rachael A. Mintz- Cole, MD, PhD, Tiina Reponen, PhD, Stephen J. Vesper, PhD, Frank Forde, BS, Brandy Ruff, BS, Stacey A. Bass, AS, Grace K. LeMasters, PhD, David I. Bernstein, MD, James Lockey, MD, Alison L. Budelsky, PhD, Gurjit K. Khurana Hershey, MD, PhD Journal of Allergy and Clinical Immunology Volume 139, Issue 1, Pages 54-65.e8 (January 2017) DOI: 10.1016/j.jaci.2016.02.031 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Fungal exposure is associated with increased asthma prevalence at age 7 years among CCAAPS children. A, Prevalence of asthma at age 7 years in ERMI-high versus ERMI-low exposed children (P < .001). B, Data in Fig 1, A, stratified by SPT response positivity to 1 or more environmental allergens any time during ages 1 to 7 years (P < .001). C, Data in Fig 1, B, excluding children with fungus sensitivity (P = .003). **P < .01 and ***P < .001. ns, Not significant. Journal of Allergy and Clinical Immunology 2017 139, 54-65.e8DOI: (10.1016/j.jaci.2016.02.031) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Coexposure to HDM and A versicolor worsens AHR and inflammation, activates TH17 responses, and exacerbates HDM-induced TH2 responses. A, Airway resistance measured 48 hours after the last intratracheal challenge. B, Total BALF cell counts. C, Representative hematoxylin and eosin staining of lung tissue. Bar = 50 μm. D, BALF cell differential counts. Eos, Eosinophils; Lymph, lymphocytes; Macro, macrophages; Neutro, neutrophils. E, IL-17A expression in lung tissue was assessed by using quantitative PCR and ELISA. F, IL-4 and IL-13 mRNA levels in lung tissue were assessed by using quantitative PCR. *P < .05, **P < .01, and ***P < .001, 2-way ANOVA for AHR. ns, Not significant. Data are from 3 separate experiments (n = 6 for control and A versicolor treatment groups, n = 7 for HDM and H+A treatment groups) and presented as means ± SEMs. Asp, A versicolor; H+A, HDM plus A versicolor; SAL, saline. Journal of Allergy and Clinical Immunology 2017 139, 54-65.e8DOI: (10.1016/j.jaci.2016.02.031) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Coexposure to HDM and curdlan worsens AHR and inflammation, activates TH17 responses, and exacerbates HDM-induced TH2 responses. A, Airway resistance measured 48 hours after the last intratracheal challenge. B, Total BALF cell counts. C, Representative hematoxylin and eosin staining of lung tissues. Bar = 50 μm. D, BALF cell differential counts. E and F, TH17 and TH2 cytokine levels in lung tissue were assessed by using either quantitative PCR (IL-17A, IL-4, and IL-13) or ELISA (IL-17A). *P < .05, **P < .01, and ***P < .001, 2-way ANOVA for AHR. Data are from 3 separate experiments (n = 6 for control and curdlan treatment groups, n = 9 per HDM and H+C treatment groups) and presented as means ± SEMs. H+C, HDM plus curdlan. Journal of Allergy and Clinical Immunology 2017 139, 54-65.e8DOI: (10.1016/j.jaci.2016.02.031) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Effect of curdlan on HDM-induced asthma is dependent on IL-17A induction through dectin-1. A, Airway resistance and BALF neutrophil counts of wild-type and dectin-1 KO mice after exposure to HDM or coexposure to curdlan and HDM per protocol in Fig E1, A. **P < .01 and ****P < .0001, 2-way ANOVA for AHR (n = 6 per group). B, Airway resistance and BALF neutrophil counts of mice treated with either IL-17A neutralizing or control IgG in HDM and curdlan–coexposed mice. **P < .01, and ***P < .001, 2-way ANOVA for AHR (n = 8 per group). Data from 3 separate experiments are presented as means ± SEMs. H+C, HDM plus curdlan. Journal of Allergy and Clinical Immunology 2017 139, 54-65.e8DOI: (10.1016/j.jaci.2016.02.031) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Coexposure to curdlan and HDM induces steroid-resistant airway resistance and TH2/TH17 dual-positive T cells in the lungs of exposed mice. A-C, Asthma was induced per the protocol outlined in Fig E1, A, in wild-type (Fig 5, A and B) and Il17rc−/− mice (Fig 5, C), and dexamethasone (1 mg/kg) was administered intraperitoneally for the last 5 days, as indicated, before assessment of mice. Fig 5, A, Airway resistance measured in the wild-type mice (n = 4 for control and curdlan treatment groups, n = 6 for HDM and H+C treatment groups). Fig 5, B, Reduction of airway resistance and BALF eosinophil and neutrophil counts after dexamethasone treatment in the HDM and H+C groups in wild-type mice, respectively. Fig 5, C, Reduction of airway resistance and BALF eosinophil and neutrophil counts after dexamethasone treatment in the H+C group in IL-17RC−/− mice (n = 6). D-F, intracellular cytokine staining for TH2 (IL-13+) cells, TH17 (IL-17A+) cells, and TH2/TH17 dual-producing T cells (IL-13+IL-17A+), respectively. *P < .05, **P < .01, and ***P < .001, 2-way ANOVA for AHR (n = 3-5 per group). Data from 3 separate experiments are presented as means ± SEMs. DEX, Dexamethasone; H+C, HDM plus curdlan. Journal of Allergy and Clinical Immunology 2017 139, 54-65.e8DOI: (10.1016/j.jaci.2016.02.031) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Fungal exposure is associated with increased serum IL-17A levels and increased asthma severity in children. A, Percentage of CCAAPS children with high IL-17A serum levels is increased in the group with high ERMI values versus those with low ERMI values (P = .014). B, Percentage of GCPCR children with asthma who have fungal exposure among those who have symptoms more than once a week (n = 258) versus those with symptoms less than once a week (n = 81, P = .026). C, Proposed working model. *P < .05. Journal of Allergy and Clinical Immunology 2017 139, 54-65.e8DOI: (10.1016/j.jaci.2016.02.031) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Coexposure to HDM and A versicolor induces enhanced HDM sensitization and mixed eosinophilia with neutrophilia. A, Experimental asthma protocol. B, HDM-specific IgG1 and IgE titers from mice represented in Fig 2. C, BALF cells from mice coexposed to HDM and A versicolor (Fig 2). **P < .01 and ***P < .001, 1-way ANOVA, followed by a Bonferroni posttest. Data are presented as means ± SEMs. Asp, A versicolor; H+A, HDM plus A versicolor; SAC, sacrifice; SAL, saline. Journal of Allergy and Clinical Immunology 2017 139, 54-65.e8DOI: (10.1016/j.jaci.2016.02.031) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Indicated cytokine and chemokine levels of the mice (represented in Fig 2) exposed to A versicolor, HDM, or both assessed by using either ELISA (BALF, A) or quantitative PCR (lung tissue, B-D). *P < .05, **P < .01, and ***P < .001 (both H+A vs Asp and H+A vs HDM for CCL11), 1-way ANOVA, followed by a Bonferroni posttest. ns, Not significant. Data are presented as means ± SEMs. Asp, A versicolor; H+A, HDM plus A versicolor; SAL, saline. Journal of Allergy and Clinical Immunology 2017 139, 54-65.e8DOI: (10.1016/j.jaci.2016.02.031) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Indicated cytokine and chemokine levels of mice (represented in Fig 3) exposed to curdlan, HDM, or both assessed by using either ELISA (BALF, A) or quantitative PCR (lung tissue, B and C). *P < .05, **P < .01, and ***P < .001 (both H+C vs Curdlan and H+C vs HDM for CCL11), 1-way ANOVA, followed by a Bonferroni posttest. Data are presented as means ± SEMs. H+C, HDM plus curdlan. Journal of Allergy and Clinical Immunology 2017 139, 54-65.e8DOI: (10.1016/j.jaci.2016.02.031) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Coexposure to HDM and curdlan induces enhanced HDM sensitization. HDM-specific IgG1 and IgE titers from mice represented in Fig 3. **P < .01, 1-way ANOVA, followed by a Bonferroni posttest. ns, Not significant. Data are presented as means ± SEMs. H+C, HDM plus curdlan. Journal of Allergy and Clinical Immunology 2017 139, 54-65.e8DOI: (10.1016/j.jaci.2016.02.031) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Representative hematoxylin and eosin staining of lung tissues from mice represented in Fig 4, A. Bar = 50 μm. H+C, HDM plus curdlan. Journal of Allergy and Clinical Immunology 2017 139, 54-65.e8DOI: (10.1016/j.jaci.2016.02.031) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 Representative hematoxylin and eosin staining of lung tissues from mice represented in Fig 5, A. Bar = 50 μm. H+C, HDM plus curdlan. Journal of Allergy and Clinical Immunology 2017 139, 54-65.e8DOI: (10.1016/j.jaci.2016.02.031) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E7 Representative fluorescence-activated cell sorting dot plots of lung cells exposed in vivo to HDM plus curdlan (H+C) and restimulated ex vivo with phorbol 12-myristate 13-acetate/ionomycin to assess intracellular cytokine accumulation in CD4+ T cells. Frequency of IL-13+ TH2 cells, IFN-γ+ TH1 cells, IL-17A+ TH17 cells, and IL-13+/IL-17A+ double producers. To properly separate the cytokine-positive cells from the negative cells, we used fluorescence minus one (FMO). Statistics done by using 1-way ANOVA with the Bonferroni multiple comparison test. *P < .05 and ***P < .001. H+C, HDM plus curdlan. Journal of Allergy and Clinical Immunology 2017 139, 54-65.e8DOI: (10.1016/j.jaci.2016.02.031) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions