Allergic skin sensitization promotes eosinophilic esophagitis through the IL-33–basophil axis in mice Nicholas Venturelli, BS, Willem S. Lexmond, MD,

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Presentation transcript:

Allergic skin sensitization promotes eosinophilic esophagitis through the IL-33–basophil axis in mice Nicholas Venturelli, BS, Willem S. Lexmond, MD, Asa Ohsaki, BS, Samuel Nurko, MD, MPH, Hajime Karasuyama, MD, PhD, Edda Fiebiger, PhD, Michiko K. Oyoshi, PhD, MSc Journal of Allergy and Clinical Immunology Volume 138, Issue 5, Pages 1367-1380.e5 (November 2016) DOI: 10.1016/j.jaci.2016.02.034 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Epicutaneous sensitization predisposes to development of experimental EoE. A, Experimental plan. i.n., Intranasal. B, Representative hematoxylin and eosin–stained sections of esophagus. Arrows indicate eosinophils (magnification ×400; inset, ×800). Scale bars = 100 μm. C, Number of eosinophils per square millimeter. D-F, Representative flow cytometric analysis (Fig 1, D), frequencies (Fig 1, E), and numbers (Fig 1, F) of eosinophils in the esophagus. G, mRNA expression of TH2 cytokines, Ccl11/eotaxin-1, and Tslp as fold induction relative to saline controls (n = 5-7 per group in Fig 1, C and G). Percentages of eosinophils within live CD45+Lin− cells are shown in Fig 1, D. EC, Epicutaneous; SAL, saline. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2016 138, 1367-1380.e5DOI: (10.1016/j.jaci.2016.02.034) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 The IL-33–ST2 axis mediates development of experimental EoE elicited by epicutaneous sensitization. A-C, Levels of Il33 mRNA in skin (Fig 2, A), IL-33 in serum (Fig 2, B), and Il33 and St2 mRNA in esophagi (Fig 2, C) of WT mice. D, Representative hematoxylin and eosin–stained sections of esophagi of OVA-sensitized WT and St2−/− mice. Arrows indicate eosinophils (magnification ×400; inset, ×800). Scale bars = 100 μm. E, Number of eosinophils per square millimeter. F-H, Representative flow cytometric analysis (Fig 2, F), frequencies (Fig 2, G), and numbers (Fig 2, H) of eosinophils in the esophagus. SSC, Side scatter. I and J, Flow cytometric analysis of frequencies (Fig 2, I) and numbers (Fig 2, J) of eosinophils in the esophagus of BM chimeras. K, mRNA expression of TH2 cytokines, Ccl11/eotaxin-1, and Tslp. Fold induction relative to unsensitized (Fig 2, A) or saline (Fig 2, C and K) controls are shown (n = 5-9 per group in Fig 2, C, E, and K). EC, Epicutaneous; SAL, saline. *P < .05, **P < .01, and ***P < .001. ns, Not significant. Journal of Allergy and Clinical Immunology 2016 138, 1367-1380.e5DOI: (10.1016/j.jaci.2016.02.034) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Blockade of the IL-33–ST2 response attenuates development of experimental EoE. A, Experimental plan. i.n., Intranasal. B, Representative hematoxylin and eosin–stained sections of esophagus. Arrows indicate eosinophils (magnification ×400; inset, ×800). Scale bars = 100 μm. C, Number of eosinophils per square millimeter. D-F, Representative flow cytometric analysis (Fig 3, D), frequencies (Fig 3, E), and numbers (Fig 3, F) of eosinophils in the esophagus. SSC, Side scatter. G, mRNA expression of TH2 cytokines, Ccl11/eotaxin-1, and Tslp as fold induction relative to saline controls treated with isotype control (n = 5-6 per group in Fig 3, C and G). EC, Epicutaneous; SAL, saline. ∗P < .05, ∗∗P < .01, and ∗∗∗P < .001. ns, Not significant. Journal of Allergy and Clinical Immunology 2016 138, 1367-1380.e5DOI: (10.1016/j.jaci.2016.02.034) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 FLG deficiency promotes IL-33–mediated esophageal eosinophil accumulation. A, Experimental plan. i.n., Intranasal. B-D, Representative flow cytometric analysis (Fig 4, B), frequencies (Fig 4, C), and numbers (Fig 4, D) of eosinophils in the esophagi of WT or ft/ft mice. SSC, Side scatter. E-G, Representative flow cytometric analysis (Fig 4, E), frequencies (Fig 4, F), and numbers (Fig 4, G) of eosinophils in the esophagi of ft/ft or ft/ft.St2−/− mice. EC, Epicutaneous; SAL, saline. *P < .05 and **P < .01. ns, Not significant. Journal of Allergy and Clinical Immunology 2016 138, 1367-1380.e5DOI: (10.1016/j.jaci.2016.02.034) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Basophils are required for development of experimental EoE. A-C, Representative flow cytometric analysis (Fig 5, A), frequencies (Fig 5, B), and numbers (Fig 5, C) of basophils in the esophagus. D, Experimental plan. i.n., Intranasal. E, Representative hematoxylin and eosin–stained sections of esophagus. Arrows indicate eosinophils (magnification ×400; inset, ×800). Scale bars = 100 μm. F, Number of eosinophils per square millimeter. G-I, Representative flow cytometric analysis (Fig 5, G), frequencies (Fig 5, H), and numbers (Fig 5, I) of eosinophils in the esophagus. SSC, Side scatter. J, mRNA expression of TH2 cytokines, Ccl11/eotaxin-1, and Tslp as fold induction relative to saline-exposed Mcpt8DTR mice treated with PBS (n = 5 per group in Fig 5, F and J). EC, Epicutaneous; SAL, saline. Percentages of basophils within live, CD45+Lin−c-kit− cells are shown in Fig 5, A. *P < .05 and ***P < .001. Journal of Allergy and Clinical Immunology 2016 138, 1367-1380.e5DOI: (10.1016/j.jaci.2016.02.034) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Basophils mediate experimental EoE through IL-33–ST2 interactions. A, Representative flow cytometric analysis of basophils in the esophagus for ST2 expression. B, Experimental plan. i.n., Intranasal. C, Representative hematoxylin and eosin–stained sections of esophagus. Arrows indicate eosinophils (magnification ×400; inset, ×800). Scale bars = 100 μm. D, Number of eosinophils per square millimeter. E-G, Representative flow cytometric analysis (Fig 6, D), frequencies (Fig 6, E), and numbers (Fig 6, F) of eosinophils in the esophagus. SSC, Side scatter. H and I, Frequencies (Fig 6, H) and numbers (Fig 6, I) of basophils in the esophagus (n = 3 per group in Fig 6, C). EC, Epicutaneous; SAL, saline. *P < .05. ns, Not significant. Journal of Allergy and Clinical Immunology 2016 138, 1367-1380.e5DOI: (10.1016/j.jaci.2016.02.034) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 Patients with EoE have increased esophageal expression of IL1RL1/ST2 mRNA. A and B, Expression of IL33 (Fig 7, A) and IL1RL1/ST2 (Fig 7, B) in esophageal biopsy specimens from healthy control subjects and patients with EoE. C and D, Expression of IL33 (Fig 7, C) and IL1RL1/ST2 (Fig 7, D) in esophageal biopsy specimens from healthy control subjects and patients with EoE with and without AD. Fig 7, A and C, and Fig 7, B and D, use the same data. ***P < .001. NS, Not significant. Journal of Allergy and Clinical Immunology 2016 138, 1367-1380.e5DOI: (10.1016/j.jaci.2016.02.034) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Allergen-specific systemic immune responses in epicutaneously sensitized mice. Serum levels of OVA-specific IgE (A) and IgG1 (B) in WT mice epicutaneously sensitized with OVA or saline are shown (n = 7-10). EC, Epicutaneous; SAL, saline. **P < .01 and ***P < .001. Journal of Allergy and Clinical Immunology 2016 138, 1367-1380.e5DOI: (10.1016/j.jaci.2016.02.034) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Analysis of tissue eosinophilia in epicutaneously sensitized mice. Flow cytometric analysis of frequencies and numbers of eosinophils in the stomach (A), jejunum (B), and lung (C) are shown. EC, Epicutaneous; SAL, saline. **P < .01. ns, Not significant. Journal of Allergy and Clinical Immunology 2016 138, 1367-1380.e5DOI: (10.1016/j.jaci.2016.02.034) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Allergen-specific systemic immune responses in epicutaneously sensitized St2−/− mice. A and B, Serum levels of OVA-specific IgE (Fig E3, A) and IgG1 (Fig E3, B) in WT or St2−/− mice with OVA. C, Cytokine production by splenocytes in vitro stimulated with OVA (n = 5-10 per group). EC, Epicutaneous; ns, not significant; SAL, saline. Journal of Allergy and Clinical Immunology 2016 138, 1367-1380.e5DOI: (10.1016/j.jaci.2016.02.034) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Development of esophageal eosinophil accumulation is independent of mast cells. A, Frequencies and numbers of mast cells and basophils in the skin of Mcpt8DTR mice 3 days after DT injection. B and C, Flow cytometric analysis of frequencies (Fig E4, B) and numbers (Fig E4, C) of eosinophils in the esophagi of OVA-sensitized KitW-sh/W-sh mice after OVA challenge. EC, Epicutaneous; ns, not significant; SAL, saline. Journal of Allergy and Clinical Immunology 2016 138, 1367-1380.e5DOI: (10.1016/j.jaci.2016.02.034) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Correlation analysis of peak esophageal eosinophil counts and IL1RL1/ST2 mRNA expression levels in esophageal biopsy specimens from patients with EoE (Pearson r = 0.30, P = .21). Journal of Allergy and Clinical Immunology 2016 138, 1367-1380.e5DOI: (10.1016/j.jaci.2016.02.034) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions