Exposure to food allergens through inflamed skin promotes intestinal food allergy through the thymic stromal lymphopoietin–basophil axis Mario Noti,

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Exposure to food allergens through inflamed skin promotes intestinal food allergy through the thymic stromal lymphopoietin–basophil axis Mario Noti, PhD, Brian S. Kim, MD, Mark C. Siracusa, PhD, Gregory D. Rak, VMD, PhD, Masato Kubo, PhD, Amin E. Moghaddam, MD, Quentin A. Sattentau, PhD, Michael R. Comeau, BSc, Jonathan M. Spergel, MD, PhD, David Artis, PhD Journal of Allergy and Clinical Immunology Volume 133, Issue 5, Pages 1390-1399.e6 (May 2014) DOI: 10.1016/j.jaci.2014.01.021 Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Epicutaneous sensitization promotes antigen-induced food allergy. A, Experimental protocol. B, TSLP protein in the skin. C, Allergy score. D, OVA-specific serum IgE levels. E, Hematoxylin and eosin staining from the jejunum. Scale bar = 100 μm. Arrows, Tissue-infiltrating granulocytes. F, Type 2 cytokine expression in the jejunum. G, Frequencies of mast cells in the lamina propria. H, Jejunal mouse mast cell protease 1 (Mcpt1) and Mcpt2 expression. Results are from 3 to 4 mice per group. Data are representative of 3 independent experiments. i.g., Intragastric; ND, no disease. *P ≤ .05; **P ≤ .01; and ***P ≤ .001. Journal of Allergy and Clinical Immunology 2014 133, 1390-1399.e6DOI: (10.1016/j.jaci.2014.01.021) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 TSLP–TSLP receptor responses mediate antigen-induced food allergy. A, Experimental protocol. B, Allergy score. C, OVA-specific serum IgE levels. D, Hematoxylin and eosin staining from the jejunum. Scale bar = 100 μm. Arrows, Tissue-infiltrating granulocytes. E, Type 2 cytokine expression in the jejunum. F, Frequencies of mast cells in the lamina propria. G, Jejunal mouse mast cell protease 1 (Mcpt1) and Mcpt2 expression. Results are from 3 to 4 mice per group. Data are representative of 3 independent experiments. i.g., Intragastric; ND, no disease; ns, not significant. *P ≤ .05; **P ≤ .01; and ***P ≤ .001. Journal of Allergy and Clinical Immunology 2014 133, 1390-1399.e6DOI: (10.1016/j.jaci.2014.01.021) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 TSLP is sufficient to promote antigen-induced intestinal food allergy. A, Experimental protocol. B, Allergy score. C, OVA-specific serum IgE levels. D, Hematoxylin and eosin staining from the jejunum. Scale bar = 100 μm. Arrows, Tissue-infiltrating granulocytes. E, Type 2 cytokine expression in the jejunum. F, Frequencies of mast cells in the lamina propria. G, Jejunal mouse mast cell protease (Mcpt1) and Mcpt2 expression. Results are from 3 mice per group. Data are representative of 3 independent experiments. i.d., Intradermal; i.g., intragastric; ND, no disease. *P ≤ .05 and **P ≤ .01. Journal of Allergy and Clinical Immunology 2014 133, 1390-1399.e6DOI: (10.1016/j.jaci.2014.01.021) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 AD-like skin lesions are associated with accumulation of TSLP-elicited basophils in the skin. A, Experimental protocol. B, Frequencies of basophils in the skin. C, Hematoxylin and eosin staining from the skin. Scale bar = 100 μm. D, Ear thickness measurement. E, TH2 cytokine responses in antigen-restimulated skin-draining lymph nodes. Results are from 3 to 4 mice per group. Data are representative of 3 independent experiments. nd, Not detected. **P ≤ .01 and ***P ≤ .001. Journal of Allergy and Clinical Immunology 2014 133, 1390-1399.e6DOI: (10.1016/j.jaci.2014.01.021) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 TSLP-elicited basophil responses regulate antigen-induced food allergy. A, Experimental protocol. B, Allergy score. C, OVA-specific serum IgE levels. D, Hematoxylin and eosin staining from the jejunum. Scale bar = 100 μm. Arrows, Tissue-infiltrating granulocytes. E, Type 2 cytokine expression in the jejunum. F, Frequencies of mast cells in the lamina propria. G, Jejunal mouse mast cell protease 1 (Mcpt1) and Mcpt2 expression. Results are from 3 to 5 mice per group. Data are representative of 3 independent experiments. i.g., Intragastric; ND, no disease; nd, not detected. *P ≤ .05; **P ≤ .01; and ***P ≤ .001. Journal of Allergy and Clinical Immunology 2014 133, 1390-1399.e6DOI: (10.1016/j.jaci.2014.01.021) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 TSLP-elicited basophils are sufficient to promote intestinal food allergy. A, Experimental protocol. B, Allergy score. C, OVA-specific serum IgE levels. D, Hematoxylin and eosin staining from the jejunum. Scale bar = 100 μm. Arrows, Tissue-infiltrating granulocytes. E, Type 2 cytokine expression in the jejunum. F, Frequencies of mast cells in the lamina propria. G, Jejunal mouse mast cell protease 1 (Mcpt1) and Mcpt2 expression. Results are from 3 mice per group. Data are representative of 3 independent experiments. i.g., Intragastric; ND, no disease. *P ≤ .05; **P ≤ .01; and ***P ≤ .001. Journal of Allergy and Clinical Immunology 2014 133, 1390-1399.e6DOI: (10.1016/j.jaci.2014.01.021) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Clinical allergy score. Allergy scores from WT BALB/c mice epicutaneously sensitized with OVA and orally challenged with OVA or BSA as a control are shown. Results are from 3 mice per group. Data are representative of 2 individual experiments. ND, No disease. Journal of Allergy and Clinical Immunology 2014 133, 1390-1399.e6DOI: (10.1016/j.jaci.2014.01.021) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Epicutaneous sensitization with CPE. A, Experimental protocol. B, Allergy score. C, CPE-specific serum IgE levels. D, Hematoxylin and eosin staining from the jejunum. Scale bar = 50 μm. Arrows, Tissue-infiltrating granulocytes. E, Jejunal type 2 cytokine expression levels. F, Frequencies of small intestinal lamina propria mast cells. Results are from 3 to 4 mice per group. Data are representative of 2 independent experiments. i.g., Intragastric; ND, no disease; ns, not significant. *P ≤ .05 and **P ≤ .01. Journal of Allergy and Clinical Immunology 2014 133, 1390-1399.e6DOI: (10.1016/j.jaci.2014.01.021) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Epicutaneous sensitization on tape-stripped skin promotes intestinal food allergy. A, Experimental protocol. B, Allergy score. C, OVA-specific serum IgE levels. D, Frequencies of small intestinal lamina propria mast cells. Results are from 3 to 4 mice per group. Data are representative of 2 independent experiments. ND, No disease. *P ≤ .05. Journal of Allergy and Clinical Immunology 2014 133, 1390-1399.e6DOI: (10.1016/j.jaci.2014.01.021) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Antigen-induced intestinal food allergy is dependent on IgE. A, Allergy score. B, OVA-specific serum IgE levels. Results are from 3 mice per group. Data are representative of 2 or more independent experiments. ND, No disease; nd, not detected. **P ≤ .01. Journal of Allergy and Clinical Immunology 2014 133, 1390-1399.e6DOI: (10.1016/j.jaci.2014.01.021) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 TSLP-dependent basophil frequencies in the skin. For statistical analysis, MC903 plus OVA Tslpr+/+ or MC903 plus OVA Tslpr−/− mice are compared. Results are from 3 mice per group. Data are representative of 2 independent experiments. **P ≤ .01. Journal of Allergy and Clinical Immunology 2014 133, 1390-1399.e6DOI: (10.1016/j.jaci.2014.01.021) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions