title: Subcutaneous Allergic Sensitization to Protease Allergen Is Dependent on Mast Cells but Not IL-33: Distinct Mechanisms between Subcutaneous and Intranasal Routes.
abstract: Protease activity of papain, a plant-derived occupational allergen homologous to mite major allergens, is essential to IgE/IgG1 production and lung eosinophilia induced by intranasal papain administration in mice, and IL-33 contributes to these responses. In this work, we investigate skin and Ab responses induced by s.c. papain administration into ear lobes and responses induced by subsequent airway challenge with papain. Subcutaneous papain injection induced swelling associated with increased epidermal thickness, dermal inflammation, serum IgE/IgG1 responses, and Th2 cytokine production in draining lymph node cells restimulated in vitro. These responses were markedly less upon s.c. administration of protease inhibitor-treated papain. Results obtained by using mast cell-deficient mice and reconstitution of tissue mast cells suggested the contribution of mast cells to papain-specific IgE/IgG1 responses and eosinophil infiltration. The responses were equivalent between wild-type and IL-33(-/-) mice. After the subsequent airway challenge, the s.c. presensitized wild-type mice showed more severe lung eosinophilia than those without the presensitization. The presensitized IL-33(-/-) mice showed modest lung eosinophilia, which was absent without the presensitization, but its severity and IgE boost by the airway challenge were markedly less than the presensitized wild-type mice, in which protease activity of inhaled papain contributed to the responses. The results suggest that mechanisms for the protease-dependent sensitization differ between skin and airway and that cooperation of mast cell-dependent, IL-33-independent initial sensitization via skin and protease-induced, IL-33-mediated mechanism in re-exposure via airway to protease allergens maximizes the magnitude of the transition from skin inflammation to asthma in natural history of progression of allergic diseases.
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan;
authors.forename: Seiji
authors.initials: S
authors.lastname: Kamijo
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; Department of Materials and Biological Sciences, Faculty of Science, Japan Women's University, Tokyo 112-8681, Japan;
authors.forename: Mayu
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan;
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Hara
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan;
authors.forename: Sakiko
authors.initials: S
authors.lastname: Shimura
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan;
authors.forename: Hirono
authors.initials: H
authors.lastname: Ochi
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan;
authors.forename: Natsuko
authors.initials: N
authors.lastname: Maruyama
authors.affiliation: Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan;
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuda
authors.affiliation: Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan;
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Saito
authors.affiliation: Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; and Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Nakae
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan;
authors.forename: Hajime
authors.initials: H
authors.lastname: Suto
authors.affiliation: Department of Materials and Biological Sciences, Faculty of Science, Japan Women's University, Tokyo 112-8681, Japan;
authors.forename: Saori
authors.initials: S
authors.lastname: Ichikawa
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan;
authors.forename: Shigaku
authors.initials: S
authors.lastname: Ikeda
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan;
authors.forename: Hideoki
authors.initials: H
authors.lastname: Ogawa
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan;
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; t-takai@juntendo.ac.jp.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Takai
mesh_terms: D000485:Allergens / Q000008:administration & dosage* / Q000276:immunology*; D000818:Animals; D001249:Asthma; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000473:pathology; D004804:Eosinophils / Q000276:immunology; D006967:Hypersensitivity / Q000276:immunology* / Q000473:pathology; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007249:Inflammation; D000067596:Interleukin-33 / Q000172:deficiency / Q000276:immunology*; D008168:Lung / Q000276:immunology; D008407:Mast Cells / Q000276:immunology*; D051379:Mice; D065588:Nasal Absorption; D010206:Papain / Q000008:administration & dosage / Q000276:immunology; D010447:Peptide Hydrolases / Q000008:administration & dosage / Q000276:immunology*; D011657:Pulmonary Eosinophilia / Q000276:immunology / Q000473:pathology; D012867:Skin / Q000276:immunology / Q000473:pathology; D065566:Subcutaneous Absorption; D018418:Th2 Cells / Q000276:immunology
chemical_list: D000485:Allergens; C506535:Il33 protein, mouse; D007074:Immunoglobulin G; D000067596:Interleukin-33; D007073:Immunoglobulin E; D010447:Peptide Hydrolases; D010206:Papain