title: IL-33 and thymic stromal lymphopoietin mediate immune pathology in response to chronic airborne allergen exposure.
abstract: Humans are frequently exposed to various airborne allergens in the atmospheric environment. These allergens may trigger a complex network of immune responses in the airways, resulting in asthma and other chronic airway diseases. In this study, we investigated the immunological mechanisms involved in the pathological changes induced by chronic exposure to multiple airborne allergens. Naive mice were exposed intranasally to a combination of common airborne allergens, including the house dust mite, Alternaria, and Aspergillus, for up to 8 wk. These allergens acted synergistically and induced robust eosinophilic airway inflammation, specific IgE Ab production, type 2 cytokine response, and airway hyperresponsiveness in 4 wk, followed by airway remodeling in 8 wk. Increased lung infiltration of T cells, B cells, and type 2 innate lymphoid cells was observed. CD4(+) T cells and type 2 innate lymphoid cells contributed to the sources of IL-5 and IL-13, suggesting involvement of both innate and adaptive immunity in this model. The lung levels of IL-33 increased quickly within several hours after allergen exposure and continued to rise throughout the chronic phase of inflammation. Mice deficient in IL-33R (Il1rl1(-/-)) and thymic stromal lymphopoietin receptor (Tslpr(-/-)) showed significant reduction in airway inflammation, IgE Ab levels, and airway hyperresponsiveness. In contrast, mice deficient in IL-25R or IL-1R showed minimal differences as compared with wild-type animals. Thus, chronic exposure to natural airborne allergens triggers a network of innate and adaptive type 2 immune responses and airway pathology, and IL-33 and thymic stromal lymphopoietin most likely play key roles in this process.
authors.affiliation: Division of Allergic Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905;
authors.forename: Koji
authors.initials: K
authors.lastname: Iijima
authors.affiliation: Division of Allergic Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905;
authors.forename: Takao
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Division of Allergic Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905;
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Hara
authors.affiliation: Division of Allergic Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905;
authors.forename: Gail M
authors.initials: GM
authors.lastname: Kephart
authors.affiliation: Immunology Program, Benaroya Research Institute, Seattle, WA 98101; and.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Ziegler
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom.
authors.forename: Andrew N
authors.initials: AN
authors.lastname: McKenzie
authors.affiliation: Division of Allergic Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905; kita.hirohito@mayo.edu.
authors.forename: Hirohito
authors.initials: H
authors.lastname: Kita
mesh_terms: D056704:Adaptive Immunity; D056151:Airway Remodeling / Q000276:immunology; D000528:Alternaria / Q000276:immunology; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000276:immunology; D001230:Aspergillus / Q000276:immunology; D001249:Asthma / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D007113:Immunity, Innate; D007073:Immunoglobulin E / Q000096:biosynthesis / Q000276:immunology; D007136:Immunoglobulins / Q000235:genetics; D007249:Inflammation / Q000276:immunology; D019570:Inhalation Exposure; D000072179:Interleukin-1 Receptor-Like 1 Protein; D018793:Interleukin-13 / Q000096:biosynthesis; D000067596:Interleukin-33; D015848:Interleukin-5 / Q000096:biosynthesis; D007378:Interleukins / Q000276:immunology*; D008168:Lung / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052638:Particulate Matter / Q000276:immunology*; D039981:Pyroglyphidae / Q000276:immunology; D018121:Receptors, Cytokine / Q000235:genetics; D018123:Receptors, Interleukin / Q000235:genetics; D017472:Receptors, Interleukin-1 / Q000235:genetics; D053722:Receptors, Interleukin-17 / Q000235:genetics; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D039741:Antigens, Dermatophagoides; D016207:Cytokines; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D007136:Immunoglobulins; D000072179:Interleukin-1 Receptor-Like 1 Protein; D018793:Interleukin-13; D000067596:Interleukin-33; D015848:Interleukin-5; D007378:Interleukins; D052638:Particulate Matter; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D017472:Receptors, Interleukin-1; D053722:Receptors, Interleukin-17; C410591:Tslpr protein, mouse; D007073:Immunoglobulin E; D000094632:Thymic Stromal Lymphopoietin