title: Cutaneous exposure to agglomerates of silica nanoparticles and allergen results in IgE-biased immune response and increased sensitivity to anaphylaxis in mice.
abstract: BACKGROUND
  The skin is a key route of human exposure to nanomaterials, which typically occurs simultaneously with exposure to other chemical and environmental allergen. However, little is known about the hazards of nanomaterial exposure via the skin, particularly when accompanied by exposure to other substances.
  
  
  RESULTS
  Repeated topical treatment of both ears and the shaved upper back of NC/Nga mice, which are models for human atopic dermatitis (AD), with a mixture of mite extract and silica nanoparticles induced AD-like skin lesions. Measurements of ear thickness and histologic analyses revealed that cutaneous exposure to silica nanoparticles did not aggravate AD-like skin lesions. Instead, concurrent cutaneous exposure to mite allergens and silica nanoparticles resulted in the low-level production of allergen-specific IgGs, including both the Th2-related IgG1 and Th1-related IgG2a subtypes, with few changes in allergen-specific IgE concentrations and in Th1 and Th2 immune responses. In addition, these changes in immune responses increased the sensitivity to anaphylaxis. Low-level IgG production was induced when the mice were exposed to allergen-silica nanoparticle agglomerates but not when the mice exposed to nanoparticles applied separately from the allergen or to well-dispersed nanoparticles.
  
  
  CONCLUSIONS
  Our data suggest that silica nanoparticles themselves do not directly affect the allergen-specific immune response after concurrent topical application of nanoparticles and allergen. However, when present in allergen-adsorbed agglomerates, silica nanoparticles led to a low IgG/IgE ratio, a key risk factor of human atopic allergies. We suggest that minimizing interactions between nanomaterials and allergens will increase the safety of nanomaterials applied to skin.
authors.affiliation: Laboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan. t-hirai@phs.osaka-u.ac.jp.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Hirai
authors.affiliation: Laboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan. y-yoshioka@biken.osaka-u.ac.jp.|Vaccine Creation Project, BIKEN Innovative Vaccine Research Alliance Laboratories, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan. y-yoshioka@biken.osaka-u.ac.jp.|BIKEN Center for Innovative Vaccine Research and Development, The Research Foundation for Microbial Diseases of Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan. y-yoshioka@biken.osaka-u.ac.jp.
authors.forename: Yasuo
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authors.lastname: Yoshioka
authors.affiliation: Laboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan. h-takahashi@biken.osaka-u.ac.jp.|Vaccine Creation Project, BIKEN Innovative Vaccine Research Alliance Laboratories, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan. h-takahashi@biken.osaka-u.ac.jp.
authors.forename: Hideki
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authors.affiliation: Laboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan. koichihashi@gmail.com.
authors.forename: Ko-ichi
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authors.affiliation: Laboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan. lemontarte.au@gmail.com.
authors.forename: Asako
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authors.lastname: Udaka
authors.affiliation: Laboratory of Innovative Antibody Engineering and Design, Center for Drug Innovation and Screening, National Institute of Biomedical Innovation, 7-6-8 Saitoasagi, Ibaraki, Osaka, 567-0085, Japan. t-mori@nibio.go.jp.
authors.forename: Takahide
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authors.affiliation: Laboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan. nishijima-n@phs.osaka-u.ac.jp.
authors.forename: Nobuo
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authors.affiliation: Laboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan. tokucox@nihs.go.jp.
authors.forename: Tokuyuki
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authors.affiliation: Laboratory of Biopharmaceutical Research, National Institute of Biomedical Innovation, 7-6-8 Saitoasagi, Ibaraki, Osaka, 567-0085, Japan. knagano@nibio.go.jp.
authors.forename: Kazuya
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authors.affiliation: Laboratory of Biopharmaceutical Research, National Institute of Biomedical Innovation, 7-6-8 Saitoasagi, Ibaraki, Osaka, 567-0085, Japan. kamada@nibio.go.jp.|The Center for Advanced Medical Engineering and Informatics, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan. kamada@nibio.go.jp.
authors.forename: Haruhiko
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authors.affiliation: Laboratory of Biopharmaceutical Research, National Institute of Biomedical Innovation, 7-6-8 Saitoasagi, Ibaraki, Osaka, 567-0085, Japan. tsunoda@nibio.go.jp.|The Center for Advanced Medical Engineering and Informatics, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan. tsunoda@nibio.go.jp.
authors.forename: Shin-ichi
authors.initials: S
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authors.affiliation: Laboratory of Environmental Pharmacometrics, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan. ttakagi@phs.osaka-u.ac.jp.|Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan. ttakagi@phs.osaka-u.ac.jp.
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authors.affiliation: Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation, 7-6-8 Saitoasagi, Ibaraki, Osaka, 567-0085, Japan. kenishii@biken.osaka-u.ac.jp.|Laboratory of Vaccine Science, Immunology Frontier Research Center, World Premier International Research Center, Osaka University, 3-1 Suita, Osaka, 565-0871, Japan. kenishii@biken.osaka-u.ac.jp.
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Ishii
authors.affiliation: Division of Foods, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan. nabeshi@nihs.go.jp.
authors.forename: Hiromi
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authors.affiliation: Laboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan. blackpug.9689@gmail.com.
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authors.affiliation: Laboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan.|Laboratory of Biopharmaceutical Research, National Institute of Biomedical Innovation, 7-6-8 Saitoasagi, Ibaraki, Osaka, 567-0085, Japan.
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authors.affiliation: Laboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan. ytsutsumi@phs.osaka-u.ac.jp.|Laboratory of Innovative Antibody Engineering and Design, Center for Drug Innovation and Screening, National Institute of Biomedical Innovation, 7-6-8 Saitoasagi, Ibaraki, Osaka, 567-0085, Japan. ytsutsumi@phs.osaka-u.ac.jp.|The Center for Advanced Medical Engineering and Informatics, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan. ytsutsumi@phs.osaka-u.ac.jp.
authors.forename: Yasuo
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mesh_terms: D000707:Anaphylaxis / Q000097:blood / Q000276:immunology*; D000818:Animals; D039741:Antigens, Dermatophagoides; D016207:Cytokines / Q000097:blood / Q000276:immunology; D017449:Dermatitis, Allergic Contact / Q000097:blood / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D051379:Mice; D053758:Nanoparticles; D018570:Risk Assessment; D012822:Silicon Dioxide; D012867:Skin / Q000276:immunology* / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: D039741:Antigens, Dermatophagoides; D016207:Cytokines; D007074:Immunoglobulin G; D007073:Immunoglobulin E; D012822:Silicon Dioxide