title: Exposure to food allergens through inflamed skin promotes intestinal food allergy through the thymic stromal lymphopoietin-basophil axis.
abstract: BACKGROUND
  Exposure to food allergens through a disrupted skin barrier has been recognized as a potential factor in the increasing prevalence of food allergy.
  
  
  OBJECTIVE
  We sought to test the immunologic mechanisms by which epicutaneous sensitization to food allergens predisposes to intestinal food allergy.
  
  
  METHODS
  Mice were epicutaneously sensitized with ovalbumin or peanut on an atopic dermatitis-like skin lesion, followed by intragastric antigen challenge. Antigen-specific serum IgE levels and T(H)2 cytokine responses were measured by ELISA. Expression of type 2 cytokines and mast cell proteases in the intestine were measured by using real-time PCR. Accumulation of basophils in the skin and mast cells in the intestine was examined by using flow cytometry. In vivo basophil depletion was achieved by using diphtheria toxin treatment of Baso-DTR mice. For cell-transfer studies, the basophil population was expanded in vivo by means of hydrodynamic tail vein injection of thymic stromal lymphopoietin (TSLP) cDNA plasmid.
  
  
  RESULTS
  Sensitization to food allergens through an atopic dermatitis-like skin lesion is associated with an expansion of TSLP-elicited basophils in the skin that promote antigen-specific T(H)2 cytokine responses, increased antigen-specific serum IgE levels, and accumulation of mast cells in the intestine, promoting the development of intestinal food allergy. Critically, disruption of TSLP responses or depletion of basophils reduced the susceptibility to intestinal food allergy, whereas transfer of TSLP-elicited basophils into intact skin promoted disease.
  
  
  CONCLUSIONS
  Epicutaneous sensitization on a disrupted skin barrier is associated with accumulation of TSLP-elicited basophils, which are necessary and sufficient to promote antigen-induced intestinal food allergy.
authors.affiliation: Department of Microbiology, University of Pennsylvania, Philadelphia, Pa; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa; Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Mario
authors.initials: M
authors.lastname: Noti
authors.affiliation: Department of Microbiology, University of Pennsylvania, Philadelphia, Pa; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa; Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Kim
authors.affiliation: Department of Microbiology, University of Pennsylvania, Philadelphia, Pa; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Siracusa
authors.affiliation: Department of Microbiology, University of Pennsylvania, Philadelphia, Pa; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Rak
authors.affiliation: Laboratory for Cytokine Regulation, Research Center for Integrative Medical Science, RIKEN Yokohama Institute, Kanagawa, Japan; Division of Molecular Pathology, Research Institute for Biomedical Science, Tokyo University of Science, Chiba, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
authors.forename: Amin E
authors.initials: AE
authors.lastname: Moghaddam
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
authors.forename: Quentin A
authors.initials: QA
authors.lastname: Sattentau
authors.affiliation: Inflammation Research, Amgen, Seattle, Wash.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Comeau
authors.affiliation: Department of Pediatrics, Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, Pa.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Spergel
authors.affiliation: Department of Microbiology, University of Pennsylvania, Philadelphia, Pa; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa; Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pa. Electronic address: dartis@mail.med.upenn.edu.
authors.forename: David
authors.initials: D
authors.lastname: Artis
mesh_terms: D000485:Allergens / Q000276:immunology*; D000818:Animals; D001491:Basophils / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D003876:Dermatitis, Atopic / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005512:Food Hypersensitivity / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007073:Immunoglobulin E / Q000235:genetics / Q000276:immunology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000276:immunology*; D008407:Mast Cells / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D012867:Skin / Q000276:immunology / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D000485:Allergens; D016207:Cytokines; D007073:Immunoglobulin E; D000094632:Thymic Stromal Lymphopoietin; C000721967:TSLP protein, mouse
keywords: Food allergy; IgE; atopic dermatitis; basophils; epicutaneous sensitization; mast cells; thymic stromal lymphopoietin