title: Dendritic cell-bound IgE functions to restrain allergic inflammation at mucosal sites.
abstract: Antigen-mediated cross-linking of Immunoglobulin E (IgE) bound to mast cells/basophils via FcɛRI, the high affinity IgE Fc-receptor, is a well-known trigger of allergy. In humans, but not mice, dendritic cells (DCs) also express FcɛRI that is constitutively occupied with IgE. In contrast to mast cells/basophils, the consequences of IgE/FcɛRI signals for DC function remain poorly understood. We show that humanized mice that express FcɛRI on DCs carry IgE like non-allergic humans and do not develop spontaneous allergies. Antigen-specific IgE/FcɛRI cross-linking fails to induce maturation or production of inflammatory mediators in human DCs and FcɛRI-humanized DCs. Furthermore, conferring expression of FcɛRI to DCs decreases the severity of food allergy and asthma in disease-relevant models suggesting anti-inflammatory IgE/FcɛRI signals. Consistent with the improved clinical parameters in vivo, antigen-specific IgE/FcɛRI cross-linking on papain or lipopolysaccharide-stimulated DCs inhibits the production of pro-inflammatory cytokines and chemokines. Migration assays confirm that the IgE-dependent decrease in cytokine production results in diminished recruitment of mast cell progenitors; providing a mechanistic explanation for the reduced mast cell-dependent allergic phenotype observed in FcɛRI-humanized mice. Our study demonstrates a novel immune regulatory function of IgE and proposes that DC-intrinsic IgE signals serve as a feedback mechanism to restrain allergic tissue inflammation.
authors.affiliation: Division of Gastroenterology and Nutrition, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: B
authors.initials: B
authors.lastname: Platzer
authors.affiliation: Division of Gastroenterology, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: K
authors.initials: K
authors.lastname: Baker
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Vera
authors.affiliation: Division of Gastroenterology and Nutrition, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: K
authors.initials: K
authors.lastname: Singer
authors.affiliation: Division of Gastroenterology and Nutrition, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: M
authors.initials: M
authors.lastname: Panduro
authors.affiliation: Division of Gastroenterology and Nutrition, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: W S
authors.initials: WS
authors.lastname: Lexmond
authors.affiliation: Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: D
authors.initials: D
authors.lastname: Turner
authors.affiliation: Departments of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: S O
authors.initials: SO
authors.lastname: Vargas
authors.affiliation: Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: J-P
authors.initials: JP
authors.lastname: Kinet
authors.affiliation: Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: D
authors.initials: D
authors.lastname: Maurer
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Baron
authors.affiliation: Division of Gastroenterology, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Blumberg
authors.affiliation: Division of Gastroenterology and Nutrition, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: E
authors.initials: E
authors.lastname: Fiebiger
mesh_terms: D000485:Allergens / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D054443:Cell Migration Assays; D002465:Cell Movement / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000737:chemistry; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D021181:Egg Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006801:Humans; D018928:Immunity, Mucosal; D007073:Immunoglobulin E / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D010206:Papain / Q000494:pharmacology; D061251:Primary Cell Culture; D011485:Protein Binding; D017455:Receptors, IgE / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction
chemical_list: D000485:Allergens; D003432:Cross-Linking Reagents; D016207:Cytokines; C543355:FcepsilonRI alpha-chain, human; D008070:Lipopolysaccharides; D017455:Receptors, IgE; D007073:Immunoglobulin E; D010047:Ovalbumin; D010206:Papain