title: A single glycan on IgE is indispensable for initiation of anaphylaxis.
abstract: Immunoglobulin ε (IgE) antibodies are the primary mediators of allergic diseases, which affect more than 1 in 10 individuals worldwide. IgE specific for innocuous environmental antigens, or allergens, binds and sensitizes tissue-resident mast cells expressing the high-affinity IgE receptor, FcεRI. Subsequent allergen exposure cross-links mast cell-bound IgE, resulting in the release of inflammatory mediators and initiation of the allergic cascade. It is well established that precise glycosylation patterns exert profound effects on the biological activity of IgG. However, the contribution of glycosylation to IgE biology is less clear. Here, we demonstrate an absolute requirement for IgE glycosylation in allergic reactions. The obligatory glycan was mapped to a single N-linked oligomannose structure in the constant domain 3 (Cε3) of IgE, at asparagine-394 (N394) in human IgE and N384 in mouse. Genetic disruption of the site or enzymatic removal of the oligomannose glycan altered IgE secondary structure and abrogated IgE binding to FcεRI, rendering IgE incapable of eliciting mast cell degranulation, thereby preventing anaphylaxis. These results underscore an unappreciated and essential requirement of glycosylation in IgE biology.
authors.affiliation: Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.
authors.forename: Kai-Ting C
authors.initials: KT
authors.lastname: Shade
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115 Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
authors.forename: Barbara
authors.initials: B
authors.lastname: Platzer
authors.affiliation: Momenta Pharmaceuticals, Cambridge, MA 02142.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Washburn
authors.affiliation: Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.
authors.forename: Vinidhra
authors.initials: V
authors.lastname: Mani
authors.affiliation: Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.
authors.forename: Yannic C
authors.initials: YC
authors.lastname: Bartsch
authors.affiliation: Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.
authors.forename: Michelle
authors.initials: M
authors.lastname: Conroy
authors.affiliation: Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.
authors.forename: Jose D
authors.initials: JD
authors.lastname: Pagan
authors.affiliation: Momenta Pharmaceuticals, Cambridge, MA 02142.
authors.forename: Carlos
authors.initials: C
authors.lastname: Bosques
authors.affiliation: Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.
authors.forename: Thorsten R
authors.initials: TR
authors.lastname: Mempel
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115 Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
authors.forename: Edda
authors.initials: E
authors.lastname: Fiebiger
authors.affiliation: Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129 robert.anthony@mgh.harvard.edu.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Anthony
mesh_terms: D000707:Anaphylaxis / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D015550:Cell Degranulation / Q000235:genetics / Q000276:immunology*; D006031:Glycosylation; D006801:Humans; D007127:Immunoglobulin Constant Regions / Q000235:genetics / Q000276:immunology; D007073:Immunoglobulin E / Q000235:genetics / Q000276:immunology*; D018836:Inflammation Mediators; D008407:Mast Cells / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011134:Polysaccharides / Q000235:genetics / Q000276:immunology*; D017455:Receptors, IgE / Q000235:genetics / Q000276:immunology*
chemical_list: D007127:Immunoglobulin Constant Regions; D018836:Inflammation Mediators; D011134:Polysaccharides; D017455:Receptors, IgE; D007073:Immunoglobulin E
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