A single glycan on IgE is indispensable for initiation of anaphylaxis

J Exp Med. 2015 Apr 6;212(4):457-67. doi: 10.1084/jem.20142182. Epub 2015 Mar 30.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anaphylaxis / genetics
  • Anaphylaxis / immunology*
  • Anaphylaxis / pathology
  • Anaphylaxis / prevention & control
  • Animals
  • Cell Degranulation / genetics
  • Cell Degranulation / immunology*
  • Glycosylation
  • Humans
  • Immunoglobulin Constant Regions / genetics
  • Immunoglobulin Constant Regions / immunology
  • Immunoglobulin E / genetics
  • Immunoglobulin E / immunology*
  • Inflammation Mediators
  • Mast Cells / immunology*
  • Mast Cells / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Polysaccharides / genetics
  • Polysaccharides / immunology*
  • Receptors, IgE / genetics
  • Receptors, IgE / immunology*

Substances

  • Immunoglobulin Constant Regions
  • Inflammation Mediators
  • Polysaccharides
  • Receptors, IgE
  • Immunoglobulin E