Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 212, Issue 4, Pages 457-467Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20142182
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Funding
- National Institutes of Health [U19AI095261, 1K22AI091684, R01CA150975, K01DK093597, RO1AI075037]
- Harvard Digestive Diseases Center [P30DK034854]
- Mizutani Foundation for Glycoscience Research Grant
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Immunoglobulin epsilon (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, Fc epsilon RI. 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 (C epsilon 3) 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 Fc epsilon RI, rendering IgE incapable of eliciting mast cell degranulation, thereby preventing anaphylaxis. These results underscore an unappreciated and essential requirement of glycosylation in IgE biology.
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