Project Summary/Abstract
It is not clear why some individuals with allergen-specific IgE suffer from allergies, while others do not. It is likely
that multiple factors contribute, including differences in IgE affinity or epitope diversity for allergens, mast cell
numbers, FceRI expression levels, Syk signaling, allergen-specific IgG antibodies, and anti-IgE antibodies. An
addition factor that has not been considered is the contribution of differences in IgE constant chains, and specific
its glycosylation. We recently compared the N-linked glycans on IgE from peanut allergic and non-allergic adults
and found reduced sialic acid on complex biantennary glycans of non-allergic IgE. Further, removal of sialic acid
from IgE resulted in markedly reduced anaphylaxis in both human and murine models. Our long-term goal is to
understand how glycosylation of antibodies regulates, and is regulated, by immune responses. Our central
hypothesis is that specific glycan on IgE lacking sialic acid engage an inhibitory receptor that attenuates mast
cell and basophil degranulation. Indeed, this is supported by preliminary data shown in this application. The
rationale for our studies is that determining how IgE lacking sialic acid is attenuated will identify novel pathways
that regulate allergic disease, identify novel therapeutic targets for atopic diseases, establish IgE glycosylation
patterns as biomarkers for disease, and rewriting the dogma of IgE biology. We will test our central hypothesis
and, thereby, attain the objective of this application by pursuing the following two specific aims: 1) Define the
inhibitory glycan structure on IgE that is exposed following sialic acid removal; 2) Determine how removing sialic
acid from IgE leads to its attenuation. Using an approach that combines biophysics, biochemistry cellular and
molecular immunology, and glycobiology, we will determine how IgE lacking sialic acid is attenuated, define a
novel anti-anaphylactic pathway, establish pathogenic IgE glycosylation patterns, and attenuate anaphylaxis by
modulating IgE glycans. In addition to enabling discovery of biomarkers marking allergy-causing IgE, the studies
here will potentially result in identification of novel therapeutic targets for allergic disease. Finally, these studies
will have impact beyond allergy in diseases in which IgE is involved, including systemic lupus erythematosus
(SLE) and helminth infection.