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Immunoglobulin (Ig) E antibodies are heterotetrameric glycoproteins.
They are formed by two antigen-binding fragments (Fab) and a
fragment crystallizable region
(Fc) (1) with seven N-linked glycosylation sites distributed across the
heavy chains.(2, 3) Allergen cross-linking of IgE bound to high affinity
IgE-receptors (i.e. , FcεRI) on mast cells (MCs) and basophils
induces the release of mediators that cause allergic symptoms.(4)
However, it is largely unknown why patients present a broad spectrum of
clinical manifestations and, paradoxically, why many individuals produce
allergen-specific IgE without developing allergic symptoms. This
indicates that relevant information is still missing about IgE
functionality.
Glycosylation is required for proper antibody maturation and determines
the specific biological properties of each antibody class (e.g.,antigen affinity, Fc receptor binding, downstream immunological
activity).(1) Data in cancer and autoimmunity show that glycosylation
affects the interaction between Igs and its receptors, thus modulating
the pro- or anti-inflammatory properties of Igs in disease-specific
patterns.(1) Significantly less is known about the role of IgE
glycosylation in allergy.(1) Niki et al . found that Galectin-9, a
lectin expressed by several MCs, suppressed effector cell degranulation
by binding to IgE glycans.(5) Furthermore, Shade et al.identified a single glycan in the IgE C3 domain that was essential for
triggering anaphylaxis in mice and LAD2 cells (a MC line that derived
from a mastocytosis patient).(6) However, the precise mechanisms of this
interaction were not fully understood. Recent data by Shade et
al . provide novel insights on how IgE glycosylation determines
disease-specific allergic responses.(7)
Shade et al . recently studied the IgE glycosylation pattern of
peanut-allergic individuals and non-atopic donors (Figure 1). Human LAD2
MCs were sensitized with serum IgE from these two cohorts and activated
by anti-IgE crosslinking. MCs sensitized with IgE from non-atopic
individuals degranulated less as compared to MCs sensitized with IgE
from peanut-allergic patients. Using glycopeptide mass spectrometry,
they determined that certain IgE glycosylation sites (N140- and
N265-linked complex glycans terminating in galactose) were enriched in
IgE from non-atopic subjects while terminal sialic acids were enriched
at the N168 and N265 IgE glycosylation sites in peanut-allergic
subjects. By analysing the glycan content of IgE from non-atopic and
peanut-allergic subjects, they demonstrated that the galactose and
sialic acid contents of IgE constituted strong predictors of allergic
disease.(7)
In addition to studying glycosylation patterns of total IgE, Shadeet al. sought to explore the effects of sialic acid removal from
IgE. They observed an attenuation of effector cell degranulation usingin vivo and in vitro models (Figure 1). Interestingly,
they showed that allergen bound to asialylated IgE did not activate MCs.
These results suggest that the removal of sialic acid from IgE may
expose an inhibitory glycan that reduces signalling downstream the FcεRI
receptor. Using in vivo models, they assessed the therapeutic
potential of modulating sialic acid content. By fusing a neuraminidase
enzyme towards the N terminus of IgE Fc Cε2–4 domains to remove sialic
acid from IgE-bearing cells, they showed an attenuation of
allergen-induced anaphylaxis. (7) (Figure 1) These findings provide
evidence for the possibility for new therapeutic strategies targeting
IgE sialylation to regulate acute allergic responses. Moreover, the role
of glycosylation in allergic reactions appears to extend beyond IgE. A
recent study by Petry et al. assessed the impact of IgG
glycosylation in anaphylaxis. Their data suggests that enriched blood
IgG Fc N-sialylation may regulate the expression of the inhibitory
receptor FcγRIIB and protect from IgG-mediated and
IgG-FcγRIIB–controlled-IgE-mediated allergic reactions.(8)
In summary, Shade et al . provide new compelling insights into the
glycobiology of IgE and its effect on allergic responses. Modification
of IgE glycosylation patterns could potentially lead to a reduction in
the severity of allergic reactions, including anaphylaxis. Sialylation
and desialylation may well present a promising diagnostic and treatment
strategy for peanut allergy and other IgE-mediated allergic diseases but
also to empower the protective inflammatory function of IgE in other
pathologies.(9)
Figure 1. Increased terminal sialylation is detected on
allergic IgE and galactose on non-atopic IgE. Compared to
sialylated-human-IgE-sensitized MCs, asialylated-human-IgE-sensitized
MCs showed a reduced degranulation following allergen challenge.
Sensitization to asialylated-mouse-IgE produced a reduced temperature
loss following a challenge. In vitro , sensitized MCs with
OVA-specific sialylated-human-IgE were incubated with NEUFcε, or an IgE
isotype control, and challenged with OVA. NEUFcε reduced OVA-induced
degranulation. In vivo, NEUFcε treatment of mice sensitized with
asialylated-mouse-IgE showed a reduced temperature drop after a
challenge, compared to those with sialylated-mouse-IgE. Ig,
Immunoglobulin; MC, mast cells; NEUFcε, neuraminidase enzyme towards the
N terminus of IgE Fc; OVA, ovalbumin.