Introduction:
IgE and its effector cells, such as basophils and mast cells, help
eradicate pathogens, like parasites and helminths, as well as degrading
venoms. However, type I hypersensitivity disorders are also IgE
mediated. IgE binds with high affinity to the FceRI receptor on effector
cells. The cross-linking of bound IgE antibodies by antigens leads to
the activation and degranulation of effector cells, resulting in an
inflammatory response and the associated typical allergic symptoms.
Since approximately one-third of the world’s population suffers from
allergic disease, it is crucial to know how levels of IgE are regulated.
Unfortunately, the mechanisms of how the body regulates IgE are poorly
understood. An important feature of IgE regulation is its short serum
half-life of 2-2.5 days compared to serum IgG, which has a half-life of
about three weeks in humans. The two Fc receptors for IgE, FcεRI and
FcεRII (CD23), have been shown to regulate IgE serum levels.
Additionally, the synthesis of new IgE antibodies is negatively
regulated by CD23 on B cells10,11. IgE is the most
glycosylated antibody, but the role of IgE-glycans in their serum
regulation is poorly understood. Glycosylation, required for antibody
maturation and effector function, has been shown to affect IgE function.
Crystal structures of human IgEs have revealed seven and nine
N-glycosylation sites for human and mice constant epsilon chains,
respectively. Recently, Shade et al. have provided insights into the
role of IgE glycosylation in allergic diseases. They showed that IgE
from peanut-allergic individuals has more sialic acid than non-atopic
individuals and that removal of sialic acids leads to an attenuation of
effector cell degranulation, contributing thereby to the effector
function of IgE. The same group also demonstrated that a conserved
oligomannose attached to N394 on the human Cε3 domain is essential for
binding to the FcεRI.
In mice, the equivalent of N394 is N384. Consistent with the findings in
humans, IgE mutated or lacking oligomannose could not elicit an
anaphylactic reaction in a passive cutaneous anaphylaxis mouse model. In
addition to endogenous regulation, external factors like anti-IgE IgG
antibodies also influence IgE levels. For example, the monoclonal
anti-IgE antibody omalizumab got approval for moderate to severe
persistent asthma, chronic idiopathic urticaria, and nasal polyps and
has shown clinical efficacy in these diseases. Omalizumab might also be
effective in other allergic conditions like food allergies.
Mechanistically, omalizumab acts primarily by neutralizing free serum
IgE but also disrupts IgE:FcεRI complexes. As a result, less IgE is
bound by FcεRI on effector cells over time, preventing their
IgE-dependent activation.
Interestingly, the body can produce anti-IgE IgG antibodies itself.
Atopic and healthy individuals express endogenous anti-IgE IgG
antibodies, which may define another way of IgE regulation. Although the
presence of these antibodies has been known for a long time, their
function is still enigmatic. Anti-IgE IgG antibodies can potentially
activate effector cells by cross-linking FcεRI-bound IgE and thus lead
to an anaphylactic reaction. On the other hand, they also have
beneficial effects by reducing type I allergic reactions. The induction
of anti-IgE antibodies significantly suppresses total and
antigen-specific IgE responses. CD23 may also play a role in the
mechanism of action of IgG and IgE antibodies. Indeed IgE immune
complexes bind better to CD23 than IgE alone, which might also increase
the protection of CD23 from being enzymatically cleaved. Recently, our
group has shown that immunizing mice with IgE in a complex with an
allergen can induce glycan-dependent anti-IgE IgG antibodies. These mice
were protected from challenges with different allergens. However, it was
unclear whether glycans on IgE antibodies are responsible for that
protection and how they promote IgE clearance. Here we performed passive
immunization with glycan-specific and non-glycan-specific IgG anti-IgE
autoantibodies and investigated differences between anti-IgE IgG
antibodies in IgE clearance and protection upon allergen challenges,
concluding that glycans are critical for IgG anti-IgE mediated
protection.