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.