Immunoglobulin E is a class of antibody "isotype") that has been found only in mammals. IgE exists
as monomers consisting of two heavy chains and two light chains, with the ε chain containing
4 Ig-like constant domains. IgE's main function is immunity to parasites such as parasitic
worms like Schistosoma mansoni, Trichinella spiralis, and Fasciola hepatica. IgE may also
be important during immune defense against certain protozoan parasites such as Plasmodium
falciparum. IgE also plays an essential role in type I
hypersensitivity, which manifests various allergic diseases, such as allergic asthma,
most types of sinusitis, allergic rhinitis, food allergy, and some types of chronic urticaria
and atopic dermatitis. IgE also plays a pivotal role in allergic conditions, such as anaphylactic
reactions to certain drugs, bee stings, and antigen preparations used in specific desensitization
immunotherapy. Although IgE is typically the least abundant
isotype—blood serum IgE levels in a normal individual are only 0.05% of the Ig concentration,
compared to 75% for the IgGs at 10 mg/ml, which are the isotypes responsible for most
of the classical adaptive immune response—it is capable of triggering the most powerful
inflammation reactions. IgE was discovered in 1966 by the Japanese
scientist couple Teruko and Kimishige Ishizaka.
Receptors IgE primes the IgE-mediated allergic response
by binding to Fc receptors found on the surface of mast cells and basophils. Fc receptors
are also found on eosinophils, monocytes, macrophages and platelets in humans. There
are two types of Fcε receptors: FcεRI, the high-affinity IgE receptor
FcεRII, also known as CD23, the low-affinity IgE receptor
IgE can upregulate the expression of both types of Fcε receptors. FcεRI is expressed
on mast cells, basophils, and the antigen-presenting dendritic cells in both mice and humans. Binding
of antigens to IgE already bound by the FcεRI on mast cells causes cross-linking of the
bound IgE and the aggregation of the underlying FcεRI, leading to the degranulation and the
release of mediators from the cells. Basophils, upon the cross-linking of their surface IgE
by antigens, release type 2 cytokines like interleukin-4 and interleukin-13 and other
inflammatory mediators. The low-affinity receptor is always expressed on B cells, but its expression
can be induced on the surfaces of macrophages, eosinophils, platelets, and some T cells by
IL-4. Physiology
There is much speculation into what physiological benefits IgE contributes, and, so far, circumstantial
evidence in animal models and statistical population trends have hinted that IgE may
be beneficial in fighting gut parasites such as Schistosoma mansoni, but this has not been
conclusively proven in humans. It is most likely beneficial in removal of hookworms
from the lung. Although it is not yet well understood, IgE
may play an important role in the immune system’s recognition of cancer, in which the stimulation
of a strong cytotoxic response against cells displaying only small amounts of early cancer
markers would be beneficial. If this were the case, anti-IgE treatments such as omalizumab
might have some undesirable side effects. However, a recent study, which was performed
based on pooled analysis using comprehensive data from 67 phase I to IV clinical trials
of omalizumab in various indications, concluded that a causal relationship between omalizumab
therapy and malignancy is unlikely. Role in disease
Atopic individuals can have up to 10 times the normal level of IgE in their blood. However,
this may not be a requirement for symptoms to occur as has been seen in asthmatics with
normal IgE levels in their blood - recent research has shown that IgE production can
occur locally in the nasal mucosa. IgE that can specifically recognise an "allergen"
has a unique long-lived interaction with its high-affinity receptor FcεRI so that basophils
and mast cells, capable of mediating inflammatory reactions, become "primed", ready to release
chemicals like histamine, leukotrienes, and certain interleukins. These chemicals cause
many of the symptoms we associate with allergy, such as airway constriction in asthma, local
inflammation in eczema, increased mucus secretion in allergic rhinitis, and increased vascular
permeability, it is presumed, to allow other immune cells to gain access to tissues, but
which can lead to a potentially fatal drop in blood pressure as in anaphylaxis. Although
the mechanisms of each response are fairly well understood, why some allergics develop
such drastic sensitivities when others merely get a runny nose is still one of science's
hot topics. IgE is known to be elevated in various autoimmune
disorders such as Lupus(SLE), Rheumatoid Arthritis(RA) & psoriasis, and is theorized to be of pathogenetic
importance in RA and SLE by eliciting a hypersensitivity reaction.
Regulation of IgE levels through control of B cell differentiation to antibody-secreting
plasma cells is thought to involve the "low-affinity" receptor FcεRII, or CD23. CD23 may also allow
facilitated antigen presentation, an IgE-dependent mechanism whereby B cells expressing CD23
are able to present allergen to specific T helper cells, causing the perpetuation of
a Th2 response, one of the hallmarks of which is the production of more antibodies.
Role in diagnosis Diagnosis of allergy is most often done when
a physician reviews a patient's history and finds a positive result for the presence of
allergen specific IgE when conducting a skin or blood test. Specific IgE testing is the
proven test for allergy detection; evidence does not show that indiscriminate IgE testing
or testing for immunoglobulin G can support allergy diagnosis.
Drugs targeting the IgE pathway Currently, allergic diseases and asthma are
usually treated with one or more of the following drugs: antihistamines and antileukotrienes,
which antagonize the inflammatory mediators histamine and leukotrienes, local or systemic
corticosteroids, which suppress a broad spectrum of inflammatory mechanisms, and short or long-acting
bronchodilators, which relax smooth muscle of constricted airway in asthma. Long-term
uses of systemic corticosteroids are known to cause many serious side effects and are
advisable to avoid, if alternative therapies are available.
IgE, the IgE synthesis pathway, and the IgE-mediated allergic/inflammatory pathway are all important
targets in intervening with the pathological processes of allergy, asthma, and other IgE-mediated
diseases. The B lymphocyte differentiation and maturation pathway that eventually generate
IgE-secreting plasma cells go through the intermediate steps of IgE-expressing B lymphoblasts
and involves the interaction with IgE-expressing memory B cells. Tanox, a biotech company based
in Houston, Texas, proposed in 1987 that by targeting membrane-bound IgE on B lymphoblast
and memory B cells, those cells can be lysed or down-regulated, thus achieving the inhibition
of the production of antigen-specific IgE and hence a shift of immune balance toward
non-IgE mechanisms. Two approaches targeting the IgE pathway were evolved and both are
in active development. In the first approach, the anti-IgE antibody drug omalizumab recognises
IgE not bound to its receptors and is used to neutralise or mop-up existing IgE and prevent
it from binding to the receptors on mast cells and basophils. Xolair has been approved in
many countries for treating severe, persistent allergic asthma. It has also been approved
in March 2014 in the European Union and the U. S. for treating chronic spontaneous urticaria,
which cannot be adequately treated with H1-antihistamines. In the second approach, antibodies specific
for a domain of 52 amino acid residues, referred to as CεmX or M1’, present only on human
mIgE on B cells and not on free, soluble IgE, have been prepared and are under clinical
development for the treatment of allergy and asthma. An anti-M1’ humanized antibody,
quilizumab, is in phase IIb clinical trial. In 2002, researchers at The Randall Division
of Cell and Molecular Biophysics determined the structure of IgE. Understanding of this
structure and of the interaction of IgE with receptor FcεRI will enable development of
a new generation of allergy drugs that seek to interfere with the IgE-receptor interaction.
It may be possible to design treatments cheaper than monoclonal antibodies that use a similar
approach to inhibit binding of IgE to its receptor.
References
External links Slide presentation of Degranulation processes