Immunoglobulin E (IgE) is a type ofantibody (orimmunoglobulin (Ig) "isoform") that has been found only inmammals. IgE is synthesised byplasma cells. Monomers of IgE consist of two heavy chains (ε chain) and two light chains, with the ε chain containing four Ig-like constant domains (Cε1–Cε4).[1] IgE is thought to be an important part of theimmune response against infection by certainparasitic worms, includingSchistosoma mansoni,Trichinella spiralis,[2][3] andFasciola hepatica.[4] IgE is also utilized during immune defense against certainprotozoanparasites such asPlasmodium falciparum.[5] IgE may have evolved as a defense to protect against venoms.[6][7][8]
IgE also has an essential role intype I hypersensitivity,[9] which manifests in various allergic diseases, such as allergicasthma, most types ofsinusitis,allergic rhinitis, food allergies, and specific types ofchronic urticaria andatopic dermatitis. IgE also plays a pivotal role in responses to allergens, such asanaphylactic reactions to drugs, bee stings, and antigen preparations used in desensitizationimmunotherapy.
IgE is typically the least abundant isotype:blood serum IgE levels in a non-atopic individual are less than 0.0001% of the total Ig concentration,[10] compared to 75% for theIgGs at 10 mg/ml. Despite this, it is capable of triggeringanaphylaxis, one of the most rapid and severe immunological reactions.[11]
IgE was simultaneously discovered in 1966 and 1967 by two independent groups:[12] byKimishige Ishizaka and his wifeTeruko Ishizaka at the Children's Asthma Research Institute and Hospital inDenver,Colorado,[13] and byGunnar Johansson andHans Bennich [sv] inUppsala,Sweden.[14] Their joint paper was published in April 1969.[15]
IgE primes the IgE-mediated allergic response by binding toFc receptors found on the surface ofmast cells andbasophils. Fc receptors are also found oneosinophils,monocytes,macrophages andplatelets in humans. There are two types of Fcε receptors:[citation needed]
IgE can upregulate the expression of both types of Fcε receptors. FcεRI is expressed on mast cells, basophils, and the antigen-presentingdendritic cells in both mice and humans. Binding ofantigens 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 todegranulation (the release of mediators) and the secretion of several types of type 2cytokines likeinterleukin(IL)-3 andstem cell factor (SCF), which both help the mast cells survive and accumulate in tissue, andIL-4,IL-5,IL-13, andIL-33, which in turn activate group 2-innate lymphoid cells (ILC2 or natural helper cells). Basophils share a common haemopoietic progenitor with mast cells; upon the cross-linking of their surface bound IgE by antigens, also release type 2 cytokines, including IL-4 and IL-13, and other inflammatory mediators. The low-affinity receptor (FcεRII) is always expressed onB cells; but IL-4 can induce its expression on the surfaces of macrophages, eosinophils, platelets, and someT cells.[16][17]
The IgE isotype has co-evolved with basophils and mast cells in the defence against parasites like helminths (like Schistosoma) but may be also effective in bacterial infections.[18]Epidemiological research shows that IgE level is increased when infected bySchistosoma mansoni,[19]Necator americanus,[20] andnematodes[21] in humans. It is most likely beneficial in removal of hookworms from the lung.[citation needed]
In 1981Margie Profet suggested that allergic reactions have evolved as a last line of defense to protect againstvenoms.[6] Although controversial at the time, new work supports some of Profet's thoughts on the adaptive role of allergies as a defense against noxious toxins.[7]
In 2013 it emerged that IgE-antibodies play an essential role in acquired resistance tohoney bee[8] andRussell's viper venoms.[8][22] The authors concluded that "a small dose of bee venom conferred immunity to a much larger, fatal dose" and "this kind of venom-specific, IgE-associated, adaptive immune response developed, at least in evolutionary terms, to protect the host against potentially toxic amounts of venom, such as would happen if the animal encountered a whole nest of bees, or in the event of a snakebite".[8][23][24] The major allergen of bee venom (phospholipase A2) induces aTh2 immune responses, associated with production of IgE antibodies, which may "increase the resistance of mice to challenge with potentially lethal doses".[25]
Although it is not yet well understood, IgE may play an important role in the immune system's recognition ofcancer,[26] 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 asomalizumab (for allergies) 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.[27]
Atopic individuals can have up to ten times the normal level of IgE in their blood (as do sufferers ofhyper-IgE syndrome). 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.[28]
IgE that can specifically recognise anallergen (typically this is a protein, such asdust miteDer p 1, catFel d 1, grass orragweed pollen, food protein, etc.) has a unique long-lived interaction with its high-affinityreceptor FcεRI so thatbasophils andmast cells, capable of mediating inflammatory reactions, become "primed", ready to release chemicals likehistamine,leukotrienes, and certain interleukins. These chemicals cause many of the symptoms we associate with allergy, such as airway constriction inasthma, local inflammation ineczema, increasedmucus secretion inallergic 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 inanaphylaxis.[citation needed]
IgE is known to be elevated in various autoimmune disorders such asSLE,rheumatoid arthritis (RA), andpsoriasis, and is theorized to be of pathogenetic importance in SLE and RA by eliciting a hypersensitivity reaction.[29][30]
Regulation of IgE levels through control of B cell differentiation to antibody-secretingplasma cells is thought to involve the "low-affinity" receptor FcεRII, orCD23.[31]CD23 may also allow facilitated antigen presentation, an IgE-dependent mechanism wherebyB cells expressingCD23 are able to present allergen to (and stimulate) specificT helper cells, causing the perpetuation of a Th2 response, one of the hallmarks of which is the production of more antibodies.[32]
Diagnosis of allergy is most often done by reviewing a person's medical history and finding a positive result for the presence of allergen specific IgE when conducting a skin or blood test.[33] Specific IgE testing is the proven test for allergy detection; evidence does not show that indiscriminate IgE testing or testing for immunoglobulin G (IgG) can support allergy diagnosis.[34]
Currently, allergic diseases and asthma are usually treated with one or more of the following drugs: (1)antihistamines andantileukotrienes, which antagonize the inflammatory mediators histamine and leukotrienes, (2) local or systemic (oral or injectable)corticosteroids, which suppress a broad spectrum of inflammatory mechanisms, (3) short or long-actingbronchodilators, which relax smooth muscle of constricted airway in asthma, or (4)mast cell stabilizers, which inhibit thedegranulation of mast cells that is normally triggered by IgE-binding atFcεRI. Long-term uses of systemic corticosteroids are known to cause many serious side effects and are advisable to avoid, if alternative therapies are available.[citation needed]
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 (mIgE) 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.[35] Two approaches targeting the IgE pathway were evolved and both are in active development. In the first approach, theanti-IgE antibody drugomalizumab (trade nameXolair) 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[36] and the U. S.[37] for treatingchronic 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' (M1 prime), 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.[38][39] An anti-M1' humanized antibody,quilizumab, is in phase IIb clinical trial.[40][41]
In 2002, researchers at theRandall Division of Cell and Molecular Biophysics determined the structure of IgE.[42] Understanding of this structure (which is atypical of other isotypes in that it is highly bent and asymmetric) 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 (for instance, small molecule drugs) that use a similar approach to inhibit binding of IgE to its receptor.[citation needed]
{{cite journal}}: CS1 maint: multiple names: authors list (link)
