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File:IgE.jpg
Mast cells

The role of mast cells in the development of allergy.

File:Allergy degranulation processes 01.svg

Immunoglobulin E (IgE) is a class of antibody (or immunoglobulin (Ig) "isotype") that has been found only in mammals. IgE exists as monomers consisting of two heavy chains (ε chain) and two light chains, with the ε chain containing 4 Ig-like constant domains (Cε1-Cε4).[1] IgE's main function is immunity to parasites such as parasitic worms[2] like Schistosoma mansoni, Trichinella spiralis, and Fasciola hepatica.[3][4][5] IgE may also be important during immune defense against certain protozoan parasites such as Plasmodium falciparum.[6]

IgE also plays an essential role in type I hypersensitivity,[7] which manifests various allergic diseases, such as allergic asthma, 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 ("non-atopic") individual are only 0.05% of the Ig concentration,[8] compared to 10 mg/ml for the IgGs (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.[9]

ReceptorsEdit

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 (type I Fcε receptor), the high-affinity IgE receptor
  • FcεRII (type II Fcε receptor), 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 (IL-4) and interleukin-13 (IL-13) and other inflammatory mediators. The low-affinity receptor (FcεRII) 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.[citation needed]

PhysiologyEdit

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.

Although it is not yet well understood, IgE may play an important role in the immune system’s recognition of cancer,[10] 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 (for asthma) 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.[11]

Role in diseaseEdit

Atopic individuals can have up to 10 times the normal level of IgE in their blood (as do sufferers of hyper-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.[12]

IgE that can specifically recognise an "allergen" (typically this is a protein, such as dust mite Der p 1, cat Fel d 1, grass or ragweed pollen, etc.) 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.

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.[13] CD23 may also allow facilitated antigen presentation, an IgE-dependent mechanism whereby B cells expressing CD23 are able to present allergen to (and stimulate) specific T helper cells, causing the perpetuation of a Th2 response, one of the hallmarks of which is the production of more antibodies.[14]

Role in diagnosisEdit

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.[15] 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.[16]

Drugs targeting the IgE pathwayEdit

Currently, allergic diseases and asthma are usually treated with one or more of the following drugs: (1) antihistamines and antileukotrienes, which antagonize the inflammatory mediators histamine and leukotrienes, (2) local or systemic (oral or injectable) corticosteroids, which suppress a broad spectrum of inflammatory mechanisms, and (3) 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 and asthma. 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.[17] 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. Antibodies specific for a domain of 52 amino acid residues, referred to as CεmX or 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.[18][19]

In 2002, researchers at The Randall Division of Cell and Molecular Biophysics determined the structure of IgE.[20] 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.

See alsoEdit

References Edit

  1. Antibody structure: http://www.cartage.org.lb/en/themes/Sciences/LifeScience/GeneralBiology/Immunology/Recognition/AntigenRecognition/Antibodystructure/Antibodystructure.htm
  2. Erb KJ (2007). Helminths, allergic disorders and IgE-mediated immune responses: where do we stand?. Eur J Immunol 37 (5): 1170–1173.
  3. Fitzsimmons C, McBeath R, Joseph S, Jones F, Walter K, Hoffmann K, Kariuki H, Mwatha J, Kimani G, Kabatereine N, Vennervald B, Ouma J, Dunne D (2007). Factors affecting human IgE and IgG responses to allergen-like Schistosoma mansoni antigens: Molecular structure and patterns of in vivo exposure. Int. Arch. Allergy Immunol. 142 (1): 40–50.
  4. Watanabe N, Bruschi F, Korenaga M (2005). IgE: a question of protective immunity in Trichinella spiralis infection. Trends Parasitol. 21 (4): 175–178.
  5. Pfister K, Turner K, Currie A, Hall E, Jarrett EE (1983). IgE production in rat fascioliasis. Parasite Immunol 5 (6): 587–593.
  6. Duarte J, Deshpande P, Guiyedi V, Mécheri S, Fesel C, Cazenave P, Mishra G, Kombila M, Pied S (2007). Total and functional parasite specific IgE responses in Plasmodium falciparum-infected patients exhibiting different clinical status. Malar. J. 6: 1.
  7. Gould H (2003). The biology of IGE and the basis of allergic disease. Annu Rev Immunol 21: 579–628.
  8. (2000). Immunoglobulin E: importance in parasitic infections and hypersensitivity responses. Archives of pathology & laboratory medicine 124 (9): 1382–5.
  9. Ishizaka K, Ishizaka T, Hornbrook MM (1966). Physico-chemical properties of human reaginic antibody. IV. Presence of a unique immunoglobulin as a carrier of reaginic activity. J. Immunol. 97 (1): 75–85.
  10. Karagiannis S (2003). Activity of human monocytes in IgE antibody-dependent surveillance and killing of ovarian tumor cells. Eur J Immunol 33 (4): 1030–1040.
  11. Busse W, Buhl R, Fernandez Vidaurre C, Blogg M, Zhu J, Eisner MD, Canvin J (April 2012). Omalizumab and the risk of malignancy: results from a pooled analysis. J. Allergy Clin. Immunol. 129 (4): 983–9.e6.
  12. Takhar P (2005). Allergen drives class switching to IgE in the nasal mucosa in allergic rhinitis. J Immunol 174 (8): 5024–32.
  13. Conrad DH, Ford JW, Sturgill JL, Gibb DR (September 2007). CD23: an overlooked regulator of allergic disease. Curr Allergy Asthma Rep. 7 (5): 331–7.
  14. Holm J, Willumsen N, Würtzen PA, Christensen LH, Lund K (April 2011). Facilitated antigen presentation and its inhibition by blocking IgG antibodies depends on IgE repertoire complexity. J. Allergy Clin. Immunol. 127 (4): 1029–37.
  15. PMID 19119701 (PMID 19119701)
    Citation will be completed automatically in a few minutes. Jump the queue or expand by hand
  16. American Academy of Allergy, Asthma, and Immunology, Five Things Physicians and Patients Should Question, American Academy of Allergy, Asthma, and Immunology, http://choosingwisely.org/wp-content/uploads/2012/04/5things_12_factsheet_AAAAI.pdf, retrieved on August 14, 2012 
  17. Chang TW, Wu PC, Hsu CL, Hung AF (2007). Anti-IgE antibodies for the treatment of IgE-mediated allergic diseases. Adv Immunol. 93: 63–119.
  18. Chen JB, Wu PC, Hung AF, Chu CY, Tsai TF, Yu HM, Chang HY, Chang TW (February 2010). Unique epitopes on C epsilon mX in IgE-B cell receptors are potentially applicable for targeting IgE-committed B cells. J Immunol. 184 (4): 1748–56.
  19. Brightbill HD, Jeet S, Lin Z, Yan D, Zhou M, Tan M, Nguyen A, Yeh S, Delarosa D, Leong SR, Wong T, Chen Y, Ultsch M, Luis E, Ramani SR, Jackman J, Gonzalez L, Dennis MS, Chuntharapai A, DeForge L, Meng YG, Xu M, Eigenbrot C, Lee WP, Refino CJ, Balazs M, Wu LC (June 2010). Antibodies specific for a segment of human membrane IgE deplete IgE-producing B cells in humanized mice. J Clin Invest. 120 (6): 2218–29.
  20. Wan T (2002). The crystal structure of IgE Fc reveals an asymmetrically bent conformation. Nat Immunol 3 (7): 681–686.



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