IgE FcεRI Receptor Signal Cascade
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Immunoglobulin E (IgE) is a type of
antibody An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...
(or
immunoglobulin An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...
(Ig) "
isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...
") that has been found only in
mammal A mammal () is a vertebrate animal of the Class (biology), class Mammalia (). Mammals are characterised by the presence of milk-producing mammary glands for feeding their young, a broad neocortex region of the brain, fur or hair, and three ...
s. IgE is synthesised by
plasma cell Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B cells and secrete large quantities of proteins called antibodies in response to being presented specific substances ca ...
s. 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). IgE is thought to be an important part of the
immune response An immune response is a physiological reaction which occurs within an organism in the context of inflammation for the purpose of defending against exogenous factors. These include a wide variety of different toxins, viruses, intra- and extracellula ...
against infection by certain
parasitic worm Parasitic worms, also known as helminths, are a polyphyletic group of large macroparasites; adults can generally be seen with the naked eye. Many are intestinal worms that are soil-transmitted and infect the gastrointestinal tract. Other par ...
s, including ''
Schistosoma mansoni A paired couple of ''Schistosoma mansoni''. ''Schistosoma mansoni'' is a water-borne parasite of humans, and belongs to the group of blood flukes (''Schistosoma''). The adult lives in the blood vessels ( mesenteric veins) near the human inte ...
'', ''
Trichinella spiralis ''Trichinella spiralis'' is a viviparous nematode parasite, occurring in rodents, pigs, bears, hyenas and humans, and is responsible for the disease trichinosis. It is sometimes referred to as the "pork worm" due to it being typically encount ...
'', and ''
Fasciola hepatica ''Fasciola hepatica'', also known as the common liver fluke or sheep liver fluke, is a parasitism, parasitic trematode (fluke (flatworm), fluke or flatworm, a type of helminth) of the class (biology), class Trematoda, phylum Platyhelminthes. It ...
''. IgE is also utilized during immune defense against certain
protozoa Protozoa (: protozoan or protozoon; alternative plural: protozoans) are a polyphyletic group of single-celled eukaryotes, either free-living or parasitic, that feed on organic matter such as other microorganisms or organic debris. Historically ...
n
parasite Parasitism is a Symbiosis, close relationship between species, where one organism, the parasite, lives (at least some of the time) on or inside another organism, the Host (biology), host, causing it some harm, and is Adaptation, adapted str ...
s such as ''
Plasmodium falciparum ''Plasmodium falciparum'' is a Unicellular organism, unicellular protozoan parasite of humans and is the deadliest species of ''Plasmodium'' that causes malaria in humans. The parasite is transmitted through the bite of a female ''Anopheles'' mos ...
''. IgE may have evolved as a defense to protect against venoms. IgE also has an essential role in
type I hypersensitivity Type I hypersensitivity (or immediate hypersensitivity), in the Hypersensitivity, Gell and Coombs classification of allergic reactions, is an allergic reaction provoked by re-exposure to a specific type of antigen referred to as an allergen. Type ...
, which manifests in various allergic diseases, such as allergic
asthma Asthma is a common long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wh ...
, most types of
sinusitis Sinusitis, also known as rhinosinusitis, is an inflammation of the mucous membranes that line the sinuses resulting in symptoms that may include production of thick nasal mucus, nasal congestion, facial congestion, facial pain, facial pressure ...
,
allergic rhinitis Allergic rhinitis, of which the seasonal type is called hay fever, is a type of inflammation in the nose that occurs when the immune system overreacts to allergens in the air. It is classified as a type I hypersensitivity reaction. Signs a ...
, food allergies, and specific types of chronic urticaria and
atopic dermatitis Atopic dermatitis (AD), also known as atopic eczema, is a long-term type of inflammation of the skin. Atopic dermatitis is also often called simply eczema but the same term is also used to refer to dermatitis, the larger group of skin conditi ...
. IgE also plays a pivotal role in responses to allergens, such as
anaphylactic Anaphylaxis (Greek: 'up' + 'guarding') is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of the use of emergency medication on site. It typically ...
reactions to drugs, bee stings, and antigen preparations used in desensitization
immunotherapy Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...
. IgE is typically the least abundant isotype:
blood serum Serum () is the fluid and solvent component of blood which does not play a role in clotting. It may be defined as blood plasma without the clotting factors, or as blood with all cells and clotting factors removed. Serum contains all proteins ex ...
IgE levels in a non-
atopic Atopy is the tendency to produce an exaggerated immunoglobulin E (IgE) immune response to otherwise harmless substances in the environment. Allergic diseases are clinical manifestations of such inappropriate, atopic responses. Atopy may have a ...
individual are less than 0.0001% of the total Ig concentration, compared to 75% for the IgGs at 10 mg/ml. Despite this, it is capable of triggering
anaphylaxis Anaphylaxis (Greek: 'up' + 'guarding') is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of the use of emergency medication on site. It typicall ...
, one of the most rapid and severe immunological reactions. __TOC__


Discovery

IgE was simultaneously discovered in 1966 and 1967 by two independent groups: by
Teruko Ishizaka was a Japanese scientist and immunologist who along with her husband Kimishige Ishizaka discovered the antibody class Immunoglobulin E (IgE) in 1966. Their work was regarded as a major breakthrough in the understanding of allergy, and for this ...
and her husband
Kimishige Ishizaka was a Japanese immunologist who, with his wife Teruko Ishizaka, discovered the antibody class Immunoglobulin E (IgE) in 1966–1967. Their work was regarded as a major breakthrough in the understanding of allergy. He was awarded the 1973 Gaird ...
at the Children's Asthma Research Institute and Hospital in
Denver Denver ( ) is a List of municipalities in Colorado#Consolidated city and county, consolidated city and county, the List of capitals in the United States, capital and List of municipalities in Colorado, most populous city of the U.S. state of ...
,
Colorado Colorado is a U.S. state, state in the Western United States. It is one of the Mountain states, sharing the Four Corners region with Arizona, New Mexico, and Utah. It is also bordered by Wyoming to the north, Nebraska to the northeast, Kansas ...
, and by Gunnar Johansson and in
Uppsala Uppsala ( ; ; archaically spelled ''Upsala'') is the capital of Uppsala County and the List of urban areas in Sweden by population, fourth-largest city in Sweden, after Stockholm, Gothenburg, and Malmö. It had 177,074 inhabitants in 2019. Loc ...
,
Sweden Sweden, formally the Kingdom of Sweden, is a Nordic countries, Nordic country located on the Scandinavian Peninsula in Northern Europe. It borders Norway to the west and north, and Finland to the east. At , Sweden is the largest Nordic count ...
. Their joint paper was published in April 1969.


Receptors

IgE primes the IgE-mediated allergic response by binding to
Fc receptor In immunology, an Fc receptor is a protein found on the surface of certain cells – including, among others, B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, human platele ...
s found on the surface of
mast cell A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a p ...
s and
basophil Basophils are a type of white blood cell White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and f ...
s. Fc receptors are also found on
eosinophil Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along wi ...
s,
monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and monocyte-derived dendritic cells. As a part of the vertebrate innate immune system monocytes also ...
s,
macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s and
platelet Platelets or thrombocytes () are a part of blood whose function (along with the coagulation#Coagulation factors, coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a thrombus, blood clot. Platelets have no ...
s in humans. There are two types of Fcε receptors: *
FcεRI The high-affinity IgE receptor, also known as FcεRI, or Fc epsilon RI, is the high-affinity receptor for the Fc region of immunoglobulin E (IgE), an antibody isotype involved in allergy disorders and parasite immunity. FcεRI is a tetrameric ...
(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 cell A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...
s in both mice and humans. Binding of
antigen In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
s 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
degranulation Degranulation is a cellular process that releases antimicrobial, cytotoxic, or other molecules from secretory vesicles called granules found inside some cells. It is used by several different cells involved in the immune system, including gran ...
(the release of mediators) and the secretion of several types of type 2
cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
s like
interleukin Interleukins (ILs) are a group of cytokines (secreted proteins and signal molecules) that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and related ...
(IL)-3 and
stem cell factor Stem cell factor (also known as SCF, KIT-ligand, KL, or steel factor) is a cytokine that binds to the c-KIT receptor (CD117). SCF can exist both as a transmembrane protein and a soluble protein. This cytokine plays an important role in hematopoie ...
(SCF), which both help the mast cells survive and accumulate in tissue, and IL-4, IL-5, IL-13, and
IL-33 Interleukin 33 (IL-33) is a protein that in humans is encoded by the ''IL33'' gene. Interleukin 33 is a member of the IL-1 family that potently drives production of T helper-2 (Th2)-associated cytokines (e.g., IL-4). IL33 is a ligand for ST2 ...
, which in turn activate group 2-innate lymphoid cells (
ILC2 ILC2 cells, or type 2 innate lymphoid cells are a type of innate lymphoid cell. Not to be confused with the ILC. They are derived from common lymphoid progenitor and belong to the lymphoid lineage. These cells lack antigen specific B or T cell r ...
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 on
B cell B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...
s; but IL-4 can induce its expression on the surfaces of macrophages, eosinophils, platelets, and some
T cell T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell ...
s.


Function


Parasite hypothesis

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. Epidemiological research shows that IgE level is increased when infected by ''Schistosoma mansoni'', ''
Necator americanus ''Necator americanus'' is a species of hookworm (a type of helminth) commonly known as the New World hookworm. Like other hookworms, it is a member of the phylum Nematoda. It is an obligatory parasitic nematode that lives in the small intestin ...
'', and
nematode The nematodes ( or ; ; ), roundworms or eelworms constitute the phylum Nematoda. Species in the phylum inhabit a broad range of environments. Most species are free-living, feeding on microorganisms, but many are parasitic. Parasitic worms (h ...
s in humans. It is most likely beneficial in removal of hookworms from the lung.


Toxin hypothesis of allergic disease

In 1981 Margie Profet suggested that allergic reactions have evolved as a last line of defense to protect against
venom Venom or zootoxin is a type of toxin produced by an animal that is actively delivered through a wound by means of a bite, sting, or similar action. The toxin is delivered through a specially evolved ''venom apparatus'', such as fangs or a sti ...
s. 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. In 2013 it emerged that IgE-antibodies play an essential role in acquired resistance to
honey bee A honey bee (also spelled honeybee) is a eusocial flying insect within the genus ''Apis'' of the bee clade, all native to mainland Afro-Eurasia. After bees spread naturally throughout Africa and Eurasia, humans became responsible for the ...
and
Russell's viper Russell's viper (''Daboia russelii)'' is a species of highly venomous snake in the Family (biology), family Viperidae. The species is native to South Asia. It was Species description, described in 1797 by George Shaw (biologist), George Shaw and ...
venoms. 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". The major allergen of bee venom (
phospholipase A2 The enzyme phospholipase A2 (EC 3.1.1.4, PLA2, systematic name phosphatidylcholine 2-acylhydrolase) catalyses the cleavage of fatty acids in position 2 of phospholipids, hydrolyzing the bond between the second fatty acid "tail" and the glycero ...
) induces a Th2 immune responses, associated with production of IgE antibodies, which may "increase the resistance of mice to challenge with potentially lethal doses".


Cancer

Although it is not yet well understood, IgE may play an important role in the immune system's recognition of
cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
, 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 Omalizumab, sold under the brand name Xolair among others, is an injectable medication to treat severe persistent allergic forms of asthma, nasal polyps, urticaria (hives), and immunoglobulin E-mediated food allergy. Omalizumab is a recombi ...
(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.


Role in disease

Atopic Atopy is the tendency to produce an exaggerated immunoglobulin E (IgE) immune response to otherwise harmless substances in the environment. Allergic diseases are clinical manifestations of such inappropriate, atopic responses. Atopy may have a ...
individuals can have up to ten 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. IgE that can specifically recognise an
allergen An allergen is an otherwise harmless substance that triggers an allergic reaction in sensitive individuals by stimulating an immune response. In technical terms, an allergen is an antigen that is capable of stimulating a type-I hypersensitivi ...
(typically this is a protein, such as
dust mite House dust mites (HDM, or simply dust mites) are various species of acariform mites belonging to the family Pyroglyphidae that are found in association with dust in dwellings. They are known for causing allergies. Biology Species The current ...
Der p 1, cat
Fel d 1 Fel d 1 is a secretoglobin protein complex that, in cats, is encoded by the ''CH1'' (chain 1/Fel d 1-A) and ''CH2'' (chain 2/Fel d 1-B) genes. Among cats, Fel d 1 is produced largely in their saliva and by the sebaceous glands located in their ...
, grass or
ragweed Ragweeds are flowering plants in the genus ''Ambrosia'' in the aster family, Asteraceae. They are distributed in the tropical and subtropical regions of the Americas, especially North America,receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...
FcεRI so that
basophils Basophils are a type of white blood cell. Basophils are the least common type of granulocyte, representing about 0.5% to 1% of circulating white blood cells. They are the largest type of granulocyte. They are responsible for inflammatory reactio ...
and
mast cells A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a ...
, capable of mediating inflammatory reactions, become "primed", ready to release chemicals like
histamine Histamine is an organic nitrogenous compound involved in local immune responses communication, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Discovered in 19 ...
,
leukotriene Leukotrienes are a family of eicosanoid inflammation, inflammatory mediators produced in leukocytes by the redox, oxidation of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid (EPA) by the enzyme arachidonate 5-lipoxyg ...
s, and certain interleukins. These chemicals cause many of the symptoms we associate with allergy, such as airway constriction in
asthma Asthma is a common long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wh ...
, local inflammation in
eczema Dermatitis is a term used for different types of skin inflammation, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened ...
, increased
mucus Mucus (, ) is a slippery aqueous secretion produced by, and covering, mucous membranes. It is typically produced from cells found in mucous glands, although it may also originate from mixed glands, which contain both Serous fluid, serous and muc ...
secretion in
allergic rhinitis Allergic rhinitis, of which the seasonal type is called hay fever, is a type of inflammation in the nose that occurs when the immune system overreacts to allergens in the air. It is classified as a type I hypersensitivity reaction. Signs a ...
, 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 Anaphylaxis (Greek: 'up' + 'guarding') is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of the use of emergency medication on site. It typicall ...
. IgE is known to be elevated in various autoimmune disorders such as SLE,
rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...
(RA), and
psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by patches of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small localized patches to complete b ...
, and is theorized to be of pathogenetic importance in SLE and RA by eliciting a hypersensitivity reaction. Regulation of IgE levels through control of B cell differentiation to antibody-secreting
plasma cells Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B cells and secrete large quantities of proteins called antibodies in response to being presented specific substances c ...
is thought to involve the "low-affinity" receptor FcεRII, or
CD23 CD23, also known as Fc epsilon RII, or FcεRII, is the "low-affinity" biochemistry, receptor for IgE, an antibody isotype involved in allergy and resistance to parasitism, parasites, and is important in regulation of IgE levels. Unlike many of the ...
.
CD23 CD23, also known as Fc epsilon RII, or FcεRII, is the "low-affinity" biochemistry, receptor for IgE, an antibody isotype involved in allergy and resistance to parasitism, parasites, and is important in regulation of IgE levels. Unlike many of the ...
may also allow facilitated antigen presentation, an IgE-dependent mechanism whereby
B cells B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...
expressing
CD23 CD23, also known as Fc epsilon RII, or FcεRII, is the "low-affinity" biochemistry, receptor for IgE, an antibody isotype involved in allergy and resistance to parasitism, parasites, and is important in regulation of IgE levels. Unlike many of the ...
are able to present allergen to (and stimulate) specific
T helper cells The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...
, 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 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. 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.


Drugs targeting the IgE pathway

Currently, allergic diseases and asthma are usually treated with one or more of the following drugs: (1)
antihistamines Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic (not patented) drug that can be bought without a prescription and provides r ...
and
antileukotriene An antileukotriene, also known as leukotriene modifier and leukotriene receptor antagonist, is a medication which functions as a leukotriene-related enzyme inhibitor (arachidonate 5-lipoxygenase) or leukotriene receptor antagonist (cysteinyl leuko ...
s, which antagonize the inflammatory mediators histamine and leukotrienes, (2) local or systemic (oral or injectable)
corticosteroids Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are invol ...
, which suppress a broad spectrum of inflammatory mechanisms, (3) short or long-acting
bronchodilators A bronchodilator or broncholytic (although the latter occasionally includes secretory inhibition as well) is a substance that dilates the bronchi and bronchioles, decreasing resistance in the respiratory airway and increasing airflow to the lung ...
, which relax smooth muscle of constricted airway in asthma, or (4)
mast cell stabilizer Mast cell stabilizers are medications used to prevent or treat certain allergic disorders. They block mast cell degranulation, stabilizing the cell and thereby preventing the release of histamine and related mediators. One suspected pharmacody ...
s, which inhibit the
degranulation Degranulation is a cellular process that releases antimicrobial, cytotoxic, or other molecules from secretory vesicles called granules found inside some cells. It is used by several different cells involved in the immune system, including gran ...
of mast cells that is normally triggered by IgE-binding at
FcεRI The high-affinity IgE receptor, also known as FcεRI, or Fc epsilon RI, is the high-affinity receptor for the Fc region of immunoglobulin E (IgE), an antibody isotype involved in allergy disorders and parasite immunity. FcεRI is a tetrameric ...
. 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 Tanox was a biopharmaceutical company based in Houston, Texas. The company was founded by two biomedical research scientists, Nancy T. Chang and Tse Wen Chang in March 1986 with $250,000, which was a large part of their family savings at that ti ...
, 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. Two approaches targeting the IgE pathway were evolved and both are in active development. In the first approach, the anti-IgE antibody drug
omalizumab Omalizumab, sold under the brand name Xolair among others, is an injectable medication to treat severe persistent allergic forms of asthma, nasal polyps, urticaria (hives), and immunoglobulin E-mediated food allergy. Omalizumab is a recombi ...
(trade name Xolair) 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 Chronic spontaneous urticaria (CSU) also known as Chronic idiopathic urticaria (CIU) is defined by the presence of wheals, angioedema, or both for more than six weeks. The most common symptoms of chronic spontaneous urticaria are angioedema and hi ...
, which cannot be adequately treated with H1-
antihistamines Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic (not patented) drug that can be bought without a prescription and provides r ...
. 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. An anti-M1' humanized antibody, quilizumab, is in phase IIb clinical trial. In 2002, researchers at the
Randall Division of Cell and Molecular Biophysics The Randall Division of Cell and Molecular Biophysics (the Randall) is a research institute of King's College London located in London United Kingdom. It is a centre for study in allergy and asthma; muscle signalling and development; structural ...
determined the structure of IgE. 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.


References

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