The role of mast cells in the development of allergy.

In biology, Immunoglobulin E (IgE) is a class of antibody (or immunoglobulin "isotype") that has only been found in mammals. Foundations of modern biology There are five unifying principles Antibodies (also known as immunoglobulins, abbreviated Ig) are Gamma globulin Proteins that are found in Blood or other Bodily Antibodies (also known as immunoglobulins, abbreviated Ig) are Gamma globulin Proteins that are found in Blood or other Bodily Mammals ( class Mammalia) are a class of Vertebrate Animals characterized by the presence of Sweat glands, including sweat glands It plays an important role in allergy, and is especially associated with type 1 hypersensitivity. Allergy is a disorder of the Immune system often also referred to as Atopy. Hypersensitivity (also called hypersensitivity reaction refers to undesirable (damaging discomfort-producing and sometimes fatal reactions produced by the normal immune system ^[1] IgE has also been implicated in immune system responses to most parasitic worms^[2] like Schistosoma mansoni, Trichinella spiralis, and Fasciola hepatica,^[3][4][5] and may be important during immune defense against certain protozoan parasites such as Plasmodium falciparum. An immune system is a collection of mechanisms within an Organism that protects against Disease by identifying and killing Pathogens and Tumor See also Parasitic worm (disambiguation Parasitic worms or helminths are a division of eukaroytic Parasites that unlike external parasites such Schistosoma mansoni is a significant parasite of humans one of the major agents of Schistosomiasis. The species Trichinella spiralis is an important Parasite, occurring in rats pigs and humans and is responsible for the disease Trichinosis. Fasciola hepatica, also known as the common liver fluke or sheep liver fluke, is a parasitic flatworm of the class Trematoda Protozoa (in Greek πρῶτον proton "first" and ζῷα zoia "animals" are unicellular Eukaryotes (singular Parasitism is a type of symbiotic relationship between Organisms of different Species. Plasmodium falciparum is a Protozoan Parasite, one of the species of Plasmodium that cause Malaria in humans ^[6]

Although IgE is typically the least abundant isotype - blood serum IgE levels in a normal ("non-atopic") individual are ~75 ng/ml, 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 immune reactions. Blood plasma is the Liquid component of Blood, in which the Blood cells are suspended Atopy (/ˈætəpi/ Greek ἀτοπία - placelessness or atopic syndrome is an allergic Hypersensitivity affecting parts of the body Immunoglobulin G ( IgG) is a Monomeric Immunoglobulin, built of two heavy chains γ and two light chains. Immune system|Passive immunity|Innate immune system The adaptive immune system is composed of highly specialized systemic cells and processes that eliminate or prevent Pathogenic

IgE was discovered in 1966 by the Japanese scientist Kimishige Ishizaka. Year 1966 ( MCMLXVI) was a Common year starting on Saturday (link will display full calendar of the 1966 Gregorian calendar. For a topic outline on this subject see List of basic Japan topics. Dr is a Japanese scientist who discovered the antibody class IgE in 1966 ^[7]

Receptors

IgE elicits an immune response by binding to Fc receptors found on the surface of mastocytes called mast cells and basophils in rodents and humans, and on eosinophils, monocytes, macrophages and platelets in humans. An Fc receptor is a protein found on the surface of certain cells - including Natural killer cells Macrophages Neutrophils and Mast cells - that A mast cell (or mastocyte) is a resident cell of several types of tissues and contains many granules rich in Histamine and Heparin A mast cell (or mastocyte) is a resident cell of several types of tissues and contains many granules rich in Histamine and Heparin Eosinophil granulocytes, usually called eosinophils (or less commonly acidophils) are White blood cells that are one of the Immune System components Monocyte is a type of Leukocyte, part of the Human body 's Immune system. Macrophages ( Greek: "big eaters" from makros "large" + phagein "eat" ( Mø) are cells within the tissues that Platelets, or Thrombocytes, are small cytoplasmic bodies derived from cells They circulate in the Blood of Mammals and are involved It has two main receptors:

• FcεRI, the high-affinity IgE receptor
• FcεRII, also known as CD23, is the low-affinity IgE receptor

IgE can upregulate the expression of both Fcε receptors. FcεRI, or Fc epsilon RI, is the high- Affinity receptor for Immunoglobulin E (IgE an Antibody Isotype involved in CD23, also known as Fc epsilon RII, or FcεRII, is the "low affinity" receptor for IgE, an Antibody isotype involved in FcεRI is expressed only on mast cells and/or basophils in both mice and humans. Aggregation of its antigens and binding of IgE to the FcεRI on mast cells causes degranulation and the release of mediators from the cells, while basophils cross-linked with IgE release type 2 cytokines like interleukin-4 (IL-4) and interleukin-13 (IL-13) and other inflammatory mediators. An antigen (from antibody-generating) or immunogen is a substance that prompts the generation of Antibodies and can cause an immune response Degranulation is a cellular process that releases Antimicrobial Cytotoxic molecules from secretory vesicles called granules found inside Cytokines are a category of signalling Proteins and Glycoproteins that like Hormones and Neurotransmitters, are used extensively in cellular Interleukin-4, abbreviated IL-4, is a Cytokine that induces differentiation of naive helper T cells ( Th0 cells to Th2 cells Upon activation by Interleukin 13 ( IL-13) is a Cytokine secreted by many cell types but especially T helper type 2 (Th2 cells that is an important mediator of allergic 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. B cells are Lymphocytes that play a large role in the humoral immune response (as opposed to the cell-mediated immune response, which is governed by T cells belong to a group of White blood cells known as Lymphocytes, and play a central role in Cell-mediated immunity. This receptor is implicated in pathogenicity during malaria. Pathogenicity is the ability of an organism a Pathogen, to produce an infectious disease in another organism Malaria is a vector -borne Infectious disease caused by Protozoan Parasites It is widespread in tropical and subtropical regions including ^[6]

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. Parasitism is a type of symbiotic relationship between Organisms of different Species. Schistosoma mansoni is a significant parasite of humans one of the major agents of Schistosomiasis.

Although it is not yet well understood, IgE may play an important role in the immune system’s recognition of cancer^[8], in which the stimulation of a strong cytotoxic response against cells displaying only small amounts of early cancer markers would be beneficial. Cancer (medical term Malignant Neoplasm) is a class of Diseases in which a group of cells display uncontrolled Of course, if this were the case, anti-IgE treatments such as omalizumab might have some undesirable side effects. Omalizumab (marketed under the name Xolair) is a Monoclonal antibody made by Genentech / Novartis and used mainly in Allergy -related

Role in disease

Atopic individuals (people who suffer from true IgE-mediated allergies) can have up to 10 times the normal level of IgE in their blood (as do sufferers of hyper-IgE syndrome). Atopy (/ˈætəpi/ Greek ἀτοπία - placelessness or atopic syndrome is an allergic Hypersensitivity affecting parts of the body Hyper IgE syndrome (HIES also called Job-Buckley syndrome, Job's syndrome and Buckley syndrome, is a heterogeneous group of disorders characterized by 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, hermetically without the involvement of lymphoid tissue^[9].

IgE, that can specifically recognise an "allergen" (typically this is a protein, such as dust mite DerP1, cat FelD1, grass or ragweed pollen, etc. The house dust mite (sometimes abbreviated by Allergists to HDM) is a cosmopolitan guest in Human habitation Ragweeds ( Ambrosia) also called bitterweeds and bloodweeds, are a Genus of flowering Plants from the sunflower ) 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, which 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, ostensibly 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. Biochemistry is the study of the chemical processes in living Organisms It deals with the Structure and function of cellular components such as A mast cell (or mastocyte) is a resident cell of several types of tissues and contains many granules rich in Histamine and Heparin Histamine is a Biogenic amine involved in local immune responses as well as regulating physiological function in the gut and acting as a Neurotransmitter Leukotrienes are naturally produced Eicosanoid lipid mediators, which may be responsible for the effects of an inflammatory response Asthma is a chronic Condition involving the Respiratory system in which the airways occasionally constrict become inflamed, and are Eczema (from Greek έκζεμα) is a form of Dermatitis, or Inflammation of the Epidermis. In vertebrates mucus is a slippery secretion produced by and covering Mucous membranes It is a viscous Colloid containing Antiseptic enzymes (such as Hay Fever is a comic play written by Noel Coward in 1924 and first produced in 1925 with Marie Tempest as the first Judith Bliss Anaphylaxis is an acute systemic (multi-system and severe Type I Hypersensitivity allergic reaction in humans and other Mammals 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. Plasma cells (also called plasma B cells or plasmocytes) are cells of the Immune system that secrete large amounts of antibodies. CD23, also known as Fc epsilon RII, or FcεRII, is the "low affinity" receptor for IgE, an Antibody isotype involved in 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. CD23, also known as Fc epsilon RII, or FcεRII, is the "low affinity" receptor for IgE, an Antibody isotype involved in B cells are Lymphocytes that play a large role in the humoral immune response (as opposed to the cell-mediated immune response, which is governed by CD23, also known as Fc epsilon RII, or FcεRII, is the "low affinity" receptor for IgE, an Antibody isotype involved in T helper cells (also known as effector T cells or Th cells) are a sub-group of Lymphocytes (a type of White blood cell or

Pharmacology

IgE may be an important target in treatments for allergy and asthma.

Currently, severe allergy and asthma is usually treated with drugs (like anti-histamines) that damp down the late stages of inflammation and relax airway smooth muscle. Unfortunately, these treatments are fairly broad in their action, and so many have unpleasant side effects; they may also inhibit important protective responses.

In 2002, researchers at The Randall Division of Cell and Molecular Biophysics determined the structure of IgE^[10]. The Randall Division of Cell and Molecular Biophysics is part of King's College London and one of Britain 's Research institutions - a centre for study in 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. A new treatment, omalizumab, a monoclonal antibody, recognises IgE not bound to its receptor and is used to neutralise or mop-up existing IgE and prevent it from binding to cells. Omalizumab (marketed under the name Xolair) is a Monoclonal antibody made by Genentech / Novartis and used mainly in Allergy -related Monoclonal antibodies ( mAb or moAb) are monospecific antibodies that are identical because they are produced by one type of immune cell It may be possible to design treatments cheaper than monoclonal antibodies (for instance, small molecule drugs) that use a similar approach to inhibit IgE binding to its receptor.

In 1975 Robert N. Hamburger, M. D. published "Peptide Inhibition of the P-K Reaction" based on blocking up to 89% of the IgE receptors on mast cells by the pentapeptide representing amino acids 320 to 324 on the epsilon chain of IgE. ^[11]

See also

• Antibodies
• IgM, IgA, IgD, IgG
• Phadia

References