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A '''mast cell''' is a type of [[white blood cell]] that protects the body from immune threats by promoting [[inflammation]].<ref name="Krystel2016" /> Mast cells are present in all tissues but especially connective tissues. They are also found in the brain, in particular along the blood-cerebrospinal fluid barrier. They are most commonly known for their role in the [[mucosal immune system|immune system]] of mucosal membranes; however, they are necessary in maintaining basic human health and defending against pathogens. When a mast cell encounters a perceived immune threat, pro-inflammatory mediators are released through a process known as degranulation. Some anti-inflammatory mediators may include [[histamine]], [[Cytokine|cytokines]], proteases, or [[heparin|heparin.]]<ref name="Krystel2016" /> ==Mast cell activation== === Activation === ===Degranulation=== Mast cells can become activated when they encounter a foreign substance. A cascade response allows for degranulation to begin and a subsequent release of inflammatory granules into the bloodstream.<ref name="Krystel2016">{{Cite journal | last = Krystel-Whittemore | first1 = M | last2 = Dileepan | first2 = KN | last3 = Wood | first3 = JG | date = 2016 | title=Mast Cell: A Multi-Functional Master Cell|doi= 10.3389/fimmu.2015.00620|url=https://www.frontiersin.org/articles/10.3389/fimmu.2015.00620/full|journal=Front. Immunol|volume=6|issue= | pages = 620|via=}}</ref> === Inhibition === One study found that [[acetylcholine]] via muscarinic receptors strongly inhibited the release of [[histamine]] in mucosal mast cells.<ref name="Reinheimer1997">{{Cite journal | last = Reinheimer | first = T. | last2 = Baumgärtner | first2 = D. | last3 =Höhle | first3 = K.D. | last4 = Racké | first4 = K. | last5 = Wessler | first5 = I. | date = 1997 | title=Acetylcholine via Muscarinic Receptors Inhibits Histamine Release from Human Isolated Bronchi|url=http://www.atsjournals.org/doi/full/10.1164/ajrccm.156.2.96-12079#.V7vo-ZMrLMV|journal =American Journal of Respiratory and Critical Care Medicine|language=en|doi=10.1164/ajrccm.156.2.96-12079#.v7vo-zmrlmv}}</ref> == Activating factors == ===Infection=== Past findings have suggested that mast cell activation due to a viral infection may play a part in initiating autoimmune disease. [[Coxsackievirus]] infection has been observed to up-regulate [[toll-like receptor]] 4 (TLR4) on mast cells in mice, immediately following the period of infection.<ref name="Fairweather">{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/15386590 | title = Viruses as adjuvants for autoimmunity: evidence from Coxsackievirus-induced myocarditis | last = Fairweather | first = D. | date = 2005 | journal=Rev Med Virol|volume=|pages=|via=}}</ref> TLR4 up-regulation may have negative consequences on the immune system because TLR4 up-regulation may activate the [[innate immune system]] and the inflammatory response system. === Sex hormones === === Physical stress === Mast cells are distributed throughout the nervous system, including in the dura, and are known to degranulate when nervous tissue is stretched.<ref name="Skaper2014">{{Cite journal | last = Skaper | first = Stephen D. | last2 = Facci | first2 = Laura | last3 = Giusti | first3 = Pietro | date = Mar 2014 | title = Mast cells, glia and neuroinflammation: partners in crime?|url=https://www.ncbi.nlm.nih.gov/pubmed/24032675|journal=Immunology|volume=141|issue=3 | pages = 314–327|doi=10.1111/imm.12170|issn=1365-2567|pmc=3930370|pmid=24032675|quote=|access-date=|via=}}</ref><ref name="Hu2014">{{Cite journal | last = Hu|first = Kenneth K. | last2 = Bruce | first2 = Marc A. | last3 = Butte | first3 = Manish J. | date = 2014-05-01 | title = Spatiotemporally and mechanically controlled triggering of mast cells using atomic force microscopy|url=https://doi.org/10.1007/s12026-014-8510-7|journal=Immunologic Research|language=en|volume=58|issue=2|pages=211–217|doi=10.1007/s12026-014-8510-7|issn=1559-0755|pmc = 4154250|pmid=24777418}}</ref> They also activate in response to vibration.{{Citation needed|reason=}} == Inhibitory factors == === Potential treatments === There are several proposed supplements or treatments that might grant temporary mast cell degranulation inhibition: Antioxidants: these are substances that are considered to remove potentially harmful reactive [[oxygen]] species from the body. [[Vitamin C]], [[vitamin A]], [[vitamin E]], and beta-carotene are examples of antioxidants. The properties of such antioxidants have been noted to be capable of reducing blood histamine levels.<ref name="Tettamenti">{{Cite journal | last = Tettamanti|first = L | date = 2018 | title = Different signals induce mast cell inflammatory activity: inhibitory effect of Vitamin E. | url = |journal=J biol regul homeost agents|volume=|pages=|via=}}</ref> The exact mechanisms that cause blood histamine levels to decrease are still unknown. However, antioxidants have been noted to be capable of inhibiting mast cell production and altering the enzymes that form ([[diamine oxidase]]) or breakdown (histidine decarboxylase) histidine. Phototherapy: UVA and UVA1 phototherapy has been observed to significantly inhibit histamine release from mast cells and other white blood cells.<ref name="Kronauer2007">{{Cite journal | last = Kronauer | first = C | date = 2007 | title=Influence of UVB, UVA and UVA1 Irradiation on Histamine Release from Human Basophils and Mast Cells In Vitro in the Presence and Absence of Antioxidants | url = |journal=Photochemistry and Photobiology|volume=|pages=|via=}}</ref> == Role in the human body == Mast cells are found within the nervous system and are capable of crossing the [[blood-brain barrier]], which separates [[blood]] from the [[central nervous system]]. The gastrointestinal tract and the brain are capable of communicating through the blood brain barrier, also known as the gut-brain axis (GBA). Exchange of information between the central (brain) and peripheral (gut) nervous systems ensures that the stomach and intestines are communicating with the brain. "Immune activation, intestinal permeability, enteric reflex, and entero-endocrine signaling" are all influenced by the GBA. Therefore mast cells may be a type of cell that indirectly affects neurological functioning when the gut is inflamed.<ref>{{Cite journal | last = Carabotti|first = Marilia | last2 = Scirocco | first2 = Annunziata | last3 = Maselli | first3 = Maria Antonietta | last4 = Severi | first4 = Annunziata | date = 2015 | title=The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems | url = |journal=Ann Gasteroenterol|volume=28|issue=2|pmc=PMC4367209|pmid=25830558|pages=203–209|via=}}</ref> Like the tissue-resident macrophages known as [[microglia]], but unlike other bone marrow-derived cells of the [[immune system]], mast cells naturally occur in the [[human brain]] where they interact with the [[neuroimmune system]].<ref name="Mast cell neuroimmmune system">{{cite journal | vauthors = Polyzoidis S, Koletsa T, Panagiotidou S, Ashkan K, Theoharides TC | title = Mast cells in meningiomas and brain inflammation | journal = J Neuroinflammation | volume = 12 | issue = 1 | pages = 170 | year = 2015 | pmid = 26377554 | pmc = 4573939 | doi = 10.1186/s12974-015-0388-3 | quote = MCs originate from a bone marrow progenitor and subsequently develop different phenotype characteristics locally in tissues. Their range of functions is wide and includes participation in allergic reactions, innate and adaptive immunity, inflammation, and autoimmunity [34]. In the human brain, MCs can be located in various areas, such as the pituitary stalk, the pineal gland, the area postrema, the choroid plexus, thalamus, hypothalamus, and the median eminence [35]. In the meninges, they are found within the dural layer in association with vessels and terminals of meningeal nociceptors [36]. MCs have a distinct feature compared to other hematopoietic cells in that they reside in the brain [37]. MCs contain numerous granules and secrete an abundance of prestored mediators such as corticotropin-releasing hormone (CRH), neurotensin (NT), [[substance P]] (SP), tryptase, chymase, vasoactive intestinal peptide (VIP), [[vascular endothelial growth factor]] (VEGF), [[Tumor necrosis factor|TNF]], prostaglandins, leukotrienes, and varieties of [[chemokine]]s and cytokines some of which are known to disrupt the integrity of the blood-brain barrier (BBB) [38–40]...<br />[The] key role of MCs in inflammation [34] and in the disruption of the BBB [41–43] suggests areas of importance for novel therapy research. Increasing evidence also indicates that MCs participate in neuroinflammation directly [44–46] and through microglia stimulation [47], contributing to the pathogenesis of such conditions such as headaches, [48] autism [49], and chronic fatigue syndrome [50]. In fact, a recent review indicated that peripheral inflammatory stimuli can cause microglia activation [51], thus possibly involving MCs outside the brain.}}</ref><ref name="Aguzzi2013">{{Cite journal | last = Aguzzi|first = A. | last2 = Barres | first2 = B.A. | last3 = Bennett | first3 = M.L. | date = 2013-01-11 | title = Microglia: Scapegoat, Saboteur, or Something Else?|url=http://www.sciencemag.org/cgi/doi/10.1126/science.1227901|journal=Science|language=en|volume=339|issue=6116|pages=156–161|doi=10.1126/science.1227901|issn=0036-8075}}</ref> In the brain, mast cells are located in a number of structures that mediate visceral sensory (e.g., pain) or [[neuroendocrine system|neuroendocrine]] functions or that are located along the [[blood–cerebrospinal fluid barrier]], including the pituitary stalk, pineal gland, thalamus, and [[hypothalamus]], area postrema, choroid plexus, and in the dural layer of the [[meninges]] near meningeal nociceptors.<ref name="Mast cell neuroimmmune system" /> Mast cells serve the same general functions in the body and [[central nervous system]], such as effecting or regulating allergic responses, innate and adaptive immunity, [[autoimmunity]], and inflammation.<ref name="Mast cell neuroimmmune system" /> Across systems, mast cells serve as the main effector cell through which pathogens can affect the [[gut–brain axis]].<ref name="Budzyński2014">{{Cite journal | last = Budzyński|first = Jacek | last2 = Kłopocka | first2 = Maria | date = 2014-05-14 | title = Brain-gut axis in the pathogenesis of Helicobacter pylori infection | url =https://www.ncbi.nlm.nih.gov/pubmed/24833851|journal=World Journal of Gastroenterology|volume=20|issue=18 | pages = 5212–5225|doi=10.3748/wjg.v20.i18.5212|issn=2219-2840|pmc=4017036|pmid=24833851}}</ref> == Role in human disease == === Mast cell activation syndrome === {{Main article|page_name=Mast cell activation syndrome}} [[Mast cell activation syndrome]] (MCAS) is a condition in which mast cells are over-responsive to various environmental triggers. When mast cells are over-responsive the result can be an increase in the release of [[histamine]] and other inflammatory molecules. Excessive inflammation can result from such a condition. MCAS is often found in patients with [[Ehlers-Danlos syndrome]] (EDS) and [[postural orthostatic tachycardia syndrome]] (POTS), a form of [[orthostatic intolerance]],<ref>Milner, Joshua, Dr. "Research Update: POTS, EDS, MCAS Genetics." 2015 Dysautonomia International Conference & CME. Washington DC. Dysautonomia International Research Update: POTS, EDS, MCAS Genetics. Web. <https://vimeo.com/142039306></ref> two conditions commonly co-morbid with [[ME/CFS|ME]]. The overlap between EDS, POTS, and MCAS is thought to be due to increased [[tryptase]] production owing to an extra copy of a gene called TPSAB.<ref name="Cheung2015">{{Cite journal | last = Cheung|first = Ingrid | date = Feb 2015 | title = A New Disease Cluster: Mast Cell Activation Syndrome, Postural Orthostatic Tachycardia Syndrome, and Ehlers-Danlos Syndrome|url=http://www.jacionline.org/article/S0091-6749(14)02927-3/abstract|journal=The Journal of Allergy and Clinical Immunology|volume=|pages=|via=}}</ref> MCAS should be distinguished from [[mastocytosis]], a genetic disorder causing excessive production of mast cells. ===Myalgic Encephalomyelitis=== Research on the relationship between mast cells and ME is in its infancy. One study found that individuals diagnosed with moderate to severe [[ME/CFS|ME]] have been noted to have higher amounts of dysfunctional mast cells in circulation.<ref name="Nguyen2017">{{Cite journal | last1 = Nguyen | first1 = T. | authorlink = Thao Nguyen | last2 = Johnston | first2 = S. | authorlink2=Samantha Johnston | last3 = Chacko | first3 = A. | authorlink3 = | last4 = Gibson | first4 = D. | authorlink4 = | last5 = Cepon | first5 = J. | authorlink5 = | last6 = Smith|first6 = D. | authorlink6 = | last7 = Staines | first7 = D. | authorlink7 = Donald Staines | last8 = Marshall-Gradisnik|first8 = S. | authorlink8 = Sonya Marshall-Gradisnik | title = Novel characterisation of mast cell phenotypes from peripheral blood mononuclear cells in chronic fatigue syndrome/myalgic encephalomyelitis patients|journal= Asian Pac J Allergy Immunol |volume =35|issue = 2|page =75-81 | date = 2017|doi= 10.12932/AP0771}}</ref> At a two-day physician summit in Salt Lake City, Utah March 2018, physicians discussed the relationship between “Chronic Fatigue Syndrome” and mast cell activation syndrome.<ref>{{Cite web|url=https://www.medscape.com/viewarticle/893858 | title = Mast Cell Activation May Underlie 'Chronic Fatigue Syndrome'|website=Medscape | date = 2018-03-13|access-date=2018-09-25}}</ref> *[[David Kaufman]]: "ME/CFS is a descriptive diagnosis of a bunch of symptoms, but it says nothing about what's causing the symptoms, which is probably part of the reason it's so hard for it to get recognition. So, the question becomes, What other pathology is driving this illness and making the person feel so ill? I think mast cell activation is one of those drivers, whether cause, effect, or perpetuator, I don't know." *[[Charles Lapp]]: "I see a lot of this. I think it's one of the many overlap syndromes that we've been missing for years." *[[Susan Levine]]: "I suspect 50% to 60% of ME/CFS patients have it. It's a very new concept."...In Levine's experience, MCAS often manifests in patients being unable to tolerate certain foods or medications. "If we can reduce the mast cell problem, we can facilitate taking other drugs to treat ME/CFS," she said. However, she also cautioned, "It's going to be a subset, not all ME/CFS patients." === Fibromyalgia === Over expression of mast cells has been observed in the skin of patients with fibromyalgia.<ref name="Ang2015">{{Cite journal | last = Ang|first = D.C. | last2 = Hilligoss | first2 = J. | last3 = Stump | first3 = T. | date = 2015 | title=Mast Cell Stabilizer (Ketotifen) in Fibromyalgia: Phase 1 Randomized Controlled Clinical Trial|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4417653/|journal=The Clinical Journal of Pain|volume=31|issue=9 | pages = 836–842|pmc=PMC4417653|pmid=25370135|via=}}</ref> === Endometriosis === ==Notable studies== *2017, Novel characterisation of mast cell phenotypes from peripheral blood mononuclear cells in [[ME/CFS|chronic fatigue syndrome/myalgic encephalomyelitis]] patients<ref name="Nguyen2017" /> - [http://apjai-journal.org/wp-content/uploads/2017/07/75-81-AP0771.pdf (Full Text)] ==See also== *[[Collagen]] *[[Mast cell activation disorder]] *[[Theoharis Theoharides]] ==Learn more== ==References== {{reflist}} [[Category:Biochemistry and cell biology]] [[Category:Immunology]] [[Category:Allergy signs and symptoms]]
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