Editing Mast cell

{{Short description|Cell found in connective tissue}}
{{Use dmy dates|date=November 2017}}
{{Infobox cell
| Name        = Mastocyte
| Latin       = mastocytus
| Greek       =
| Image       = Mastocyte.jpg
| Caption     = Mast cell (large dark cell in the center of the field of view) surrounded by bone marrow cells, Giemsa stain, 1000x.
| Width       =
| Image2      =
| Caption2    =
| Precursor   =
| System      = [[Immune system]]
}}

A '''mast cell''' (also known as a '''mastocyte''' or a '''labrocyte'''<ref>{{cite web|url=http://www.memidex.com/labrocytes|title=labrocytes|publisher=Memidex|access-date=19 February 2011|archive-url=https://web.archive.org/web/20181106182610/http://www.memidex.com/labrocytes|archive-date=6 November 2018|url-status=dead}}</ref>) is a resident cell of connective tissue that contains many [[granule (cell biology)|granules]] rich in [[histamine]] and [[heparin]]. Specifically, it is a type of [[granulocyte]] derived from the [[CFU-GEMM|myeloid stem cell]] that is a part of the [[immune system|immune]] and [[neuroimmune system|neuroimmune]] systems. Mast cells were discovered by [[Friedrich Daniel von Recklinghausen|Friedrich von Recklinghausen]] and later rediscovered by [[Paul Ehrlich]] in 1877.<ref>{{Cite journal|last=Ehrlich|first=Paul|year=1878|title=Beiträge zur Theorie und Praxis der Histologischen Färbung|journal=Leipzig University}}</ref> Although best known for their role in [[allergy]] and [[anaphylaxis]], mast cells play an important protective role as well, being intimately involved in wound healing, [[angiogenesis]], [[immune tolerance]], defense against [[pathogen]]s, and vascular permeability in brain tumors.<ref name="Mast cell function">{{cite journal | vauthors = da Silva EZ, Jamur MC, Oliver C | title = Mast cell function: a new vision of an old cell | journal = J. Histochem. Cytochem. | volume = 62 | issue = 10 | pages = 698–738 | year = 2014 | pmid = 25062998 | pmc = 4230976 | doi = 10.1369/0022155414545334 | quote = Mast cells can recognize pathogens through different mechanisms including direct binding of pathogens or their components to PAMP receptors on the mast cell surface, binding of antibody or complement-coated bacteria to complement or immunoglobulin receptors, or recognition of endogenous peptides produced by infected or injured cells (Hofmann and Abraham 2009). The pattern of expression of these receptors varies considerably among different mast cell subtypes. TLRs (1–7 and 9), NLRs, RLRs, and receptors for complement are accountable for most mast cell innate responses}}</ref><ref name="Mast cell neuroimmmune system" />

The mast cell is very similar in both appearance and function to the [[Basophil granulocyte|basophil]], another type of [[white blood cell]]. Although mast cells were once thought to be tissue-resident basophils, it has been shown that the two cells develop from different [[Haematopoiesis|hematopoietic]] lineages and thus cannot be the same cells.<ref>{{cite journal |pmid=20362540 | doi=10.1016/j.stem.2010.02.013 | volume=6 | issue=4 | title=Distinguishing mast cell and granulocyte differentiation at the single-cell level | pmc=2852254 | year=2010 | journal=Cell Stem Cell | pages=361–8 | vauthors=Franco CB, Chen CC, Drukker M, Weissman IL, Galli SJ}}</ref>

==Structure==
[[File:Blausen 0018 Anaphylaxis.png|thumb|Illustration depicting mast cell activation and anaphylaxis]]
[[Image:Mast cell.png|thumb|Mast cell]]

Mast cells are very similar to [[basophil granulocyte]]s (a class of [[white blood cell]]s) in [[blood]], in the sense that both are [[granulocyte|granulated cells]] that contain [[histamine]] and [[heparin]], an [[anticoagulant]]. Their [[cell nucleus|nuclei]] differ in that the basophil nucleus is [[lobation|lobated]] while the mast cell nucleus is round. The [[Fragment crystallizable region|Fc region]] of [[immunoglobulin E]] (IgE) becomes bound to mast cells and basophils, and when IgE's [[paratope]]s bind to an antigen, it causes the cells to release histamine and other inflammatory mediators.<ref name="Marieb, Elaine N. 2007. pg. 659">{{cite book | title = Human Anatomy and Physiology | last1 = Marieb | first1 = Elaine N. | last2 = Hoehn | first2 = Katja | name-list-style = vanc | publisher = Pearson Benjamin Cummings | year = 2004 | isbn = 978-0-321-20413-4 | edition = 6th | location = San Francisco | page = [https://archive.org/details/humananatomyphys0006mari/page/805 805] | url = https://archive.org/details/humananatomyphys0006mari/page/805 }}</ref> These similarities have led many to speculate that mast cells are basophils that have "homed in" on tissues. Furthermore, they share a common precursor in [[bone marrow]] expressing the [[CD34]] molecule. Basophils leave the bone marrow already mature, whereas the mast cell circulates in an immature form, only maturing once in a tissue site. The site an immature mast cell settles in probably determines its precise characteristics.<ref name=Prussin>{{cite journal |vauthors=Prussin C, Metcalfe DD |title=4. IgE, mast cells, basophils, and eosinophils |journal=The Journal of Allergy and Clinical Immunology |volume=111 |issue=2 Suppl |pages=S486–94 |date=February 2003  |pmid=12592295 |doi=10.1067/mai.2003.120|pmc=2847274 }}</ref> The first ''in vitro'' differentiation and growth of a pure population of mouse mast cells was carried out using conditioned medium derived from concanavalin A-stimulated splenocytes.<ref name="pmid6166010">{{cite journal |author1=Razin E |author2=Cordon-Cardo C |author2-link=Carlos Cordon-Cardo |author3=Good RA |title=Growth of a pure population of mouse mast cells in vitro with conditioned medium derived from concanavalin A-stimulated splenocytes |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=78 |issue=4 |pages=2559–61 |date=April 1981  |pmid=6166010 |pmc=319388 |doi=10.1073/pnas.78.4.2559|bibcode=1981PNAS...78.2559R |doi-access=free }}</ref> Later, it was discovered that T cell-derived [[interleukin 3]] was the component present in the conditioned media that was required for mast cell differentiation and growth.<ref name="pmid6198393">{{cite journal |vauthors=Razin E, Ihle JN, Seldin D, etal |title=Interleukin 3: A differentiation and growth factor for the mouse mast cell that contains chondroitin sulfate E proteoglycan |journal=Journal of Immunology |volume=132 |issue=3 |pages=1479–86 |date=March 1984 |doi=10.4049/jimmunol.132.3.1479 |pmid=6198393 |s2cid=22811807 |doi-access=free }}</ref>

Mast cells in rodents are classically divided into two subtypes: [[connective tissue]]-type mast cells and [[mucosa]]l mast cells. The activities of the latter are dependent on [[T-cell]]s.<ref name="Denburg_1998">{{cite book | last = Denburg | first = Judah A. | name-list-style =vanc | title = Allergy and allergic diseases: the new mechanisms and therapeutics | publisher = Humana Press | location = Totowa, NJ | year = 1998 | isbn = 978-0-89603-404-4 }}{{page needed|date=April 2014}}</ref>

Mast cells are present in most tissues characteristically surrounding blood vessels, nerves and lymphatic vessels,<ref>{{cite journal |title=Histamine-mediated autocrine signaling in mesenteric perilymphatic mast cells |journal= American Journal of Physiology. Regulatory, Integrative and Comparative Physiology |volume=318 |issue=3 |pages=R590-604 |date=March 2020  |doi= 10.1152/ajpregu.00255.2019 |pmid=31913658 |last1= Pal |first1= Sarit |last2= Gasheva |first2= Olga Y. |last3= Zawieja |first3= David C. |last4= Meininger |first4= Cynthia J. |last5= Gashev |first5= Anatoliy A. |pmc= 7099465 }}</ref> and are especially prominent near the boundaries between the outside world and the internal milieu, such as the [[skin]], mucosa of the [[lung]]s, and [[digestive tract]], as well as the [[mouth]], [[conjunctiva]], and [[Human nose|nose]].<ref name=Prussin/>

==Function==
[[Image:Mast cells.jpg|thumb|right|220px|The role of mast cells in the development of allergy.]]
Mast cells play a key role in the inflammatory process. When activated, a mast cell can either selectively release ('''piecemeal degranulation''') or rapidly release ('''anaphylactic degranulation''') "mediators", or compounds that induce inflammation, from storage [[Granule (cell biology)|granules]] into the local microenvironment.<ref name="Mast cell function" /><ref name="Mast cell mediators - eoxins" /> Mast cells can be stimulated to [[Degranulation|degranulate]] by [[allergen]]s through [[cross-link]]ing with [[immunoglobulin E]] receptors (e.g., [[FcεRI]]), physical injury through [[pattern recognition receptor]]s for [[damage-associated molecular patterns]] (DAMPs), [[pathogen|microbial pathogen]]s through pattern recognition receptors for [[pathogen-associated molecular patterns]] (PAMPs), and various compounds through their associated [[G-protein coupled receptor]]s (e.g., morphine through [[opioid receptor]]s) or [[ligand-gated ion channel]]s.<ref name="Mast cell function" /><ref name="Mast cell mediators - eoxins" /> [[Complement system|Complement proteins]] can activate membrane receptors on mast cells to exert various functions as well.<ref name=Prussin/>

Mast cells express a high-affinity receptor ([[FcεRI]]) for the Fc region of IgE, the least-abundant member of the antibodies. This receptor is of such high affinity that binding of IgE molecules is in essence irreversible. As a result, mast cells are coated with IgE, which is produced by [[plasma cell]]s (the antibody-producing cells of the immune system). IgE antibodies are typically specific to one particular [[antigen]].

In allergic reactions, mast cells remain inactive until an [[allergen]] binds to IgE already coated upon the cell. Other membrane activation events can either prime mast cells for subsequent degranulation or act in synergy with FcεRI signal transduction.<ref name="pmid18463655">{{cite journal |vauthors=Pulendran B, Ono SJ | title = A shot in the arm for mast cells | journal = Nat. Med. | volume = 14 | issue = 5 | pages = 489–90 |date=May 2008 | pmid = 18463655 | doi = 10.1038/nm0508-489 | s2cid = 205378470 | doi-access = free }}</ref> In general, allergens are [[protein]]s or [[polysaccharide]]s. The allergen binds to the antigen-binding sites, which are situated on the variable regions of the IgE molecules bound to the mast cell surface. It appears that binding of two or more IgE molecules (cross-linking) is required to activate the mast cell. The clustering of the intracellular domains of the cell-bound Fc receptors, which are associated with the cross-linked IgE molecules, causes a complex sequence of reactions inside the mast cell that lead to its activation. Although this reaction is most well understood in terms of allergy, it appears to have evolved as a defense system against parasites and bacteria.<ref>{{cite journal |vauthors=Lee J, Veatch SL, Baird B, Holowka D |title=Molecular mechanisms of spontaneous and directed mast cell motility |journal=J. Leukoc. Biol. |volume=92 |issue=5 |pages=1029–41 |year=2012 |pmid=22859829 |pmc=3476239 |doi=10.1189/jlb.0212091 }}</ref>

Mast cells (MCs) have been shown to release their nuclear DNA and subsequently form mast cell extracellular traps (MCETs) comparable to neutrophil extracellular traps, which are able to entrap and kill various microbes.<ref>{{Cite journal |last1=Möllerherm |first1=Helene |last2=von Köckritz-Blickwede |first2=Maren |last3=Branitzki-Heinemann |first3=Katja |date=2016-07-18 |title=Antimicrobial Activity of Mast Cells: Role and Relevance of Extracellular DNA Traps |journal=Frontiers in Immunology |language=en |volume=7 |page=265 |doi=10.3389/fimmu.2016.00265 |doi-access=free |pmid=27486458 |pmc=4947581 |issn=1664-3224 }}</ref>

===Mast cell mediators===
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A unique, stimulus-specific set of mast cell mediators is released through degranulation following the activation of [[cell surface receptor]]s on mast cells.<ref name="Mast cell mediators - eoxins" /> Examples of mediators that are released into the extracellular environment during mast cell degranulation include:<ref name=Prussin/><ref name="Mast cell mediators - eoxins" /><ref name="pmid23600539">{{cite journal | vauthors = Ashmole I, Bradding P | title = Ion channels regulating mast cell biology | journal = Clin. Exp. Allergy | volume = 43 | issue = 5 | pages = 491–502 | date = May 2013 | pmid = 23600539 | doi = 10.1111/cea.12043 | s2cid = 1127584 | quote = P2X receptors are ligand-gated non-selective cation channels that are activated by extracellular ATP.&nbsp;... Increased local ATP concentrations are likely to be present around mast cells in inflamed tissues due to its release through cell injury or death and platelet activation [40]. Furthermore, mast cells themselves store ATP within secretory granules, which is released upon activation [41]. There is therefore the potential for significant Ca2+ influx into mast cells through P2X receptors. Members of the P2X family differ in both the ATP concentration they require for activation and the degree to which they desensitise following agonist activation [37, 38]. This opens up the possibility that by expressing a number of different P2X receptors mast cells may be able to tailor their response to ATP in a concentration dependent manner [37].}}</ref>
* [[serine protease]]s, such as [[tryptase]] and [[chymase]]
* [[histamine]] (2–5&nbsp;[[picogram]]s per mast cell)
* [[serotonin]]
* [[proteoglycan]]s, mainly [[heparin]] (active as [[anticoagulant]]) and some [[chondroitin sulfate proteoglycan]]s
* [[adenosine triphosphate]] (ATP)
* [[lysosomal enzymes]]
** [[Hexosaminidase|β-hexosaminidase]]
** [[β-glucuronidase]]
** [[arylsulfatase]]s
* newly formed lipid mediators ([[eicosanoid]]s):
** [[thromboxane]]
** [[prostaglandin D2]]
** [[leukotriene C4]]
** [[platelet-activating factor]]
* [[cytokine]]s
** [[TNF-α]]
** [[basic fibroblast growth factor]]
** [[interleukin-4]]
** [[stem cell factor]]
** [[chemokine]]s, such as [[eosinophil chemotactic factor]]
* [[reactive oxygen species]]

[[Image:Histamine.svg|thumb|right|250px|Structure of histamine]]
Histamine dilates post-capillary venules, [[endothelial activation|activates the endothelium]], and increases blood vessel permeability. This leads to local [[edema]] (swelling), warmth, redness, and the attraction of other inflammatory cells to the site of release. It also depolarizes [[nerve ending]]s (leading to [[itching]] or [[pain]]). Cutaneous signs of histamine release are the "flare and [[wheal response|wheal]]"-reaction. The bump and redness immediately following a mosquito bite are a good example of this reaction, which occurs seconds after challenge of the mast cell by an allergen.<ref name=Prussin/>

The other physiologic activities of mast cells are much less-understood. Several lines of evidence suggest that mast cells may have a fairly fundamental role in [[innate immunity]]: They are capable of elaborating a vast array of important cytokines and other inflammatory mediators such as TNF-α; they express multiple "pattern recognition receptors" thought to be involved in recognizing broad classes of pathogens; and mice without mast cells seem to be much more susceptible to a variety of infections.{{Citation needed|date=June 2007}}

Mast cell granules carry a variety of bioactive chemicals. These granules have been found to be transferred to adjacent cells of the immune system and [[neurons]] in a process of transgranulation via mast cell [[pseudopodia]].<ref name="pmid16262662">{{cite journal |vauthors=Wilhelm M, Silver R, Silverman AJ |title=Central nervous system neurons acquire mast cell products via transgranulation |journal=The European Journal of Neuroscience |volume=22 |issue=9 |pages=2238–48 |date=November 2005  |pmid=16262662 |pmc=3281766 |doi=10.1111/j.1460-9568.2005.04429.x}}</ref>

===In the nervous system===
Unlike other [[hematopoietic cell]]s 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), TNF, prostaglandins, leukotrienes, and varieties of chemokines and cytokines some of which are known to disrupt the integrity of the blood-brain barrier (BBB) [38–40].<br /><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. | doi-access = free }}</ref> In the brain, mast cells are located in a number of structures that mediate visceral sensory (e.g. pain) or [[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 [[nociceptor]]s.<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" /><ref name="pmid32423330">{{cite journal | vauthors = Ren H, Han R, Chen X, Liu X, Wan J, Wang L, Yang X, Wang J | title =  Potential therapeutic targets for intracerebral hemorrhage-associated inflammation: An update | journal = J Cereb Blood Flow Metab | date = May 2020 | volume = 40 | issue = 9 | pages = 1752–1768 | pmid = 32423330 | doi = 10.1177/0271678X20923551 | pmc = 7446569 }}</ref> Across systems, mast cells serve as the main [[effector cell]] through which pathogens can affect the [[gut–brain axis]].<ref name="pmid24833851" /><ref name="Microbiome-CNS-ENS" />

===In the gut===
In the gastrointestinal tract, mucosal mast cells are located in close proximity to sensory nerve fibres, which communicate bidirectionally.<ref name="FGID mast cell" /><ref name="pmid24833851">{{cite journal | vauthors = Budzyński J, Kłopocka M | title = Brain-gut axis in the pathogenesis of Helicobacter pylori infection | journal = World J. Gastroenterol. | volume = 20 | issue = 18 | pages = 5212–25 | year = 2014 | pmid = 24833851 | pmc = 4017036 | doi = 10.3748/wjg.v20.i18.5212 | quote = In digestive tissue, H. pylori can alter signaling in the brain-gut axis by mast cells, the main brain-gut axis effector | doi-access = free }}</ref><ref name="Microbiome-CNS-ENS">{{cite journal | vauthors = Carabotti M, Scirocco A, Maselli MA, Severi C | title = The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems | journal = Ann Gastroenterol | volume = 28 | issue = 2 | pages = 203–209 | year = 2015 | pmid = 25830558 | pmc = 4367209 }}</ref> When these mast cells initially degranulate, they release mediators (e.g., histamine, tryptase, and serotonin) which activate, sensitize, and [[Downregulation and upregulation|upregulate membrane expression]] of [[nociceptor]]s (i.e., [[TRPV1]]) on visceral [[afferent neuron]]s via their receptors (respectively, [[HRH1]], [[HRH2]], [[HRH3]], [[Protease-activated receptor 2|PAR2]], [[5-HT3]]);<ref name="FGID mast cell" /> in turn, neurogenic inflammation, [[visceral hypersensitivity]], and [[Gastrointestinal physiology#Motility|intestinal dysmotility]] (i.e., impaired [[peristalsis]]) result.<ref name="FGID mast cell" /> Neuronal activation induces neuropeptide ([[substance P]] and [[calcitonin gene-related peptide]]) signaling to mast cells where they bind to their associated [[G-protein coupled receptor|receptor]]s and trigger degranulation of a distinct set of mediators ([[hexosaminidase|β-Hexosaminidase]], [[cytokines]], [[chemokines]], [[PGD2]], [[leukotriene]]s, and [[eoxin]]s<!--"15-LO" in the lipid body biogenesis diagram is the synthesizing enzyme for eoxins-->).<ref name="FGID mast cell">{{cite journal | vauthors = Wouters MM, Vicario M, Santos J | title = The role of mast cells in functional GI disorders | journal = Gut | volume = 65| issue = 1| pages = 155–168| year = 2015 | pmid = 26194403 | doi = 10.1136/gutjnl-2015-309151 | quote = Functional gastrointestinal disorders (FGIDs) are characterized by chronic complaints arising from disorganized brain-gut interactions leading to dysmotility and hypersensitivity. The two most prevalent FGIDs, affecting up to 16–26% of worldwide population, are functional dyspepsia and irritable bowel syndrome.&nbsp;... It is well established that mast cell activation can generate epithelial and neuro-muscular dysfunction and promote visceral hypersensitivity and altered motility patterns in FGIDs, postoperative ileus, food allergy and inflammatory bowel disease.<br /> ▸ Mast cells play a central pathophysiological role in IBS and possibly in functional dyspepsia, although not well defined.<br /> ▸ Increased mast cell activation is a common finding in the mucosa of patients with functional GI disorders.&nbsp;...<br /> ▸ Treatment with mast cell stabilisers offers a reasonably safe and promising option for the management of those patients with IBS non-responding to conventional approaches, though future studies are warranted to evaluate efficacy and indications.| doi-access = free }}</ref><ref name="Mast cell mediators - eoxins">{{cite journal | vauthors = Moon TC, Befus AD, Kulka M | title = Mast cell mediators: their differential release and the secretory pathways involved | journal = Front Immunol | volume = 5 | pages = 569 | year = 2014 | pmid = 25452755 | pmc = 4231949 | doi = 10.3389/fimmu.2014.00569 | quote = Two types of degranulation have been described for MC: piecemeal degranulation (PMD) and anaphylactic degranulation (AND) (Figures 1 and 2). Both PMD and AND occur in vivo, ex vivo, and in vitro in MC in human (78–82), mouse (83), and rat (84). PMD is selective release of portions of the granule contents, without granule-to-granule and/or granule-to-plasma membrane fusions.&nbsp;... In contrast to PMD, AND is the explosive release of granule contents or entire granules to the outside of cells after granule-to-granule and/or granule-to-plasma membrane fusions (Figures 1 and 2). Ultrastructural studies show that AND starts with granule swelling and matrix alteration after appropriate stimulation (e.g., FcεRI-crosslinking).| doi-access = free }}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231949/figure/F1/ Figure 1: Mediator release from mast cells] {{webarchive|url=https://web.archive.org/web/20180429024530/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231949/figure/F1/ |date=29 April 2018 }}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231949/figure/F2/ Figure 2: Model of genesis of mast cell secretory granules] {{webarchive|url=https://web.archive.org/web/20180429024530/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231949/figure/F2/ |date=29 April 2018 }}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231949/figure/F3/ Figure 3: Lipid body biogenesis] {{webarchive|url=https://web.archive.org/web/20180429024530/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231949/figure/F3/ |date=29 April 2018 }}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231949/table/T2/ Table 2: Stimuli-selective mediator release from mast cells] {{webarchive|url=https://web.archive.org/web/20180429024530/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231949/table/T2/ |date=29 April 2018 }}</ref>

==Physiology==
[[File:FcεR1.jpg|thumb|Structure of FcεR1 on mast cell. FcεR1 is a tetramer made of one alpha (α) chain, one beta (β) chain, and two gamma (γ) chains. IgE is binding to α chain, signal is transduced by ITAM motifs on β and γ chains.]]

===Structure of the high-affinity IgE receptor, FcεR1===
[[FCER1|FcεR1]] is a high affinity IgE-receptor that is expressed on the surface of the mast cell. FcεR1 is a tetramer made of one alpha (α) chain, one beta (β) chain, and two identical, disulfide-linked gamma (γ) chains. The binding site for [[IgE]] is formed by the extracellular portion of the α chain that contains two domains that are similar to Ig. One transmembrane domain contains an [[aspartic acid]] residue, and one contains a short cytoplasmic tail.<ref name=pmid10358778>{{cite journal |author=Kinet JP |title=The high-affinity IgE receptor (FcεRI): from physiology to pathology |journal=Annual Review of Immunology |volume=17 |pages=931–72 |year=1999 |pmid=10358778 |doi=10.1146/annurev.immunol.17.1.931}}</ref> The β chain contains, a single immunoreceptor tyrosine-based activation motif [[Immunoreceptor tyrosine-based activation motif|ITAM]], in the cytoplasmic region. Each γ chain has one [[Immunoreceptor tyrosine-based activation motif|ITAM]] on the cytoplasmic region. The signaling cascade from the receptor is initiated when the ITAMs of the β and γ chains are phosphorylated by a tyrosine kinase. This signal is required for the activation of mast cells.<ref name="Role of Mast Cells">{{cite book |first1=Abul K. |last1=Abbas |first2=Andrew H. H. |last2=Lichtman |first3=Shiv |last3=Pillai | name-list-style = vanc |year=2011 |title=Cellular and Molecular Immunology |edition=7th |location=New York, NY |publisher=Elsevier |chapter=Role of Mast Cells, Basophils and Eosinophils in Immediate Hypersensitivity |chapter-url=https://www.inkling.com/read/cellular-and-molecular-immunology-abbas-7th/chapter-19/role-of-mast-cells-basophils |isbn=978-1-4377-1528-6}}{{page needed|date=April 2014}}</ref> Type 2 helper T cells,([[Th2]]) and many other cell types lack the β chain, so signaling is mediated only by the γ chain. This is due to the α chain containing endoplasmic reticulum retention signals that causes the α-chains to remain degraded in the ER. The assembly of the α chain with the co-transfected β and γ chains mask the ER retention and allows the α β γ complex to be exported to the golgi apparatus to the plasma membrane in rats. In humans, only the γ complex is needed to counterbalance the α chain ER retention.<ref name=pmid10358778/>

===Allergen process===
Allergen-mediated FcεR1 cross-linking signals are very similar to the signaling event resulting in antigen binding to [[lymphocytes]]. The [[LYN|Lyn]] [[tyrosine kinase]] is associated with the cytoplasmic end of the FcεR1 β chain. The antigen cross-links the FcεR1 molecules, and Lyn tyrosine kinase phosphorylates the ITAMs in the FcεR1 β and γ chain in the cytoplasm. Upon the [[phosphorylation]], the [[Syk]] tyrosine kinase gets recruited to the ITAMs located on the γ chains. This causes activation of the Syk tyrosine kinase, causing it to phosphorylate.<ref name="Role of Mast Cells"/> Syk functions as a signal amplifying kinase activity due to the fact that it targets multiple proteins and causes their activation.<ref name=pmid12217392>{{cite journal  |vauthors=Rivera J, Cordero JR, Furumoto Y, etal |title=Macromolecular protein signaling complexes and mast cell responses: a view of the organization of IgE-dependent mast cell signaling |journal=Molecular Immunology |volume=38 |issue=16–18 |pages=1253–8 |date=September 2002  |pmid=12217392 |doi=10.1016/S0161-5890(02)00072-X}}</ref> This [[antigen]] stimulated phosphorylation causes the activation of other proteins in the FcεR1-mediated signaling cascade.<ref>{{cite journal |vauthors=Li W, Deanin GG, Margolis B, Schlessinger J, Oliver JM |title=FcεR1-mediated tyrosine phosphorylation of multiple proteins, including phospholipase Cγ1 and the receptor βγ2 complex, in RBL-2H3 rat basophilic leukemia cells |journal=Molecular and Cellular Biology |volume=12 |issue=7 |pages=3176–82 |date=July 1992  |pmid=1535686 |pmc=364532 |doi=10.1128/MCB.12.7.3176 }}</ref>

===Degranulation and fusion===
An important adaptor protein activated by the Syk phosphorylation step is the [[linker for activation of T cells]] (LAT). LAT can be modified by phosphorylation to create novel binding sites.<ref name=pmid12217392/> [[PLCG1|Phospholipase C gamma]] (PLCγ) becomes phosphorylated once bound to LAT, and is then used to catalyze phosphatidylinositol bisphosphate breakdown to yield [[inositol trisphosphate]] (IP3) and [[diacyglycerol]] (DAG). IP3 elevates calcium levels, and DAG activates [[protein kinase C]] (PKC). This is not the only way that PKC is made. The tyrosine kinase [[FYN]] phosphorylates [[GAB2|Grb2-associated-binding protein 2]] (Gab2), which binds to [[PI3K|phosphoinositide 3-kinase]], which activates PKC. PKC leads to the activation of myosin light-chain phosphorylation granule movements, which disassembles the actin–myosin complexes to allow [[granule (cell biology)|granule]]s to come into contact with the plasma membrane.<ref name="Role of Mast Cells"/> The mast cell granule can now [[lipid bilayer fusion|fuse]] with the plasma membrane. Soluble N-ethylmaleimide sensitive fusion attachment protein receptor [[SNARE]] complex mediates this process. Different SNARE proteins interact to form different complexes that catalyze fusion. [[Rab (G-protein)|Rab3]] guanosine triphosphatases and Rab-associated kinases and phosphatases regulate granule membrane fusion in resting mast cells.

===MRGPRX2 mast cell receptor===

Human mast-cell-specific G-protein-coupled receptor [[MRGPRX2]] plays a key role in the recognition of pathogen associated molecular patterns (PAMPs) and initiating an antibacterial response. MRGPRX2 is able to bind to [[competence stimulating peptide]] (CSP) 1 - a quorum sensing molecule (QSM) produced by Gram-positive bacteria.<ref>{{cite journal |last1=Pundir |first1=Priyanka |last2=Liu |first2=Rui |last3=Vasavda |first3=Chirag |last4=Serhan |first4=Nadine |last5=Limjunyawong |first5=Nathachit |last6=Yee |first6=Rebecca |last7=Zhan |first7=Yingzhuan |last8=Dong |first8=Xintong |last9=Wu |first9=Xueqing |last10=Zhang |first10=Ying |last11=Snyder |first11=Solomon H |last12=Gaudenzio |first12=Nicolas |last13=Vidal |first13=Jorge E |last14=Dong |first14=Xinzhong |title=A Connective Tissue Mast-Cell-Specific ReceptorDetects Bacterial Quorum-Sensing Moleculesand Mediates Antibacterial Immunity |journal=Cell Host & Microbe |date=July 2019 |volume=26 |issue=1 |pages=114–122 |doi=10.1016/j.chom.2019.06.003 |pmid=31278040 |url=https://www.cell.com/cell-host-microbe/pdfExtended/S1931-3128(19)30292-6 |access-date=7 July 2021|pmc=6649664 }}</ref> This leads to signal transduction to a G protein and activation of the mast cell. Mast cell activation induces the release of antibacterial mediators including ROS, TNF-α and PRGD2 which institute the recruitment of other immune cells to inhibit bacterial growth and [[biofilm]] formation.

The [[MRGPRX2]] receptor is a possible therapeutic target and can be pharmacologically activated using the agonist [[compound 48/80]] to control bacterial infection.<ref>{{cite journal |first1=Kazuhiko|last1=Tatemoto|first2=Yuko|last2=Nozaki|first3=Ryoko|last3=Tsuda|first4=Shinobu|last4=Konno|first5=Keiko|last5=Tomura|first6=Masahiro|last6=Furuno|first7=Hiroyuki|last7=Ogasawara|first8=Koji|last8=Edamura|first9=Hideo|last9=Takagi|first10=Hiroyuki|last10=Iwamura|first11=Masato|last11=Noguchi|first12=Takayuki|last12=Naito|title=Immunoglobulin E-independent activation of mast cell is mediated by Mrg receptors|journal=Biochemical and Biophysical Research Communications|volume=349|issue=4|date=2006|pages=1322–1328|doi=10.1016/j.bbrc.2006.08.177|pmid=16979137|url=https://www.sciencedirect.com/science/article/pii/S0006291X06019966|access-date=7 July 2021|url-access=subscription}}</ref> It is also hypothesised that other QSMs and even Gram-negative bacterial signals can activate this receptor. This might particularly be the case during [[Bartonella]] chronic infections where it appears clearly in human symptomatology that these patients all have a [[mast cell activation syndrome]] due to the presence of a not yet defined quorum sensing molecule (basal histamine itself?). Those patients are prone to food intolerance driven by another less specific path than the IgE receptor path: certainly the MRGPRX2 route. These patients also show cyclical skin pathergy and dermographism, every time the bacteria exits its hidden intracellular location.

===Enzymes===
{| class="wikitable"
|-
! Enzyme !! Function
|-
| [[Lyn (Src family kinase)|Lyn]] tyrosine kinase || Phosphorylates the ITAMs in the FcεR1 β and γ chain in the cytoplasm. It causes Syk tyrosine kinase to get recruited to the ITAMS located on the γ chains. This causes activation of the Syk tyrosine kinase, causing it to phosphorylate
|-
| [[Syk]] tyrosine kinase || Targets multiple proteins and causes their activation
|-
| [[Phospholipase C]] || Catalyzes [[phosphatidylinositol 4,5-bisphosphate]]
|-
| [[Inositol trisphosphate]] || Elevates calcium levels
|-
| [[Diacylglycerol]] || Activates protein kinase C
|-
| [[FYN]] || Phosphorylates GAB2
|-
| [[GAB2]] || Binds to phosphoinositide 3-kinase
|-
| [[Phosphoinositide 3-kinase]] || Activates protein kinase C
|-
| [[Protein kinase C]] || Activates myosin light-chain phosphorylation granule movements that disassemble the [[actin-myosin complexes]]
|-
| Rab-associated kinases and phosphatases || Regulate cell granule membrane fusion in resting mast cells
|}

==Clinical significance==

===Parasitic infections===

Mast cells are activated in response to infection by pathogenic parasites, such as certain [[helminth]]s and [[protozoa]], through [[immunoglobulin E|IgE]] signaling.<ref name=":1">{{Cite journal |last1=Huang |first1=Hua |last2=Li |first2=Yapeng |last3=Liu |first3=Bing |date=September 2016 |title=Transcriptional regulation of mast cell and basophil lineage commitment |journal=Seminars in Immunopathology |language=en |volume=38 |issue=5 |pages=539–548 |doi=10.1007/s00281-016-0562-4 |issn=1863-2297 |pmc=5010465 |pmid=27126100}}</ref> Various species known to be affected include ''[[Trichinella spiralis|T.spiralis]]'', ''[[Strongyloides|S.ratti]]'', and ''[[Strongyloides|S.venezuelensis]]''.<ref name=":1" /> This is accomplished via Type 2 cell-mediated effector immunity, which is characterized by signaling from [[Interleukin 4|IL-4]], [[Interleukin 5|IL-5]], and [[Interleukin 13|IL-13]].<ref name=":1" /><ref name=":2">{{Cite journal |last1=Annunziato |first1=Francesco |last2=Romagnani |first2=Chiara |last3=Romagnani |first3=Sergio |date=March 2015 |title=The 3 major types of innate and adaptive cell-mediated effector immunity |url=https://linkinghub.elsevier.com/retrieve/pii/S0091674914015851 |journal=Journal of Allergy and Clinical Immunology |language=en |volume=135 |issue=3 |pages=626–635 |doi=10.1016/j.jaci.2014.11.001|pmid=25528359 }}</ref> It is the same immune response that is responsible for allergic inflammation more generally, and includes effectors beyond mast cells.<ref name=":1" /><ref name=":2" /> In this response, mast cells are known to release significant quantities of IL-4 and IL-13 along with mast cell chymase 1 ([[CMA1]]), which is considered to help expel some worms by increasing vascular permeability.<ref name=":1" />

===Mast cell activation disorders {{anchor|Mast cell activation disorders}}===

'''Mast cell activation disorders''' ('''MCAD''')<!--MOS:BOLD - term redirects here--> are a spectrum of [[immune disorder]]s that are unrelated to pathogenic infection and involve similar symptoms that arise from secreted mast cell intermediates, but differ slightly in their [[pathophysiology]], treatment approach, and distinguishing symptoms.<ref name="MCAS 2015 review">{{cite journal | vauthors = Frieri M | title = Mast Cell Activation Syndrome | journal = Clin Rev Allergy Immunol | volume = 54| issue = 3| pages = 353–365| year = 2018 | pmid = 25944644 | doi = 10.1007/s12016-015-8487-6 | s2cid = 5723622 | quote= Table 1<br />Classification of diseases associated with mast cell activation from Akin et al. [14]<br />1. Primary<br />&nbsp;&nbsp;a. Anaphylaxis with an associated clonal mast cell disorder<br />&nbsp;&nbsp;b. Monoclonal mast cell activation syndrome (MMAS), see text for explanation<br />2. Secondary<br />&nbsp;&nbsp;a. Allergic disorders<br />&nbsp;&nbsp;b. Mast cell activation associated with chronic inflammatory or neoplastic disorders<br />&nbsp;&nbsp;c. Physical urticarias (requires a primary stimulation)<br />&nbsp;&nbsp;d. Chronic autoimmune urticaria<br />3. Idiopathic (When mast cell degranulation has been documented; may be either primary or secondary. Angioedema may be associated with hereditary or acquired angioedema where it may be mast cell independent and result from kinin generation)<br />&nbsp;&nbsp;a. Anaphylaxis<br />&nbsp;&nbsp;b. Angioedema<br />&nbsp;&nbsp;c. Urticaria<br />&nbsp;&nbsp;d. Mast cell activation syndrome (MCAS)...<br />Recurrent idiopathic anaphylaxis presents with allergic signs and symptoms—hives and angioedema which is a distinguishing feature—eliminates identifiable allergic etiologies, considers mastocytosis and carcinoid syndrome, and is treated with H1 and H2 antihistamines, epinephrine, and steroids [21, 22].}}</ref><ref name="MCAS 2010">{{cite journal | vauthors = Akin C, Valent P, Metcalfe DD | title = Mast cell activation syndrome: Proposed diagnostic criteria | journal = J. Allergy Clin. Immunol. | volume = 126 | issue = 6 | pages = 1099–104.e4 | year = 2010 | pmid = 21035176 | pmc = 3753019 | doi = 10.1016/j.jaci.2010.08.035 }}</ref> The classification of mast cell activation disorders was laid out in 2010.<ref name="MCAS 2015 review" /><ref name="MCAS 2010" />

====Allergic disease====

Allergies are mediated through [[immunoglobulin E|IgE]] signaling which triggers mast cell degranulation.<ref name="MCAS 2015 review" /> Recently, IgE-independent "[[Pseudo-anaphylaxis|pseudo-allergic]]" reactions are thought to also be mediated via the MRGPRX2 receptor activation of mast cells (e.g. drugs such as [[muscle relaxants]], [[opioids]], [[Icatibant]] and [[fluoroquinolones]]).<ref>{{cite journal |vauthors=Kumar M, Duraisamy K, Chow BK |title=Unlocking the Non-IgE Mediated Pseudo-Allergic Reaction Puzzle with Mas-Related G-Protein Coupled Receptor Member X2 (MRGPRX2) |journal=Cells |volume=10 |issue=5 |pages=1033 |date=May 2021  |pmid=33925682 |doi=10.3390/cells10051033 |pmc=8146469 |doi-access=free }}</ref>

Many forms of cutaneous and mucosal [[allergy]] are mediated in large part by mast cells; they play a central role in [[asthma]], [[eczema]], [[itch]] (from various causes), [[allergic rhinitis]] and [[allergic conjunctivitis]]. [[Antihistamine]] drugs act by blocking [[histamine]] action on nerve endings. [[Cromoglicate]]-based drugs (sodium cromoglicate, nedocromil) block a calcium channel essential for mast cell degranulation, stabilizing the cell and preventing release of histamine and related mediators. [[Leukotriene antagonist]]s (such as [[montelukast]] and [[zafirlukast]]) block the action of leukotriene mediators and are being used increasingly in allergic diseases.<ref name=Prussin/>

Calcium triggers the secretion of histamine from mast cells after previous exposure to sodium fluoride. The secretory process can be divided into a fluoride-activation step and a calcium-induced secretory step. It was observed that the fluoride-activation step is accompanied by an elevation of [[cyclic adenosine monophosphate]] (cAMP) levels within the cells. The attained high levels of cAMP persist during histamine release. It was further found that catecholamines do not markedly alter the fluoride-induced histamine release. It was also confirmed that the second, but not the first, step in sodium fluoride-induced histamine secretion is inhibited by theophylline.<ref>{{cite journal |author=Alm PE |title=Sodium fluoride evoked histamine release from mast cells. A study of cyclic AMP levels and effects of catecholamines |journal=Agents and Actions |volume=13 |issue=2–3 |pages=132–7 |date=April 1983  |pmid=6191542 |doi=10.1007/bf01967316|s2cid=6977280 }}</ref> Vasodilation and increased permeability of capillaries are a result of both H1 and H2 receptor types.<ref name=pmid8151062>{{cite journal |vauthors=Dachman WD, Bedarida G, Blaschke TF, Hoffman BB |title=Histamine-induced venodilation in human beings involves both H1 and H2 receptor subtypes |journal=The Journal of Allergy and Clinical Immunology |volume=93 |issue=3 |pages=606–14 |date=March 1994  |pmid=8151062 |doi=10.1016/S0091-6749(94)70072-9|doi-access=free }}</ref>

Stimulation of histamine activates a histamine (H2)-sensitive adenylate cyclase of oxyntic cells, and there is a rapid increase in cellular [cAMP] that is involved in activation of H+ transport and other associated changes of oxyntic cells.<ref>{{cite journal |vauthors=Machen TE, Rutten MJ, Ekblad EB |title=Histamine, cAMP, and activation of piglet gastric mucosa |journal=The American Journal of Physiology |volume=242 |issue=2 |pages=G79–84 |date=February 1982  |pmid=6175225 |doi=10.1152/ajpgi.1982.242.2.G79 }}</ref>

====Anaphylaxis====
In [[anaphylaxis]] (a severe systemic reaction to [[allergen]]s, such as nuts, bee stings, or drugs), the body-wide degranulation of mast cells leads to vasodilation and, if severe, symptoms of life-threatening [[Shock (circulatory)|shock]].<ref name=":3">{{Cite journal |last=Gülen |first=Theo |date=2023-10-25 |title=A Puzzling Mast Cell Trilogy: Anaphylaxis, MCAS, and Mastocytosis |journal=Diagnostics |language=en |volume=13 |issue=21 |pages=3307 |doi=10.3390/diagnostics13213307 |doi-access=free |issn=2075-4418 |pmc=10647312 |pmid=37958203}}</ref><ref>{{Cite journal |last1=Gülen |first1=Theo |last2=Akin |first2=Cem |date=2022-02-01 |title=Anaphylaxis and Mast Cell Disorders |journal=Immunology and Allergy Clinics of North America |series=Allergic and Non-Allergic Systemic Reactions including Anaphylaxis |volume=42 |issue=1 |pages=45–63 |doi=10.1016/j.iac.2021.09.007 |pmid=34823750 |issn=0889-8561|doi-access=free }}</ref> Products released from these granules include [[histamine]], [[serotonin]], [[heparin]], [[Chondroitin sulfate|chondroitin sulphate]], [[tryptase]], [[chymase]], [[carboxypeptidase]], and [[Tumor necrosis factor|TNF-α]].<ref name=":3" /> These can vary in their quantities and proportions between individuals, which may explain some of the differences in symptoms seen across patients.<ref name=":3" />

[[Histamine]] is a vasodilatory substance released during anaphylaxis.<ref name=pmid8151062/>

====Autoimmunity====
Mast cells may be implicated in the pathology associated with autoimmune, inflammatory disorders of the joints. They have been shown to be involved in the recruitment of inflammatory cells to the joints (e.g., [[rheumatoid arthritis]]) and skin (e.g., [[bullous pemphigoid]]), and this activity is dependent on antibodies and complement components.<ref>{{cite journal |vauthors=Lee DM, Friend DS, Gurish MF, Benoist C, Mathis D, Brenner MB |title=Mast cells: a cellular link between autoantibodies and inflammatory arthritis |journal=Science |volume=297 |issue=5587 |pages=1689–92 |date=September 2002  |pmid=12215644 |doi=10.1126/science.1073176|bibcode=2002Sci...297.1689L |s2cid=38504601 }}</ref>

====Mastocytosis and clonal disorders====
{{expand section|date=October 2015}}
[[Mastocytosis]] is a rare clonal mast cell disorder involving the presence of too many mast cells (''mastocytes'') and [[CD34]]+ mast cell precursors.<ref name="pmid17587883">{{cite journal |vauthors=Horny HP, Sotlar K, Valent P |title=Mastocytosis: state of the art |journal=Pathobiology |volume=74 |issue=2 |pages=121–32 |year=2007 |pmid=17587883 |doi=10.1159/000101711|doi-access=free }}</ref> Mutations in [[CD117|c-Kit]] are associated with mastocytosis.<ref name="MCAS 2015 review" /> More specifically, the majority (>80%) of patients with mastocytosis have a mutation at codon 816 in the kinase domain of KIT, known as the ''KIT'' D816V mutation.<ref>{{Cite journal |last1=Arock |first1=M |last2=Sotlar |first2=K |last3=Akin |first3=C |last4=Broesby-Olsen |first4=S |last5=Hoermann |first5=G |last6=Escribano |first6=L |last7=Kristensen |first7=T K |last8=Kluin-Nelemans |first8=H C |last9=Hermine |first9=O |last10=Dubreuil |first10=P |last11=Sperr |first11=W R |last12=Hartmann |first12=K |last13=Gotlib |first13=J |last14=Cross |first14=N C P |last15=Haferlach |first15=T |date=June 2015 |title=KIT mutation analysis in mast cell neoplasms: recommendations of the European Competence Network on Mastocytosis |journal=Leukemia |language=en |volume=29 |issue=6 |pages=1223–1232 |doi=10.1038/leu.2015.24 |issn=0887-6924 |pmc=4522520 |pmid=25650093}}</ref><ref name=":0">{{Cite journal |last1=Jackson |first1=Clayton Webster |last2=Pratt |first2=Cristina Marie |last3=Rupprecht |first3=Chase Preston |last4=Pattanaik |first4=Debendra |last5=Krishnaswamy |first5=Guha |date=2021-10-19 |title=Mastocytosis and Mast Cell Activation Disorders: Clearing the Air |journal=International Journal of Molecular Sciences |volume=22 |issue=20 |pages=11270 |doi=10.3390/ijms222011270 |doi-access=free |issn=1422-0067 |pmc=8540348 |pmid=34681933}}</ref> This mutation, as well as expression of either [[CD2]] or [[IL2RA|CD25]] (confirmed by [[immunostaining]] or [[flow cytometry]]), are characteristic of primary clonal/monoclonal mast cell activation syndrome (CMCAS/MMAS).<ref name=":0" /> The most commonly affected organs in mastocytosis are the skin and bone marrow.<ref>{{Cite journal |last1=Hartmann |first1=Karin |last2=Escribano |first2=Luis |last3=Grattan |first3=Clive |last4=Brockow |first4=Knut |last5=Carter |first5=Melody C. |last6=Alvarez-Twose |first6=Ivan |last7=Matito |first7=Almudena |last8=Broesby-Olsen |first8=Sigurd |last9=Siebenhaar |first9=Frank |last10=Lange |first10=Magdalena |last11=Niedoszytko |first11=Marek |last12=Castells |first12=Mariana |last13=Oude Elberink |first13=Joanna N.G. |last14=Bonadonna |first14=Patrizia |last15=Zanotti |first15=Roberta |date=January 2016 |title=Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology |url=https://linkinghub.elsevier.com/retrieve/pii/S0091674915012580 |journal=Journal of Allergy and Clinical Immunology |language=en |volume=137 |issue=1 |pages=35–45 |doi=10.1016/j.jaci.2015.08.034|pmid=26476479 }}</ref>

====Monoclonal disorders====
{{expand section|date=October 2015}}

====Neoplastic disorders====
[[Mastocytoma]]s, or mast cell tumors, can secrete excessive quantities of degranulation products.<ref name="MCAS 2015 review" /><ref name="MCAS 2010" /> They are often seen in dogs and cats.<ref>{{cite web | title = Cutaneous Mast Cell Tumors | work = The Merck Veterinary Manual | year = 2006 | url = http://www.merckvetmanual.com/mvm/index.jsp?cfile=htm/bc/72231.htm | access-date = 8 July 2007 | url-status = live | archive-url = https://web.archive.org/web/20070523225427/http://www.merckvetmanual.com/mvm/index.jsp?cfile=htm%2Fbc%2F72231.htm | archive-date = 23 May 2007 | df = dmy-all }}</ref> Other [[neoplasm|neoplastic disorder]]s associated with mast cells include [[mast cell sarcoma]] and [[mast cell leukemia]].

====Mast cell activation syndrome====

[[Mast cell activation syndrome]] (MCAS) is an [[idiopathic]] [[immune disorder]] that involves recurrent and excessive mast cell [[degranulation]] and which produces symptoms that are similar to other mast cell activation disorders.<ref name="MCAS 2015 review" /><ref name="MCAS 2010" /> The syndrome is diagnosed based upon four sets of criteria involving treatment response, symptoms, a [[differential diagnosis]], and [[biomarker]]s of mast cell degranulation.<ref name="MCAS 2015 review" /><ref name="MCAS 2010" />

==History==
Mast cells were first described by [[Paul Ehrlich]] in his 1878 [[Thesis|doctoral thesis]] on the basis of their unique staining characteristics and large granules. These granules also led him to the incorrect belief that they existed to nourish the surrounding tissue, so he named them ''Mastzellen'' ({{ety|de|Mast|fattening}}, as of animals).<ref>{{cite book |last=Ehrlich |first=P. | name-list-style = vanc |title=Beiträge zur Theorie und Praxis der histologischen Färbung |trans-title=Contribution to the theory and practice of histological dyes |language=de |type=Dissertation |publisher=Leipzig University |year=1878 |oclc=63372150}}</ref><ref>{{cite web |url=http://www.mondofacto.com/facts/dictionary?mastocyte |title=Mastocyte - Definition |access-date=2010-08-16 |url-status=dead |archive-url=https://web.archive.org/web/20100203224711/http://mondofacto.com/facts/dictionary?mastocyte |archive-date=3 February 2010 |df=dmy-all }}{{full citation needed|date=April 2014}}</ref> They are now considered to be part of the [[immune system]].

==Research==
===Autism===
Research into an immunological contribution to [[autism]] suggests that [[autism spectrum disorder]] (ASD) children may present with "allergic-like" problems in the absence of elevated serum IgE and chronic [[urticaria]], suggesting non-allergic mast cell activation in response to environmental and stress triggers. This mast cell activation could contribute to brain inflammation and neurodevelopmental problems.<ref>{{cite journal  |vauthors=Theoharides TC, Angelidou A, Alysandratos KD, etal |title=Mast cell activation and autism |journal=Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease |volume=1822 |issue=1 |pages=34–41 |date=January 2012  |pmid=21193035 |doi=10.1016/j.bbadis.2010.12.017|doi-access= }}</ref>

===Histological staining===
[[Toluidine blue stain|Toluidine blue]]: one of the most common stains for acid [[mucopolysaccharides]] and [[glycoaminoglycans]], components of mast cells granules.<ref>{{cite journal |vauthors=Blumenkrantz N, Asboe-Hansen G |title=A selective stain for mast cells |journal=The Histochemical Journal |volume=7 |issue=3 |pages=277–82 |date=May 1975  |pmid=47855 |doi=10.1007/BF01003596|s2cid=32711203 }}</ref>

[[Bismarck brown Y|Bismarck brown:]] stains mast cell granules brown.<ref>{{Cite journal|last1=Tomov|first1=N.|last2=Dimitrov|first2=N.|date=2017|title=Modified bismarck brown staining for demonstration of soft tissue mast cells|url=http://tru.uni-sz.bg/tsj/Vol15_N3_2017/2_N.Tomov.pdf|journal=Trakia Journal of Sciences|volume=15|issue=3|pages=195–197|doi=10.15547/tjs.2017.03.001|doi-access=free}}</ref>

Surface markers: cell surface markers of mast cells were discussed in detail by Heneberg,<ref name=Heneberg>{{cite journal |author=Heneberg P |title=Mast cells and basophils: trojan horses of conventional lin- stem/progenitor cell isolates |journal=Current Pharmaceutical Design |volume=17 |issue=34 |pages=3753–71 |date=November 2011  |pmid=22103846 |doi=10.2174/138161211798357881}}</ref> claiming that mast cells may be inadvertently included in the stem or progenitor cell isolates, since part of them is positive for the CD34 antigen. The classical mast cell markers include the high-affinity IgE receptor, CD117 (c-Kit), and CD203c (for most of the mast cell populations). Expression of some molecules may change in course of the mast cell activation.<ref name=Lebduska>{{cite journal |vauthors=Lebduska P, Korb J, Tůmová M, Heneberg P, Dráber P |title=Topography of signaling molecules as detected by electron microscopy on plasma membrane sheets isolated from non-adherent mast cells |journal=Journal of Immunological Methods |volume=328 |issue=1–2 |pages=139–51 |date=December 2007  |pmid=17900607 |doi=10.1016/j.jim.2007.08.015}}</ref>

===Heterogeneity===
Mast cell heterogeneity significantly impacts the efficacy of mast cell stabilizing drugs [[disodium cromoglycate]] and [[ketotifen]] in preventing mediator release. In experiments, ketotifen inhibits mast cells from lung and tonsillar tissues when stimulated via an IgE-dependent histamine release mechanism, while disodium cromoglycate is less effective but still inhibited these mast cells. However, both agents fail to inhibit mediator release from skin mast cells, indicating that these cells are unresponsive to these stabilizers. Such differences in mast cell activation suggests the existence of different mast cell types across various tissues{{emdash}}a topic of ongoing research.<ref name="pmid23441583">{{cite journal |vauthors=Finn DF, Walsh JJ |title=Twenty-first century mast cell stabilizers |journal=Br J Pharmacol |volume=170 |issue=1 |pages=23–37 |date=September 2013 |pmid=23441583 |pmc=3764846 |doi=10.1111/bph.12138}}</ref><ref name="pmid26755686">{{Cite journal |last1=Zhang L |last2=Song J |last3=Hou X |date=April 2016 |title=Mast Cells and Irritable Bowel Syndrome: From the Bench to the Bedside |url=https://www.jnmjournal.org/journal/view.html?uid=1103&vmd=Full |url-status=live |archive-url=https://web.archive.org/web/20211121114113/https://www.jnmjournal.org/journal/view.html?uid=1103&vmd=Full |archive-date=21 November 2021 |journal=[[Journal of Neurogastroenterology and Motility|J Neurogastroenterol Motil.]] |volume=22 |issue=2 |pages=181–192 |doi=10.5056/jnm15137 |pmc=4819856 |pmid=26755686 |access-date=26 May 2025}}</ref>

== Other organisms ==
Mast cells and [[enterochromaffin cell]]s are the source of most [[serotonin]] in the [[stomach]] in [[rodent]]s.<ref name = "Motility" >{{Cite journal |year=2000 |issue=10 |volume=21 |publisher=[[Elsevier BV]] |journal=[[Peptides (journal)|Peptides]] |issn=0196-9781 |first2=Akio |first1=Mineko |last2=Inui |last1=Fujimiya |pages=1565–1582 |s2cid=45185196 |doi=10.1016/s0196-9781(00)00313-2 |title=Peptidergic regulation of gastrointestinal motility in rodents |pmid=11068106}}</ref>

==See also==
* [[Allergy]]
* [[Diamine oxidase]]
* [[Food intolerance]]
* [[Granulocyte]]
* [[Histamine intolerance]]
* [[Histamine N-methyltransferase]] or HNMT
* [[Histamine]]
* [[List of distinct cell types in the adult human body]]
* [[Mast cell activation syndrome]]

==References==
{{Reflist}}

==External links==
{{Wiktionary}}
* {{MeSH name|Mast+cells}}

{{Myeloid blood cells and plasma}}
{{Authority control}}

{{DEFAULTSORT:Mast cell}}
[[Category:Cell biology]]
[[Category:Connective tissue cells]]
[[Category:Granulocytes]]
[[Category:Human cells]]