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Mast cell

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Mastocyte
Mast cell (large dark cell in the center of the field of view) surrounded by bone marrow cells, Giemsa stain, 1000x.
Details
SystemImmune system
Identifiers
Latinmastocytus
MeSHD008407
THH2.00.03.0.01010
FMA66784
Anatomical terms of microanatomy
External videos
video icon Real-Time Activation of One Mast Cell by the Neuropeptide Substance P, The New England Journal of Medicine, 2015

A mast cell (also known as a mastocyte or a labrocyte[1]) is a resident cell that develops and lives in connective tissue and contains many small secretory granules for the storage and release of histamine, heparin and other chemicals.[2] A part of the immune and neuroimmune systems, a mast cell is a type of granulocyte derived from myeloid progenitor cells. Mast cells were discovered by Friedrich von Recklinghausen in 1863 and later rediscovered by Paul Ehrlich in 1877.[3][4]

Mast cells are best known for their roles in allergy, anaphylaxis, and atopic dermatitis.[5][6] They also play an important protective role in the defense and repair of cells through wound healing, angiogenesis, vascular permeability, and responses to bacteria, other pathogens, and venoms.[7][3] They are involved in regulation of autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and type 1 diabetes, and may be linked to the development of some types of cancer.[8]

Development

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Mast cells are considered to have originated nearly 500 million years ago, in urochordates, making them one of the most ancient types of immune cells.[9] Mast cells (MCs) are specialized immune cells derived through hematopoiesis, the formation of blood cell components. Mast cells develop from circulating mast cell progenitors (MCps). Once they are recruited to a given type of connective tissue, they specialize and become resident mast cells. Mature MCs exhibit context-specific modifications in their effector properties related to local tissue types and diseases.[10]

Mast cells may have dual methods of origin in the hematopoietic system.[11] In 1989, Leonore Herzenberg and Leonard Herzenberg proposed that different types of stem cells produce specific types of immune cells through multiple waves of development. Specific types of immune cells have been shown to arise sequentially at different points in embryonic development. The original layered immune theory proposed that hematopoietic stem cells (HSCs) were the basis for such development.[11] In the classical sequence of hematopoiesis, hematopoietic stem cells (HSCs) were described as becoming multipotent progenitors (MPPs), then differentiating into common myeloid progenitors (CMPs), followed by granulocyte/monocyte progenitors (GMPs). GMPs then differentiate into mast cells and basophils.[10][3][7]

However, lineage relationships in human hematopoiesis have been hotly debated.[10] Subsequent research suggests that multiple waves of immune cells develop through hematopoiesis from hemogenic endothelial cells (ECs), in an HSC-independent manner with HSCs arising in a final hematopoietic wave.[11] Tissue-resident immune cells either may be fetal-derived or be the progeny of adult HSCs.[11]

In vertebrates, the earliest source of mast cells is the extraembryonic yolk sac, where blood and immune cells first develop.[12] However, there are differences in the embryonic development of vertebrates such as mice compared to primates (including humans). In primates, yolk sac formation involves a transient primary yolk sac, and the formation of extraembryonic mesoderm, prior to generation of a secondary yolk sac where the first blood cells of the embryo develop.[13]

During embryonic development, mast cell progenitors (MCps) form in a series of developmentally discrete waves.[10] The first wave of mast cells in the embryo is derived from erythro-myeloid progenitors (EMPs) in the yolk sac, before hematopoietic stem cells (HSC) emerge.[12] In mouse models, the earliest mast cell progenitors originate in the embryo around embryonic day 7[14] (E7.5-E8.5).[12] Transient erythro-myeloid progenitors (EMPs) develop in the yolk sac between E8.5-E10.5 and in fetal liver (FL) between E11.5-E13.5.[12] Embryonic multipotent progenitors (eMPPs) and hematopoietic stem cells (HSCs) emerge around E10.5.[12] Mast cell differentiation in the fetal liver (FL) starts from E11, along with a peak in the number of mast cell progenitors. Mast cell progenitors then enter the circulation and seed other tissues including the brain, heart, lung, peritoneal cavity, skin, and, spleen, where they complete their maturation.[12] eMPPs and HSCs start producing mature hematopoietic cells in in the fetal liver around E12.5 and E14.5 respectively.[12] HSCs can produce mast cells within a limited time window which declines after embryonic day E14.5.[11]

Whether mast cell origination is mostly independent of HSCs, or "adult" mast cells originate in bone marrow (BM) from HSCs is debated.[11] MC precursors of myeloid origin are found in bone marrow, but mature MCs are absent.[3] Mast cells are easily generated from adult BM cells in vitro, but this has been less successful following HSC transplantation in vivo.[11] It is unclear whether fetal-derived immune cells may be produced by HSCs during the fetal to neonatal period.[11]

In humans, the first yolk sac-derived MCs originate from mesodermal precursors that form in blood islands of the yolk sac, starting around three weeks into gestation. From there, circulating progenitors migrate into peripheral tissues for complete differentiation and maturation.[3] Hematopoietic progenitors subsequently differentiate into multiple lineages, including erythroid, lymphoid, megakaryocytic, and myeloid precursors, which emerge in the fetal liver. Immature MCs are activated by antigens and cytokines and become specialized in response to their resident environment.[3] MCs become widely distributed throughout all tissues.[3] Sizeable populations of fetal‐derived MCs persist in connective tissue into adulthood, and appear to self‐maintain mostly independent of bone marrow.[5]

Structure

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Mast cell (NIH BioArt), darker nucleus surrounded by granules.

Mast cells are highly versatile immune cells that first appear during fetal development. Individual mast cells likely reflect the processes by which they originally develop as well as the microenvironments where they mature.[5]

Mast cell progenitors, sometimes referred to as "immature" mast cells, circulate in the bloodstream as undifferentiated mononuclear cells.[5][14] Circulating progenitors are similar in size to lymphocytes, and have fewer granules than mature mast cells. Circulating MC progenitors in human blood and in human bone marrow have been identified using the expression of the c-Kit (CD117) marker and the CD34 marker. CD34 is a widely expressed cell surface antigen found in cells with both progenitor-like and mature properties, making it difficult to distinquish between origins.[15][3][16]

Once mast cell progenitors reach a destination tissue, they mature into resident granulated mast cells. Mature mast cells are also mononuclear. Mast cells are present in most tissues. and characteristically surround blood vessels, nerves and lymphatic vessels. They are especially prominent near the boundaries between the outside world and the internal milieu, such as the skin, mucosa of the lungs, and digestive tract, as well as the mouth, conjunctiva, and nose.[17][18]

Mature resident mast cells are categorized based on their tissue location, granule protease content, and functional characteristics. In rodents, the two major categories of mature mast cells are connective tissue-resident mast cells (CTMCs) and mucosal mast cells (MMCs). Connective tissue mast cells contain heparin and large amounts of histamine and carboxypeptidase in their granules, and are distributed in the skin, peritoneal cavity, intestinal submucosa, and perivascular space around blood vessels. Mucosal mast cells predominantly contain chondroitin sulfate with small amounts of histamine and carboxypeptidase and are distributed in the mucosa of the lung and gastrointestinal tract.[19]

In humans, three main categories of MCs have been identified based on the proteases they express. MCT expresses tryptase and resides primarily in mucosa of the lung and small intestine. MCTC expresses tryptase, chymase, and carboxypeptidase and resides primarily in the skin, lymph nodes, and lung and gut submucosa. ∼98% of all mast cells in the mucosa of the human small intestine are MCT, while only ∼13% of MCs in submucosa are MCT. A third form, MCC, expresses chymase but not tryptase. MCT somewhat resembles rodent MMC, while MCTC somewhat resembles rodent CTMC.[19] Mast cells are still heterogenous within these main categories. In humans, at least six possible subsets of MCs with consistently expressed genes (or transcripts) have been observed across twelve organs. Some of these appear to be preferentially distributed (MC1, skin and lungs; MC2, MC3, MC4, skin and bladder; MC5, lymph node and vasculature; MC6, trachea and lungs).[19][20]

Function

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Illustration depicting mast cell activation and anaphylaxis
The role of mast cells in the development of allergy.

Mast cells are best known for their roles in allergy, anaphylaxis, and atopic dermatitis.[5][6] They also play an important protective role in the defense and repair of cells through wound healing, angiogenesis, vascular permeability, and responses to bacteria, parasites, fungi, viruses and venoms.[21][7][3]

Mast cells are seen as "first responders" that deal with pathogens by alerting other immune cells and coordinating immune responses in the innate and acquired immune systems. When activated, a mast cell can either selectively release (piecemeal degranulation) or rapidly release (anaphylactic degranulation) compounds or "mediators" from storage granules into the local environment.[22]

Mast cells can be stimulated to degranulate by allergens through cross-linking with immunoglobulin E receptors (e.g., FcεRI), physical injury through pattern recognition receptors for damage-associated molecular patterns (DAMPs), microbial pathogens through pattern recognition receptors for pathogen-associated molecular patterns (PAMPs), and various compounds through their associated G-protein coupled receptors (e.g., morphine through opioid receptors) or ligand-gated ion channels. Complement proteins can activate membrane receptors on mast cells to exert various functions as well.[3]

Mast cell and possible activators

Mast cells use a variety of cell surface receptors to detect pathogens. Best known is (FcεRI), a high-affinity receptor for the Fc region of IgE antibodies which is involved in allergies. As a molecular target, FcεRI initiates various outcomes in mast cells (MCs) in response to antigens (Ags). Ags bind to immunoglobulin E (IgE) that is bound to FcεRI to cause the crosslinking of IgE–FcεRI complexes and trigger mast cell activation. Activation leads within minutes to degranulation of mast cells and the release of mediators such as histamine, serotonin, and leukotrienes, followed over a period of hours by the secretion of cytokines, chemokines, and growth factors.[23]

FcεRI regulates the Ag–IgE interaction, driving allergic responses. FcεRI clustering controls signal transduction and the quality of MC responses. Under resting conditions in the cell membrane, the IgE–FcεRI complex diffuses freely. Multivalent Ag binding to IgE reorganizes FcεRI within seconds to minutes, forming large aggregates on the cell surface, and causing a transition in the receptor from a diffuse to an immobile state. Small aggregates remain mobile on the cell surface, whereas large aggregates abruptly become immobile. Changes in the mobility, kinetics, and size of FcεRI clusters may govern signal initiation and termination.[23]

Mast cells (MCs) also have been shown to form mast cell extracellular traps (MCETs) to entrap and kill microbes. In a multistage process, MCs become activated, the nuclear membrane disintegrates, chromatin is released into the cytoplasm, cytoplasmic granules adhere to an emerging DNA web, and the complex is released into the extracellular space.[24]

Mast cell mediators

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Mast cells include secretory granules (also known as lysosome-related organelles, LROs) that hold and release pre-formed inflammatory mediators.[21] A unique, stimulus-specific set of mast cell mediators is released through degranulation following the activation of cell surface receptors on mast cells. Examples of mediators that are released into the extracellular environment during mast cell degranulation include:[21][25]

Structure of histamine

Mast cells play a key role in the inflammatory process. Histamine dilates post-capillary venules, 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 endings (leading to itching or pain). Cutaneous signs of histamine release are the "flare and 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.[26]

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]

In the nervous system

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Unlike other hematopoietic cells of the immune system, mast cells naturally occur in the human brain where they interact with the neuroimmune system.[27] 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 nociceptors.[27] 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.[27][28] Across systems, mast cells serve as the main effector cell through which pathogens can affect the gut–brain axis.[29][30]

In the gut

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In the gastrointestinal tract, mucosal mast cells are located in close proximity to sensory nerve fibres, which communicate bidirectionally.[31][29][30] When these mast cells initially degranulate, they release mediators (e.g., histamine, tryptase, and serotonin) which activate, sensitize, and upregulate membrane expression of nociceptors (i.e., TRPV1) on visceral afferent neurons via their receptors (respectively, HRH1, HRH2, HRH3, PAR2, 5-HT3);[31] in turn, neurogenic inflammation, visceral hypersensitivity, and intestinal dysmotility (i.e., impaired peristalsis) result.[31] Neuronal activation induces neuropeptide (substance P and calcitonin gene-related peptide) signaling to mast cells where they bind to their associated receptors and trigger degranulation of a distinct set of mediators (β-Hexosaminidase, cytokines, chemokines, PGD2, leukotrienes, and eoxins).[31][32]

Physiology

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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

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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.[33] The β chain contains, a single immunoreceptor tyrosine-based activation motif ITAM, in the cytoplasmic region. Each γ chain has one 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.[34] 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.[33]

Allergen process

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Allergen-mediated FcεR1 cross-linking signals are very similar to the signaling event resulting in antigen binding to lymphocytes. The 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.[34] Syk functions as a signal amplifying kinase activity due to the fact that it targets multiple proteins and causes their activation.[35] This antigen stimulated phosphorylation causes the activation of other proteins in the FcεR1-mediated signaling cascade.[36]

Degranulation and fusion

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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.[35] 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 Grb2-associated-binding protein 2 (Gab2), which binds to 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 granules to come into contact with the plasma membrane.[34] The mast cell granule can now 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. Rab3 guanosine triphosphatases and Rab-associated kinases and phosphatases regulate granule membrane fusion in resting mast cells.

MRGPRX2 mast cell receptor

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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.[37] 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.[38] 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

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Enzyme Function
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

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Parasitic infections

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Mast cells are activated in response to infection by pathogenic parasites, such as certain helminths and protozoa, through IgE signaling.[39] Various species known to be affected include T.spiralis, S.ratti, and S.venezuelensis.[39] This is accomplished via Type 2 cell-mediated effector immunity, which is characterized by signaling from IL-4, IL-5, and IL-13.[39][40] It is the same immune response that is responsible for allergic inflammation more generally, and includes effectors beyond mast cells.[39][40] 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.[39]

Mast cell activation disorders

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Mast cell activation disorders (MCAD) are a spectrum of immune disorders 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.[41][42] The classification of mast cell activation disorders was laid out in 2010.[41][42]

Allergic disease

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Allergies are mediated through IgE signaling which triggers mast cell degranulation.[41] Recently, IgE-independent "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).[43]

Many forms of cutaneous[44] and mucosal allergy[45] are mediated in large part by mast cells; they play a central role in asthma,[46] eczema, itch (from various causes),[47][44] allergic rhinitis[48] and allergic conjunctivitis.[49] Antihistamine drugs act by blocking histamine action at nerve endings.[50] 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.[51] Leukotriene antagonists (such as montelukast and zafirlukast) block the action of leukotriene mediators.[52]

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.[53] Vasodilation and increased permeability of capillaries are a result of both H1 and H2 receptor types.[54]

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.[55]

Anaphylaxis

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In anaphylaxis (a severe systemic reaction to allergens, 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.[56][57] Products released from these granules include histamine, serotonin, heparin, chondroitin sulphate, tryptase, chymase, carboxypeptidase, and TNF-α.[56] These can vary in their quantities and proportions between individuals, which may explain some of the differences in symptoms seen across patients.[56]

Histamine is a vasodilatory substance released during anaphylaxis.[54]

Autoimmunity

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Mast cells may be implicated in autoimmune, inflammatory disorders involving the joints, muscles, and tendons. Musculoskeletal diseases include rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, Ehlers–Danlos syndrome, heterotopic ossification, tendinopathy, and gout.[58]

Mastocytosis and clonal disorders

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Mastocytosis is a rare clonal mast cell disorder involving the presence of too many mast cells (mastocytes) and CD34+ mast cell precursors.[59] Mutations in c-Kit are associated with mastocytosis.[41] 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.[60][61] This mutation, as well as expression of either CD2 or CD25 (confirmed by immunostaining or flow cytometry), are characteristic of primary clonal/monoclonal mast cell activation syndrome (CMCAS/MMAS).[61] The most commonly affected organs in mastocytosis are the skin and bone marrow.[62]

Monoclonal disorders

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Neoplastic disorders

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Mastocytomas, or mast cell tumors, can secrete excessive quantities of degranulation products.[41][42] They are often seen in dogs and cats.[63] Other neoplastic disorders associated with mast cells include mast cell sarcoma and mast cell leukemia.

Mast cell activation syndrome

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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.[41][42] The syndrome is diagnosed based upon four sets of criteria involving treatment response, symptoms, a differential diagnosis, and biomarkers of mast cell degranulation.[41][42]

History

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Mast cells were first described by Friedrich von Recklinghausen in 1863. They were later rediscovered by Paul Ehrlich, who described them in his 1878 doctoral thesis on the basis of their unique staining characteristics and large granules. These granules led him to the incorrect belief that they existed to nourish the surrounding tissue, so he named them Mastzellen (from German Mast 'fattening', as of animals).[3][4][64] They are now considered to be part of the immune system.[8]

Research

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Autism

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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.[65]

Histological staining

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Toluidine blue: one of the most common stains for acid mucopolysaccharides and glycoaminoglycans, components of mast cells granules.[66]

Bismarck brown: stains mast cell granules brown.[67]

Surface markers: cell surface markers of mast cells were discussed in detail by Heneberg,[68] 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.[69]

Heterogeneity

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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—a topic of ongoing research.[70][71]

See also

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References

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  16. ^ Wu, C; Boey, D; Bril, O; Grootens, J; Vijayabaskar, MS; Sorini, C; Ekoff, M; Wilson, NK; Ungerstedt, JS; Nilsson, G; Dahlin, JS (9 August 2022). "Single-cell transcriptomics reveals the identity and regulators of human mast cell progenitors". Blood Advances. 6 (15): 4439–4449. doi:10.1182/bloodadvances.2022006969. PMC 9636317. PMID 35500226.
  17. ^ Plum, T; Feyerabend, TB; Rodewald, HR (10 December 2024). "Beyond classical immunity: Mast cells as signal converters between tissues and neurons". Immunity. 57 (12): 2723–2736. doi:10.1016/j.immuni.2024.11.016. PMID 39662090.
  18. ^ Pal, Sarit; Gasheva, Olga Y.; Zawieja, David C.; Meininger, Cynthia J.; Gashev, Anatoliy A. (March 2020). "Histamine-mediated autocrine signaling in mesenteric perilymphatic mast cells". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 318 (3): R590-604. doi:10.1152/ajpregu.00255.2019. PMC 7099465. PMID 31913658.
  19. ^ a b c Ribatti, D (2023). "Mast cells are at the interface between the external environment and the inner organism". Frontiers in Medicine. 10 1332047. doi:10.3389/fmed.2023.1332047. PMC 10794488. PMID 38239615.
  20. ^ Tauber, M; Basso, L; Martin, J; Bostan, L; Pinto, MM; Thierry, GR; Houmadi, R; Serhan, N; Loste, A; Blériot, C; Kamphuis, JBJ; Grujic, M; Kjellén, L; Pejler, G; Paul, C; Dong, X; Galli, SJ; Reber, LL; Ginhoux, F; Bajenoff, M; Gentek, R; Gaudenzio, N (5 February 2024). "Correction: Landscape of mast cell populations across organs in mice and humans". The Journal of Experimental Medicine. 221 (2) e2023057001172024c. doi:10.1084/jem.2023057001172024c. PMC 10818104. PMID 38265438.
  21. ^ a b c Montero-Hernández, JE; Zhang, K; Blank, U; Ménasché, G (2025). "LRO biogenesis and function: what can we learn from mast cells?". Frontiers in cell and developmental biology. 13 1613677. doi:10.3389/fcell.2025.1613677. PMID 40636674.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  22. ^ Sandhu, JK; Kulka, M (22 January 2021). "Decoding Mast Cell-Microglia Communication in Neurodegenerative Diseases". International Journal of Molecular Sciences. 22 (3): 1093. doi:10.3390/ijms22031093. PMC 7865982. PMID 33499208.
  23. ^ a b Nagata, Y; Suzuki, R (11 February 2022). "FcεRI: A Master Regulator of Mast Cell Functions". Cells. 11 (4). doi:10.3390/cells11040622. PMID 35203273.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  24. ^ Elieh Ali Komi, D; Kuebler, WM (February 2022). "Significance of Mast Cell Formed Extracellular Traps in Microbial Defense". Clinical Reviews in Allergy & Immunology. 62 (1): 160–179. doi:10.1007/s12016-021-08861-6. PMC 8140557. PMID 34024033.
  25. ^ Ashmole I, Bradding P (May 2013). "Ion channels regulating mast cell biology". Clinical & Experimental Allergy. 43 (5): 491–502. doi:10.1111/cea.12043. PMID 23600539. S2CID 1127584. P2X receptors are ligand-gated non-selective cation channels that are activated by extracellular ATP. ... 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].
  26. ^ Conway, MJ (21 July 2021). "Type I hypersensitivity promotes Aedes aegypti blood feeding". Scientific Reports. 11 (1) 14891. Bibcode:2021NatSR..1114891C. doi:10.1038/s41598-021-94416-w. PMC 8295252. PMID 34290316.
  27. ^ a b c Polyzoidis S, Koletsa T, Panagiotidou S, Ashkan K, Theoharides TC (2015). "Mast cells in meningiomas and brain inflammation". Journal of Neuroinflammation. 12 (1) 170. doi:10.1186/s12974-015-0388-3. PMC 4573939. PMID 26377554. 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].

    [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.
  28. ^ Ren H, Han R, Chen X, Liu X, Wan J, Wang L, Yang X, Wang J (May 2020). "Potential therapeutic targets for intracerebral hemorrhage-associated inflammation: An update". Journal of Cerebral Blood Flow & Metabolism. 40 (9): 1752–1768. doi:10.1177/0271678X20923551. PMC 7446569. PMID 32423330.
  29. ^ a b Budzyński J, Kłopocka M (2014). "Brain-gut axis in the pathogenesis of Helicobacter pylori infection". World Journal of Gastroenterology. 20 (18): 5212–25. doi:10.3748/wjg.v20.i18.5212. PMC 4017036. PMID 24833851. In digestive tissue, H. pylori can alter signaling in the brain-gut axis by mast cells, the main brain-gut axis effector
  30. ^ a b Carabotti M, Scirocco A, Maselli MA, Severi C (2015). "The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems". Annals of Gastroenterology. 28 (2): 203–209. PMC 4367209. PMID 25830558.
  31. ^ a b c d Wouters MM, Vicario M, Santos J (2015). "The role of mast cells in functional GI disorders". Gut. 65 (1): 155–168. doi:10.1136/gutjnl-2015-309151. PMID 26194403. 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. ... 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.
    ▸ Mast cells play a central pathophysiological role in IBS and possibly in functional dyspepsia, although not well defined.
    ▸ Increased mast cell activation is a common finding in the mucosa of patients with functional GI disorders. ...
    ▸ 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.
  32. ^ Moon TC, Befus AD, Kulka M (2014). "Mast cell mediators: their differential release and the secretory pathways involved". Frontiers in Immunology. 5: 569. doi:10.3389/fimmu.2014.00569. PMC 4231949. PMID 25452755. 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. ... 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).
    Figure 1: Mediator release from mast cells Archived 29 April 2018 at the Wayback Machine
    Figure 2: Model of genesis of mast cell secretory granules Archived 29 April 2018 at the Wayback Machine
    Figure 3: Lipid body biogenesis Archived 29 April 2018 at the Wayback Machine
    Table 2: Stimuli-selective mediator release from mast cells Archived 29 April 2018 at the Wayback Machine
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    Classification of diseases associated with mast cell activation from Akin et al. [14]
    1. Primary
      a. Anaphylaxis with an associated clonal mast cell disorder
      b. Monoclonal mast cell activation syndrome (MMAS), see text for explanation
    2. Secondary
      a. Allergic disorders
      b. Mast cell activation associated with chronic inflammatory or neoplastic disorders
      c. Physical urticarias (requires a primary stimulation)
      d. Chronic autoimmune urticaria
    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)
      a. Anaphylaxis
      b. Angioedema
      c. Urticaria
      d. Mast cell activation syndrome (MCAS)...
    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].
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