Mast cell
Mast cell | |
---|---|
Details | |
System | Immune system |
Identifiers | |
Latin | mastocytus |
MeSH | D008407 |
TH | H2.00.03.0.01010 |
FMA | 66784 |
Anatomical terms of microanatomy |
A mast cell (also known as a mastocyte or a labrocyte[1]) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a part of the immune and neuroimmune systems. Mast cells were discovered by Paul Ehrlich in 1877.[2] 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 pathogens, and vascular permeability in brain tumors.[3][4]
The mast cell is very similar in both appearance and function to the
Structure
Mast cells are very similar to
Mast cells in rodents are classically divided into two subtypes:
Mast cells are present in most tissues characteristically surrounding blood vessels, nerves and lymphatic vessels,
Function
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
Mast cells express a high-affinity receptor (
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.[13] In general, allergens are proteins or polysaccharides. 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.[14]
Mast cell mediators
A unique, stimulus-specific set of mast cell mediators is released through degranulation following the activation of cell surface receptors on mast cells.[12] Examples of mediators that are released into the extracellular environment during mast cell degranulation include:[7][12][15]
- serine proteases, such as tryptase and chymase
- picogramsper mast cell)
- serotonin
- proteoglycans, mainly heparin (active as anticoagulant) and some chondroitin sulfate proteoglycans
- adenosine triphosphate (ATP)
- lysosomal enzymes
- β-hexosaminidase
- β-glucuronidase
- arylsulfatases
- newly formed lipid mediators (eicosanoids):
- cytokines
- TNF-α
- basic fibroblast growth factor
- interleukin-4
- stem cell factor
- chemokines, such as eosinophil chemotactic factor
- reactive oxygen species
Histamine dilates post-capillary venules,
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
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
In the nervous system
Unlike other
In the gut
In the gastrointestinal tract, mucosal mast cells are located in close proximity to sensory nerve fibres, which communicate bidirectionally.
Physiology
Structure of the high-affinity IgE receptor, FcεR1
Allergen process
Allergen-mediated FcεR1 cross-linking signals are very similar to the signaling event resulting in antigen binding to
Degranulation and fusion
An important adaptor protein activated by the Syk phosphorylation step is the
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.[25] 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.[26] 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
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
Parasitic infections
Mast cells are activated in response to infection by pathogenic parasites, such as certain
signaling.Mast cell activation disorders
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.[27][28] The classification of mast cell activation disorders was laid out in 2010.[27][28]
Allergic disease
Allergies are mediated through
Many forms of cutaneous and mucosal
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.[30] Vasodilation and increased permeability of capillaries are a result of both H1 and H2 receptor types.[31]
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.[32]
Anaphylaxis
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.[citation needed]
Histamine is a vasodilatory substance released during anaphylaxis.[31]
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.[33]
Mastocytosis and clonal disorders
This section needs expansion. You can help by adding to it. (October 2015) |
Monoclonal disorders
This section needs expansion. You can help by adding to it. (October 2015) |
Neoplastic disorders
Mastocytomas, or mast cell tumors, can secrete excessive quantities of degranulation products.[27][28] They are often seen in dogs and cats.[35] Other neoplastic disorders associated with mast cells include mast cell sarcoma and mast cell leukemia.
Mast cell activation syndrome
History
Mast cells were first described by Paul Ehrlich in his 1878 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 (from German Mast 'fattening', as of animals).[36][37] They are now considered to be part of the immune system.
Research
Autism
Research into an immunological contribution to
Histological staining
Bismarck brown: stains mast cell granules brown.[40]
Surface markers: cell surface markers of mast cells were discussed in detail by Heneberg,[41] 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.[42]
Other organisms
Mast cells and enterochromaffin cells are the source of most serotonin in the stomach in rodents.[43]
See also
- Allergy
- Mast cell activation syndrome
- Diamine oxidase
- Granulocyte
- Food intolerance
- Histamine
- Histamine intolerance
- Histamine N-methyltransferase or HNMT
- List of distinct cell types in the adult human body
References
- ^ "labrocytes". Memidex. Archived from the original on 6 November 2018. Retrieved 19 February 2011.
- ^ Ehrlich, Paul (1878). "Beiträge zur Theorie und Praxis der Histologischen Färbung". Leipzig University.
- ^ PMID 25062998.
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
- ^ 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. - PMID 20362540.
- ISBN 978-0-321-20413-4.
- ^ PMID 12592295.
- PMID 6166010.)
{{cite journal}}
: CS1 maint: multiple names: authors list (link - S2CID 22811807.
- ISBN 978-0-89603-404-4.[page needed]
- PMID 31913658.
- ^ 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 - S2CID 205378470.
- PMID 22859829.
- 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].
- PMID 16262662.
- PMID 32423330.
- ^ PMID 24833851.
In digestive tissue, H. pylori can alter signaling in the brain-gut axis by mast cells, the main brain-gut axis effector
- ^ PMID 25830558.
- ^ 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. - ^ PMID 10358778.
- ^ ISBN 978-1-4377-1528-6.[page needed]
- ^ PMID 12217392.
- PMID 1535686.
- PMID 31278040. Retrieved 7 July 2021.
- PMID 16979137. Retrieved 7 July 2021.
- ^ S2CID 5723622.
Table 1
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]. - ^ PMID 21035176.
- PMID 33925682.
- S2CID 6977280.
- ^ PMID 8151062.
- PMID 6175225.
- S2CID 38504601.
- PMID 17587883.
- ^ "Cutaneous Mast Cell Tumors". The Merck Veterinary Manual. 2006. Archived from the original on 23 May 2007. Retrieved 8 July 2007.
- OCLC 63372150.
- ^ "Mastocyte - Definition". Archived from the original on 3 February 2010. Retrieved 16 August 2010.[full citation needed]
- PMID 21193035.
- S2CID 32711203.
- .
- PMID 22103846.
- PMID 17900607.
- ^
Fujimiya, Mineko; Inui, Akio (2000). "Peptidergic regulation of gastrointestinal motility in rodents". S2CID 45185196.
External links
- Mast+cells at the U.S. National Library of Medicine Medical Subject Headings (MeSH)