Mast cell

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Mastocytes
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Mast cell
Two mast cells in bone marrow
Details
SystemImmune system
Identifiers
Latinmastocytus
MeSHD008407
THH2.00.03.0.01010
FMA66784
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

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 hematopoietic lineages and thus cannot be the same cells.[5]

Structure

Illustration depicting mast cell activation and anaphylaxis
Mast cell

Mast cells are very similar to

basophil granulocytes (a class of white blood cells) in blood, in the sense that both are granulated cells that contain histamine and heparin, an anticoagulant. Their nuclei differ in that the basophil nucleus is lobated while the mast cell nucleus is round. The Fc region of immunoglobulin E (IgE) becomes bound to mast cells and basophils, and when IgE's paratopes bind to an antigen, it causes the cells to release histamine and other inflammatory mediators.[6] 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.[7] The first in vitro differentiation and growth of a pure population of mouse mast cells has been carried out using conditioned medium derived from concanavalin A-stimulated splenocytes.[8] 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.[9]

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,

digestive tract, as well as the mouth, conjunctiva, and nose.[7]

Function

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

G-protein coupled receptors (e.g., morphine through opioid receptors) or ligand-gated ion channels.[3][12] Complement proteins can activate membrane receptors on mast cells to exert various functions as well.[7]

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 cells (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.[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]

Structure of histamine

Histamine dilates post-capillary venules,

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.[7]

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
]

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.[16]

In the nervous system

Unlike other

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.[4] 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.[4][17] Across systems, mast cells serve as the main effector cell through which pathogens can affect the gut–brain axis.[18][19]

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 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

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.[21]

Allergen process

Allergen-mediated FcεR1 cross-linking signals are very similar to the signaling event resulting in antigen binding to

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.[22] Syk functions as a signal amplifying kinase activity due to the fact that it targets multiple proteins and causes their activation.[23] This antigen stimulated phosphorylation causes the activation of other proteins in the FcεR1-mediated signaling cascade.[24]

Degranulation and fusion

An important adaptor protein activated by the Syk phosphorylation step is the

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

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

helminths and protozoa, through IgE
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

fluoroquinolones).[29]

Many forms of cutaneous and mucosal

Leukotriene antagonists (such as montelukast and zafirlukast) block the action of leukotriene mediators and are being used increasingly in allergic diseases.[7]

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

c-Kit are associated with mastocytosis.[27]

Monoclonal disorders

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

idiopathic immune disorder that involves recurrent and excessive mast cell degranulation and which produces symptoms that are similar to other mast cell activation disorders.[27][28] The syndrome is diagnosed based upon four sets of criteria involving treatment response, symptoms, a differential diagnosis, and biomarkers of mast cell degranulation.[27][28]

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

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.[38]

Histological staining

glycoaminoglycans, components of mast cells granules.[39]

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

References

  1. ^ "labrocytes". Memidex. Archived from the original on 6 November 2018. Retrieved 19 February 2011.
  2. ^ Ehrlich, Paul (1878). "Beiträge zur Theorie und Praxis der Histologischen Färbung". Leipzig University.
  3. ^
    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
  4. ^ . 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.
  5. .
  6. .
  7. ^ .
  8. PMID 6166010.{{cite journal}}: CS1 maint: multiple names: authors list (link
    )
  9. .
  10. ]
  11. .
  12. ^
    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
  13. .
  14. .
  15. . 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].
  16. .
  17. .
  18. ^ . In digestive tissue, H. pylori can alter signaling in the brain-gut axis by mast cells, the main brain-gut axis effector
  19. ^ .
  20. ^ . 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.
  21. ^ .
  22. ^ ]
  23. ^ .
  24. .
  25. . Retrieved 7 July 2021.
  26. . Retrieved 7 July 2021.
  27. ^ . 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].
  28. ^ .
  29. .
  30. .
  31. ^ .
  32. .
  33. .
  34. .
  35. ^ "Cutaneous Mast Cell Tumors". The Merck Veterinary Manual. 2006. Archived from the original on 23 May 2007. Retrieved 8 July 2007.
  36. OCLC 63372150
    .
  37. ^ "Mastocyte - Definition". Archived from the original on 3 February 2010. Retrieved 16 August 2010.[full citation needed]
  38. PMID 21193035
    .
  39. .
  40. .
  41. .
  42. .
  43. ^ Fujimiya, Mineko; Inui, Akio (2000). "Peptidergic regulation of gastrointestinal motility in rodents".
    S2CID 45185196
    .

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