Mast cell

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Mastocyte
Mast cells in bone marrow.jpg
Two mast cells in bone marrow
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 Friedrich von Recklinghausen and later rediscovered 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]

Contents

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 Blausen 0018 Anaphylaxis.png
Illustration depicting mast cell activation and anaphylaxis
Mast cell Mast cell.png
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: connective tissue-type mast cells and mucosal mast cells. The activities of the latter are dependent on T-cells. [10]

Mast cells are present in most tissues characteristically surrounding blood vessels, nerves and lymphatic vessels, [11] and 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. [7]

Function

The role of mast cells in the development of allergy. Mast cells.jpg
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 granules into the local microenvironment. [3] [12] 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. [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.svg
Structure of histamine

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. [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 hematopoietic cells of the immune system, mast cells naturally occur in the human brain where they interact with the neuroimmune system. [4] 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. [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. [20] [18] [19] 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); [20] in turn, neurogenic inflammation, visceral hypersensitivity, and intestinal dysmotility (i.e., impaired peristalsis) result. [20] 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 ). [20] [12]

Physiology

Structure of FceR1 on mast cell. FceR1 is a tetramer made of one alpha (a) chain, one beta (b) chain, and two gamma (g) chains. IgE is binding to a chain, signal is transduced by ITAM motifs on b and g chains. FceR1.jpg
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

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. [21] 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. [22] 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. [21]

Allergen process

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. [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 linker for activation of T cells (LAT). LAT can be modified by phosphorylation to create novel binding sites. [23] 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. [22] 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

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

EnzymeFunction
Lyn tyrosine kinasePhosphorylates 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 kinaseTargets 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 phosphatasesRegulate 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. [27] Various species known to be affected include T.spiralis , S.ratti , and S.venezuelensis . [27] This is accomplished via Type 2 cell-mediated effector immunity, which is characterized by signaling from IL-4, IL-5, and IL-13. [27] [28] It is the same immune response that is responsible for allergic inflammation more generally, and includes effectors beyond mast cells. [27] [28] 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. [27]

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. [29] [30] The classification of mast cell activation disorders was laid out in 2010. [29] [30]

Allergic disease

Allergies are mediated through IgE signaling which triggers mast cell degranulation. [29] 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). [31]

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 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. [32] Vasodilation and increased permeability of capillaries are a result of both H1 and H2 receptor types. [33]

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. [34]

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. [35] [36] Products released from these granules include histamine, serotonin, heparin, chondroitin sulphate, tryptase, chymase, carboxypeptidase, and TNF-α. [35] These can vary in their quantities and proportions between individuals, which may explain some of the differences in symptoms seen across patients. [35]

Histamine is a vasodilatory substance released during anaphylaxis. [33]

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. [37]

Mastocytosis and clonal disorders

Mastocytosis is a rare clonal mast cell disorder involving the presence of too many mast cells (mastocytes) and CD34+ mast cell precursors. [38] Mutations in c-Kit are associated with mastocytosis. [29] 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. [39] [40] 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). [40] The most commonly affected organs in mastocytosis are the skin and bone marrow. [41]

Monoclonal disorders

Neoplastic disorders

Mastocytomas, or mast cell tumors, can secrete excessive quantities of degranulation products. [29] [30] They are often seen in dogs and cats. [42] Other neoplastic disorders 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. [29] [30] The syndrome is diagnosed based upon four sets of criteria involving treatment response, symptoms, a differential diagnosis, and biomarkers of mast cell degranulation. [29] [30]

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). [43] [44] 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. [45]

Histological staining

Toluidine blue: one of the most common stains for acid mucopolysaccharides and glycoaminoglycans, components of mast cells granules. [46]

Bismarck brown: stains mast cell granules brown. [47]

Surface markers: cell surface markers of mast cells were discussed in detail by Heneberg, [48] 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. [49]

Other organisms

Mast cells and enterochromaffin cells are the source of most serotonin in the stomach in rodents. [50]

See also

Related Research Articles

<span class="mw-page-title-main">Mastocytosis</span> Medical condition

Mastocytosis, a type of mast cell disease, is a rare disorder affecting both children and adults caused by the accumulation of functionally defective mast cells and CD34+ mast cell precursors.

<span class="mw-page-title-main">Eosinophil</span> Variety of white blood cells

Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along with mast cells and basophils, they also control mechanisms associated with allergy and asthma. They are granulocytes that develop during hematopoiesis in the bone marrow before migrating into blood, after which they are terminally differentiated and do not multiply.

<span class="mw-page-title-main">Basophil</span> Type of white blood cell

Basophils are a type of white blood cell. Basophils are the least common type of granulocyte, representing about 0.5% to 1% of circulating white blood cells. They are the largest type of granulocyte. They are responsible for inflammatory reactions during immune response, as well as in the formation of acute and chronic allergic diseases, including anaphylaxis, asthma, atopic dermatitis and hay fever. They also produce compounds that coordinate immune responses, including histamine and serotonin that induce inflammation, and heparin that prevents blood clotting, although there are less than that found in mast cell granules. Mast cells were once thought to be basophils that migrated from the blood into their resident tissues, but they are now known to be different types of cells.

<span class="mw-page-title-main">Histamine</span> Organic compound involved in immune responses

Histamine is an organic nitrogenous compound involved in local immune responses communication, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Discovered in 1910, histamine has been considered a local hormone (autocoid) because it's produced without involvement of the classic endocrine glands; however, in recent years, histamine has been recognized as a central neurotransmitter. Histamine is involved in the inflammatory response and has a central role as a mediator of itching. As part of an immune response to foreign pathogens, histamine is produced by basophils and by mast cells found in nearby connective tissues. Histamine increases the permeability of the capillaries to white blood cells and some proteins, to allow them to engage pathogens in the infected tissues. It consists of an imidazole ring attached to an ethylamine chain; under physiological conditions, the amino group of the side-chain is protonated.

<span class="mw-page-title-main">Immunoglobulin E</span> Immunoglobulin E (IgE) Antibody

Immunoglobulin E (IgE) is a type of antibody that has been found only in mammals. IgE is synthesised by plasma cells. Monomers of IgE consist of two heavy chains and two light chains, with the ε chain containing four Ig-like constant domains (Cε1–Cε4). IgE is thought to be an important part of the immune response against infection by certain parasitic worms, including Schistosoma mansoni, Trichinella spiralis, and Fasciola hepatica. IgE is also utilized during immune defense against certain protozoan parasites such as Plasmodium falciparum. IgE may have evolved as a defense to protect against venoms.

<span class="mw-page-title-main">Granulocyte</span> Category of white blood cells

Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. Such granules distinguish them from the various agranulocytes. All myeloblastic granulocytes are polymorphonuclear, that is, they have varying shapes (morphology) of the nucleus ; and are referred to as polymorphonuclear leukocytes. In common terms, polymorphonuclear granulocyte refers specifically to "neutrophil granulocytes", the most abundant of the granulocytes; the other types have varying morphology. Granulocytes are produced via granulopoiesis in the bone marrow.

<span class="mw-page-title-main">Type I hypersensitivity</span> Type of allergic reaction

Type I hypersensitivity, in the Gell and Coombs classification of allergic reactions, is an allergic reaction provoked by re-exposure to a specific type of antigen referred to as an allergen. Type I is distinct from type II, type III and type IV hypersensitivities. The relevance of the Gell and Coombs classification of allergic reactions has been questioned in the modern-day understanding of allergy, and it has limited utility in clinical practice.

<span class="mw-page-title-main">Fc receptor</span> Surface protein important to the immune system

In immunology, an Fc receptor is a protein found on the surface of certain cells – including, among others, B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, human platelets, and mast cells – that contribute to the protective functions of the immune system. Its name is derived from its binding specificity for a part of an antibody known as the Fc region. Fc receptors bind to antibodies that are attached to infected cells or invading pathogens. Their activity stimulates phagocytic or cytotoxic cells to destroy microbes, or infected cells by antibody-mediated phagocytosis or antibody-dependent cell-mediated cytotoxicity. Some viruses such as flaviviruses use Fc receptors to help them infect cells, by a mechanism known as antibody-dependent enhancement of infection.

<span class="mw-page-title-main">FCER1</span> An instance of macromolecular complex in Homo sapiens with Reactome ID (R-HSA-2454198)

The high-affinity IgE receptor, also known as FcεRI, or Fc epsilon RI, is the high-affinity receptor for the Fc region of immunoglobulin E (IgE), an antibody isotype involved in allergy disorders and parasite immunity. FcεRI is a tetrameric receptor complex that binds Fc portion of the ε heavy chain of IgE. It consists of one alpha, one beta, and two gamma chains connected by two disulfide bridges on mast cells and basophils. It lacks the beta subunit on other cells. It is constitutively expressed on mast cells and basophils and is inducible in eosinophils.

<span class="mw-page-title-main">Allergic inflammation</span>

Allergic inflammation is an important pathophysiological feature of several disabilities or medical conditions including allergic asthma, atopic dermatitis, allergic rhinitis and several ocular allergic diseases. Allergic reactions may generally be divided into two components; the early phase reaction, and the late phase reaction. While the contribution to the development of symptoms from each of the phases varies greatly between diseases, both are usually present and provide us a framework for understanding allergic disease.

<span class="mw-page-title-main">Degranulation</span> Process by which cells lose secretory granules

Degranulation is a cellular process that releases antimicrobial, cytotoxic, or other molecules from secretory vesicles called granules found inside some cells. It is used by several different cells involved in the immune system, including granulocytes. It is also used by certain lymphocytes such as natural killer (NK) cells and cytotoxic T cells, whose main purpose is to destroy invading microorganisms.

<span class="mw-page-title-main">SIGLEC8</span> Protein-coding gene in the species Homo sapiens

Sialic acid-binding Ig-like lectin 8 is a protein that in humans is encoded by the SIGLEC8 gene. This gene is located on chromosome 19q13.4, about 330 kb downstream of the SIGLEC9 gene. Within the siglec family of transmembrane proteins, Siglec-8 belongs to the CD33-related siglec subfamily, a subfamily that has undergone rapid evolution.

The following outline is provided as an overview of and topical guide to immunology:

<span class="mw-page-title-main">Basophil activation</span>

Allergic symptoms are caused by an initial systemic histamine release by activated basophils and mast cells, that may lead to shock with laryngeal edema, lower-airway obstruction and hypotension. This is why basophils are considered with mast cells to be the key cells in allergic diseases.

Pseudoallergy, sometimes known as nonallergic hypersensitivity, is a type of hypersensitivity reaction mostly described in the context of drug allergy. The mechanism is somewhat similar to the type 1 hypersensitivity in the Gell and Coombs classification in that the effector cell is also mast cell. In pseudoallergic reaction, the mast cell is directly activated, rather than through the mediation of Immunoglobulin E (IgE). Therefore, it is also known as direct mast cell activation.

<span class="mw-page-title-main">RBL cells</span>

RBL are cancerous basophil cells that are well suited for the study of allergies.

Mast cell activation syndrome (MCAS) is a term referring to one of two types of mast cell activation disorder (MCAD); the other type is idiopathic MCAD. MCAS is an immunological condition in which mast cells, a type of white blood cell, inappropriately and excessively release chemical mediators, such as histamine, resulting in a range of chronic symptoms, sometimes including anaphylaxis or near-anaphylaxis attacks. Primary symptoms include cardiovascular, dermatological, gastrointestinal, neurological, and respiratory problems.

<span class="mw-page-title-main">Proxicromil</span> Chemical compound

Proxicromil is a detergent-like, lipophilic oral medication developed in the late 1970s that was not admitted on the market because of its possible carcinogenic effects. It suppresses allergic reactions by binding to FcεRI receptor in mast cells, thereby inhibiting production of histamines. It is absorbed through the gastrointestinal tract, and has been proven hepatotoxic for dogs as a result of its accumulation in biliary canaliculi.

<span class="mw-page-title-main">Autoimmune urticaria</span> Autoimmune disease causing hives and itching

Autoimmune urticaria, also known as chronic autoimmune urticaria, is a type of chronic urticaria characterized by the presence of autoantibodies in the patient's immune system that target the body's own mast cells, leading to episodes of hives (urticaria). This immunologically distinct type of urticaria is considered autoimmune because the immune system, which normally protects the body from foreign organisms, mistakenly attacks the body's own cells, causing inflammation and other symptoms.

<span class="mw-page-title-main">K252b</span> Chemical compound

K252b is an ectoprotein kinase inhibitor, which is involved in the abolishment of the effects of nerve growth factors on PC12 cell and peripheral neuron system (PNS) neurons. When it is present in very low concentrations, it prolongs the survivorship of hippocampal, septal and cortical neurons deprived of glucose.

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. 1 2 3 da Silva EZ, Jamur MC, Oliver C (2014). "Mast cell function: a new vision of an old cell". J. Histochem. Cytochem. 62 (10): 698–738. doi:10.1369/0022155414545334. PMC   4230976 . 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. 1 2 3 4 Polyzoidis S, Koletsa T, Panagiotidou S, Ashkan K, Theoharides TC (2015). "Mast cells in meningiomas and brain inflammation". J 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.
  5. ↑ Franco CB, Chen CC, Drukker M, Weissman IL, Galli SJ (2010). "Distinguishing mast cell and granulocyte differentiation at the single-cell level". Cell Stem Cell. 6 (4): 361–8. doi:10.1016/j.stem.2010.02.013. PMC   2852254 . PMID   20362540.
  6. ↑ Marieb EN, Hoehn K (2004). Human Anatomy and Physiology (6th ed.). San Francisco: Pearson Benjamin Cummings. p.  805. ISBN   978-0-321-20413-4.
  7. 1 2 3 4 5 6 Prussin C, Metcalfe DD (February 2003). "4. IgE, mast cells, basophils, and eosinophils". The Journal of Allergy and Clinical Immunology. 111 (2 Suppl): S486–94. doi:10.1067/mai.2003.120. PMC   2847274 . PMID   12592295.
  8. ↑ Razin E, Cordon-Cardo C, Good RA (April 1981). "Growth of a pure population of mouse mast cells in vitro with conditioned medium derived from concanavalin A-stimulated splenocytes". Proceedings of the National Academy of Sciences of the United States of America. 78 (4): 2559–61. Bibcode:1981PNAS...78.2559R. doi: 10.1073/pnas.78.4.2559 . PMC   319388 . PMID   6166010.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ↑ Razin E, Ihle JN, Seldin D, et al. (March 1984). "Interleukin 3: A differentiation and growth factor for the mouse mast cell that contains chondroitin sulfate E proteoglycan". Journal of Immunology. 132 (3): 1479–86. doi: 10.4049/jimmunol.132.3.1479 . PMID   6198393. S2CID   22811807.
  10. ↑ Denburg JA (1998). Allergy and allergic diseases: the new mechanisms and therapeutics. Totowa, NJ: Humana Press. ISBN   978-0-89603-404-4.[ page needed ]
  11. ↑ 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.
  12. 1 2 3 4 5 Moon TC, Befus AD, Kulka M (2014). "Mast cell mediators: their differential release and the secretory pathways involved". Front Immunol. 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
  13. ↑ Pulendran B, Ono SJ (May 2008). "A shot in the arm for mast cells". Nat. Med. 14 (5): 489–90. doi: 10.1038/nm0508-489 . PMID   18463655. S2CID   205378470.
  14. ↑ Lee J, Veatch SL, Baird B, Holowka D (2012). "Molecular mechanisms of spontaneous and directed mast cell motility". J. Leukoc. Biol. 92 (5): 1029–41. doi:10.1189/jlb.0212091. PMC   3476239 . PMID   22859829.
  15. ↑ Ashmole I, Bradding P (May 2013). "Ion channels regulating mast cell biology". Clin. Exp. 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].
  16. ↑ Wilhelm M, Silver R, Silverman AJ (November 2005). "Central nervous system neurons acquire mast cell products via transgranulation". The European Journal of Neuroscience. 22 (9): 2238–48. doi:10.1111/j.1460-9568.2005.04429.x. PMC   3281766 . PMID   16262662.
  17. ↑ 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". J Cereb Blood Flow Metab. 40 (9): 1752–1768. doi:10.1177/0271678X20923551. PMC   7446569 . PMID   32423330.
  18. 1 2 Budzyński J, Kłopocka M (2014). "Brain-gut axis in the pathogenesis of Helicobacter pylori infection". World J. Gastroenterol. 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
  19. 1 2 Carabotti M, Scirocco A, Maselli MA, Severi C (2015). "The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems". Ann Gastroenterol. 28 (2): 203–209. PMC   4367209 . PMID   25830558.
  20. 1 2 3 4 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.
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  23. 1 2 Rivera J, Cordero JR, Furumoto Y, et al. (September 2002). "Macromolecular protein signaling complexes and mast cell responses: a view of the organization of IgE-dependent mast cell signaling". Molecular Immunology. 38 (16–18): 1253–8. doi:10.1016/S0161-5890(02)00072-X. PMID   12217392.
  24. ↑ Li W, Deanin GG, Margolis B, Schlessinger J, Oliver JM (July 1992). "FcεR1-mediated tyrosine phosphorylation of multiple proteins, including phospholipase Cγ1 and the receptor βγ2 complex, in RBL-2H3 rat basophilic leukemia cells". Molecular and Cellular Biology. 12 (7): 3176–82. doi:10.1128/MCB.12.7.3176. PMC   364532 . PMID   1535686.
  25. ↑ Pundir, Priyanka; Liu, Rui; Vasavda, Chirag; Serhan, Nadine; Limjunyawong, Nathachit; Yee, Rebecca; Zhan, Yingzhuan; Dong, Xintong; Wu, Xueqing; Zhang, Ying; Snyder, Solomon H; Gaudenzio, Nicolas; Vidal, Jorge E; Dong, Xinzhong (July 2019). "A Connective Tissue Mast-Cell-Specific ReceptorDetects Bacterial Quorum-Sensing Moleculesand Mediates Antibacterial Immunity". Cell Host & Microbe. 26 (1): 114–122. doi:10.1016/j.chom.2019.06.003. PMC   6649664 . PMID   31278040 . Retrieved 7 July 2021.
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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].
  30. 1 2 3 4 5 Akin C, Valent P, Metcalfe DD (2010). "Mast cell activation syndrome: Proposed diagnostic criteria". J. Allergy Clin. Immunol. 126 (6): 1099–104.e4. doi:10.1016/j.jaci.2010.08.035. PMC   3753019 . PMID   21035176.
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  33. 1 2 Dachman WD, Bedarida G, Blaschke TF, Hoffman BB (March 1994). "Histamine-induced venodilation in human beings involves both H1 and H2 receptor subtypes". The Journal of Allergy and Clinical Immunology. 93 (3): 606–14. doi: 10.1016/S0091-6749(94)70072-9 . PMID   8151062.
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  40. 1 2 Jackson, Clayton Webster; Pratt, Cristina Marie; Rupprecht, Chase Preston; Pattanaik, Debendra; Krishnaswamy, Guha (19 October 2021). "Mastocytosis and Mast Cell Activation Disorders: Clearing the Air". International Journal of Molecular Sciences. 22 (20): 11270. doi: 10.3390/ijms222011270 . ISSN   1422-0067. PMC   8540348 . PMID   34681933.
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