Mast cell

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Mastocyte
Mastocyte.jpg
Mast cell (large dark cell in the center of the field of view) surrounded by bone marrow cells, Giemsa stain, 1000x.
Details
System Immune system
Identifiers
Latin mastocytus
MeSH D008407
TH H2.00.03.0.01010
FMA 66784
Anatomical terms of microanatomy
External videos
Nuvola apps kaboodle.svg 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]

Contents

Mast cells act as sentinels, sensing danger signals from pathogens, tissues, and other immune cells and modulating immune responses according to the stimuli detected. [5] MCs are best known for their roles in allergy, anaphylaxis, and atopic dermatitis. [6] [7] 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. [8] [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. [9]

Development

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. [10] 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, and are highly heterogenous. [11]

Mast cells may have dual methods of origin in the hematopoietic system. [12] 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. [12] 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. [11] [3] [8]

However, lineage relationships in human hematopoiesis have been hotly debated. [11] 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. [12] Tissue-resident immune cells either may be fetal-derived or be the progeny of adult HSCs. [12]

In vertebrates, the earliest source of mast cells is the extraembryonic yolk sac, where blood and immune cells first develop. [13] 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. [14]

During embryonic development, mast cell progenitors (MCps) form in a series of developmentally discrete waves. [11] 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. [13] In mouse models, the earliest mast cell progenitors originate in the embryo around embryonic day 7 [15] (E7.5-E8.5). [13] 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. [13] Embryonic multipotent progenitors (eMPPs) and hematopoietic stem cells (HSCs) emerge around E10.5. [13] 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. [13] eMPPs and HSCs start producing mature hematopoietic cells in in the fetal liver around E12.5 and E14.5 respectively. [13] HSCs can produce mast cells within a limited time window which declines after embryonic day E14.5. [12]

Whether mast cell origination is mostly independent of HSCs, or "adult" mast cells originate in bone marrow (BM) from HSCs is debated. [12] 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. [12] It is unclear whether fetal-derived immune cells may be produced by HSCs during the fetal to neonatal period. [12]

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. [6]

Structure

Mast cell (NIH BioArt), darker nucleus surrounded by granules. Mast Cell (NIH BioArt 335 - 638079).png
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. [6]

Mast cell progenitors, sometimes referred to as "immature" mast cells, circulate in the bloodstream as undifferentiated mononuclear cells. [6] [15] 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. [16] [3] [17]

Once mast cell progenitors reach a destination tissue, they mature into resident granulated mast cells. [18] Mature mast cells are also mononuclear. Healthy mature mast cells present a distinct immunophenotype in which expression of CD117 is high; CD33, CD9 and CD71 are intermediate; CD11b and CD38 are low; and HLA-DR, CD34, and CD123 are absent. [19] 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. [18] [20]

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. [21]

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

Function

Illustration depicting mast cell activation and anaphylaxis Blausen 0018 Anaphylaxis.png
Illustration depicting mast cell activation and anaphylaxis
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 are best known for their roles in allergy, anaphylaxis, and atopic dermatitis. [6] [7] [5] 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. [23] [8] [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. [24]

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 Mastcell800px.jpg
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. [25] [26]

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. [25]

In addition to IgE-dependent MC activation, forms of IgE-independent MC activation have been studied. One of these involves MRGPRX2, a G protein-coupled receptor (GPCR). The MRGPRX2 activation pathway in humans involves four primate-specific families of MRGPRX genes (MRGPRX1-X4) as well as the MrgprD-H families, while the MrgprA, MrgprB and MrgprC families are specific to rodents. MRGPRX2 recognizes a wide variety of basic amino acids and low-molecular-weight compounds without amino acid sequence motifs. [5]

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. [27]

Metabolic mechanisms in IgE mediated and non-IgE mediated MC activation are not well understood. Healthy mitochondrial respiration involves maximal production of adenosine triphosphate (ATP) and minimal production of reactive oxygen species (ROS). [26]

Mast cell mediators

Mast cells contain secretory granules (also known as lysosome-related organelles, LROs) that hold and release pre-formed inflammatory mediators. [23] A unique, stimulus-specific set of mast cell mediators is released through degranulation following the activation of cell surface receptors on mast cells. In addition to such pre-formed mediators, mast cells can also secrete newly synthesized mediators in response to allergic and nonallergic triggers. Examples of mediators that are released into the extracellular environment include: [23] [28] [29] [30]

Inflammation

Structure of histamine Histamine.svg
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. [32]

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

Unlike other hematopoietic cells of the immune system, mast cells naturally occur in the human brain where they interact with the neuroimmune system. [33] 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. [33] 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. [33] [34] Across systems, mast cells serve as the main effector cell through which pathogens can affect the gut–brain axis. [35] [36]

In the gut

In the gastrointestinal tract, mucosal mast cells are located in close proximity to sensory nerve fibres, which communicate bidirectionally. [37] [35] [36] 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); [37] in turn, neurogenic inflammation, visceral hypersensitivity, and intestinal dysmotility (i.e., impaired peristalsis) result. [37] 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 ). [37] [38]

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. [39] 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. [40] 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. [39]

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. [40] Syk functions as a signal amplifying kinase activity due to the fact that it targets multiple proteins and causes their activation. [41] This antigen stimulated phosphorylation causes the activation of other proteins in the FcεR1-mediated signaling cascade. [42]

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. [41] 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. [40] 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. [43] 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. [44] 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

Allergic disease

MCs may be linked to allergic diseases including allergic asthma, [45] food allergies [46] [47] and atopic dermatitis. [7] [48] Allergies generally result from reduced tolerance to environmental factors which causes Type 2 inflammation characterized by increased TH2 cytokines and IgE antibodies. Allergens are recognized by specific IgE antibodies bound to FcεRI receptor on the surface of tissue MCs, triggering degranulation and the release of mediators including histamine and tryptase. [49]

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). [50]

Many forms of cutaneous [48] and mucosal allergy [51] are mediated in large part by mast cells; they play a central role in asthma, [52] eczema, itch (from various causes), [7] [48] allergic rhinitis [53] and allergic conjunctivitis. [54] Antihistamine drugs act by blocking histamine action at nerve endings. [55] 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. [56] Leukotriene antagonists (such as montelukast and zafirlukast) block the action of leukotriene mediators. [57]

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. [58] Vasodilation and increased permeability of capillaries are a result of both H1 and H2 receptor types. [59]

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. [60]

Anaphylaxis

A systemic allergic response can cause life-threatening anaphylaxis. [49] 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. [61] [62] Products released from these granules include histamine, serotonin, heparin, chondroitin sulphate, tryptase, chymase, carboxypeptidase, and TNF-α. [61] These can vary in their quantities and proportions between individuals, which may explain some of the differences in symptoms seen across patients. [61] Anaphylaxis and MCAS are interrelated but distinct conditions. [63]

Chronic urticaria

Chronic urticaria (CU) is characterized by wheal and flare symptoms of the skin lasting more than six weeks at a time. Symptoms of CU appear to be caused by the degranulation of mast cells in skin. CU has two subtypes: chronic inducible urticaria (CIndU, identifiable triggers) and chronic spontaneous urticaria (CSU, unpredictable triggers). In type I CSU, IgE autoantibodies are directed against self-antigens. In type IIb CSU, autoantibodies are directed against IgE or FcεRI. [49]

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. [64] The classification of mast cell disorders is complex and has been repeatedly modified. The World Health Organization (WHO) classification of 2016 was updated in the WHO 5th Edition Classification of Haematolymphoid Tumours of 2022 and the International Consensus Classification (ICC) schema of 2022, which differ somewhat in their classification of subcategories of systemic mastocytosis. [19] The incidence and prevalence of MCAD's subcategories of mastocytosis and MCAS have not yet been established through epidemiological studies. [65]

Mastocytosis

Mastocytosis involves both excessive accumulation and activation of mast cells and is considered a primary type of mast cell activation disorder (MCAD). [66] [30] Mastocytosis is a rare clonal mast cell disorder involving rapid, uncontrolled cell growth and the presence of too many mast cells (mastocytes). In 2016, the World Health Organization (WHO) classified mastocytosis as cutaneous (CM, skin only), systemic (SM, involving at least one additional organ) or mast cell sarcoma (MCS, involving rapidly spreading solid tumors). [49] [19] In 2022, WHO divided SM into subcategories which include the less advanced forms of bone marrow mastocytosis (BMM), indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), and the more advanced forms of aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). [19] [67]

Symptoms of mastocytosis depend upon the organs involved. [49] [65] [68] Although not always present, mutations in KIT appear to result in uncontrolled growth of MCs. The KITD816V mutation is present in over 90% of mastocytosis patients. It is located in exon 17 in the intracellular tyrosine kinase 2 (TK2) domain. [49] 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). [66] The most commonly affected organs in mastocytosis are bone marrow, skin, liver, spleen, and lymph nodes. [69]

Mast cell activation syndrome

Mast cell activation syndrome (MCAS) is a type of immune disorder and a subcategory of MCAD. [49] MCAS is not considered a subtype of mastocytosis. [19] MCAS includes multiple disorders with varying etiologies [63] that are characterized by severe, acute, recurrent over-activation and degranulation of mast cells, marked by a transient increase in MC-derived mediators such as tryptase or histamine. [49] Suggested causes of abnormal activation include changes in MC activation threshold, abnormal expression of receptors and mediators, environmental tissue changes affecting mediators, and regulatory gene mutations. [65]

Consensus diagnostic criteria for MCAS have been proposed, but as of 2022, diagnostic criteria for MCAS were not established by either the WHO 5th edition or ICC. [19] Appropriate usage of the term MCAS and its diagnosis in patients continue to be debated. [19] [70] Three criteria may be required as a standard for an MCAS diagnosis: [68] a clinical criterion (severe, episodic MC activation symptoms in 2 or more organ systems); a laboratory criterion (detection of a substantial transient increase in a marker of MC activation such as tryptase, accompanying activation events); and a response criterion (control of symptoms with MC stabilizers or inhibitors of MC mediators). [63] [68] Since many clinical conditions can display symptoms similar to those resulting from MC activation, caution is recommended in the diagnosis of MCAS. It is essential to confirm that symptoms derive from MC activation and mediator release, not other mechanisms. [63] [19]

Given a diagnosis of MCAS as described above, various subclassifications of MCAS have been proposed depending on the presence of specific pathologies or triggers. MCAS may be considered primary (if KIT genetic mutations or clonal MCs in bone marrow are detected), secondary (if IgE-mediated or non-IgE-mediated allergy mechanisms are present), combined (involving multiple variants), or idiopathic (if specific causes cannot be identified). [63] [19] There is debate over whether HαT, a genetic trait involving copies of the TPSAB1 gene which encodes for alpha-tryptase, should be considered a modifying factor that influences mediator-related symptoms [63] or an initiator for a subcategory of MCAS. [19] [68]

Parasitic infections

Mast cells are activated in response to infection by pathogenic parasites, such as certain helminths and protozoa, through IgE signaling. [71] Various species known to be affected include T.spiralis , S.ratti , and S.venezuelensis . [71] This is accomplished via Type 2 cell-mediated effector immunity, which is characterized by signaling from IL-4, IL-5, and IL-13. [71] [72] It is the same immune response that is responsible for allergic inflammation more generally, and includes effectors beyond mast cells. [71] [72] 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. [71]

Preliminary research

Mast cells have been suggested to play a role in a wide variety of additonal conditions, with differing degrees of evidence in support. [30] Cardiac mast cells (CMCs) in the human heart differ functionally from mast cells in other organs, and may be involved in both inducing and protecting against cardiovascular disease. [73] They are suggested to play important roles in angiogenesis, atherosclerosis, fibrosis, and tissue regeneration. [74] MCs may also be involved in neurologic disorders such as migraine. [75] [30]

In some cases the role of MCs is uncertain or is being reassessed. This includes autoimmune and inflammatory disorders involving the joints, muscles, and tendons such as rheumatoid arthritis, psoriatic arthritis, heterotopic ossification, and gout. [76]

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. [77]

Drug treatments

Given the heterogeneity of mast cells and the complexity of the processes by which they release mediators, many compounds can affect mast cell behavior with both intended and unintended results. These include antihistamines, vitamins, glucocorticosteroids, monoclonal antibodies (mAbs), and flavonoids. [29] Mast cell stabilizers block mast cell degranulation by stabilizing the cell membrane, preventing the release of mediators such as histamine. Mast cell stabilizers include sodium cromoglycate, ketotifen, pemirolast, nedocromil, and olopatadine. [29] Glucocorticosteroids (GCs) reduce mast cell numbers, maturation and activation. [29]

Other approved therapies which directly target MCs include the following: Omalizumab (targets IgE); Imatinib, Midostaurin and Avapritinib (target KIT); and Cetirizine, Levocetirizine, Bilastine, Rupatadine, and Fexofenadine (target H1 histamine receptor). [49]

Anti-IgE mAbs such as Omalizumab block activation by themselves binding to the Cε3 domain of IgE. Omalizumab has been approved in the USA for treatment of allergic asthma, CSU, chronic rhinosinusitis with nasal polyps, and food allergies. [49]

Second generation H1 antihistamines, such as cetirizine, levocetirizine, bilastine, rupatadine and fexofenadine, neutralize histamine effector molecules by binding to the H1R receptor. Long-term regular administration of H1 antihistamines has been found to decrease symptoms in allergic rhinitis and CSU. [49]

A number of small molecule tyrosine kinase inhibitors (TKIs) have been approved for the treatment of mastocytosis. TKIs target KIT and can deplete the number of mast cells, but inhibit other tyrosine kinases as well causing side effects. [49] The TKI midostaurin, which has multiple targets, was approved for the treatment of advanced systemic mastocytosis (ASM) in 2017. Avapritinib was approved for ASM in 2021. [49] Anti-KIT mAbs also have been evaluated in chronic urticaria and are reported to reduce symptoms. They appear to induce MC deficiency and reduce serum tryptase. [49]

History

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] [78] They are now considered to be part of the immune system. [9]

Histological staining

Toluidine blue: one of the most common stains for acid mucopolysaccharides and glycoaminoglycans, components of mast cells granules. [79]

Bismarck brown: stains mast cell granules brown. [80]

Surface markers: cell surface markers of mast cells were discussed in detail by Heneberg, [81] 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. [82]

See also

References

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    [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.
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    ▸ 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.
  38. ↑ 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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