INTRODUCTION — Mast cells are found in varying numbers in practically all tissues. They are positioned as sentinels at the body's portals of entry within mucosal membranes lining the respiratory, digestive, and urogenital systems, throughout the dermis, and surrounding blood vessels [1-3]. They are found in invertebrates as well as lower vertebrates, suggesting that they serve a fundamental role within the immune system [4,5].
Mast cells have long been recognized for their participation in allergic disease, including asthma, rhinitis, conjunctivitis, atopic dermatitis, urticaria, and anaphylaxis. However, they also have a variety of protective and regenerative roles throughout the body.
The anatomic location, development, cellular identification, and physiologic roles of mast cells are discussed in this topic review. Their activating and inhibitory surface receptors, signal transduction, and mediators are reviewed separately. (See "Mast cells: Surface receptors and signal transduction" and "Mast cell-derived mediators".)
The contributions of mast cells to specific atopic diseases and mastocytosis are discussed elsewhere. (See "Pathogenesis of asthma" and "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)
ANATOMIC LOCATIONS — Mast cells reside within the connective tissue of a variety of tissues and all vascularized organs. Their numbers and densities are highest at interfaces between the internal and external environments where they can respond to foreign organisms and antigens, providing a sentinel function [6]. Sites include the dermis, skeletal muscle, oral mucosa, gut mucosa and submucosa, conjunctiva, pulmonary alveoli and airways, and the atrial appendage of the heart [6-14]. Dermal mast cells are often located in close proximity to blood vessels, nerves, and lymphatics, with an estimated density of 7000 to 20,000 mast cells per cubic millimeter of skin [9,15]. From this strategic location, they can influence the function of vascular structures, monitor the blood for inflammatory and infectious changes, capture circulating immunoglobulin E (IgE) molecules onto their surface, and distribute their mediators throughout the body [16,17]. Mast cells are found in the choroid plexus of the brain and in the vascular bed of the meninges. Low numbers of mast cells are found in the kidneys and bone marrow.
Mast cell numbers increase at inflammatory sites in different diseases, including asthma, nasal polyposis, allergic rhinitis, eosinophilic esophagitis, psoriasis, rheumatoid synovitis, inflammatory bowel diseases, pulmonary fibrosis, cancer, atherosclerotic cardiovascular diseases, and cardiomyopathy, although it is not clear if their role in these diseases is pathogenic, regenerative, or both [18-29]. (See 'Physiologic roles' below.)
Mast cell numbers also increase dramatically at multiple anatomic sites in the rare condition known as mastocytosis and are directly responsible for the pathologic changes observed in this disorder. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)
COLLECTION AND CULTURE — Mast cells are challenging to collect and study [30]. Mast cell progenitors (MCps) pass transiently through the circulation, at which point they are difficult to distinguish from other cell types. A rare circulating committed MCp that is expanded in those with severe asthma has been identified in humans; however, this cell has very limited proliferative capacity, and its relationship to mature tissue resident mast cells is not yet clear [31]. In systemic mastocytosis where mast cells carry the D816V KIT mutation, early MCps were identified in peripheral blood [32].
For studies on mast cell function, mature human mast cells can be isolated from solid tissues and cultured through a relatively complicated series of enzymatic and other techniques. Alternatively, transformed human mast cell lines can be used, although the cellular functions of these cells may be abnormal. Uncommitted progenitor cells can be collected from human cord blood or peripheral blood and developed in culture, although the resultant cells differ significantly from natural tissue mast cells.
Because of the difficulties in collecting human mast cells, mast cells from mice are often utilized instead. However, the distribution and phenotype of murine mast cells are substantively different from that of human cells [30]. Mice have much lower numbers of mature mast cells in their tissues but large numbers in the peritoneal cavity, whereas humans normally do not have significant numbers of peritoneal mast cells. Mouse mast cell precursors can be obtained from bone marrow and cultured to relative maturity with the same issues regarding the resultant cells that are present with human cell cultures.
DEVELOPMENT — Mast cells arise from pluripotential CD34+ stem cells that reside in the bone marrow and spleen [33-36]. They differentiate from the common myeloid progenitor, sharing intermediates with the megakaryocyte/erythrocyte progenitor, and are closely linked to basophils and eosinophils [37,38]. When mast cell progenitors (MCps) leave the hematopoietic tissues, some are committed to a mast cell lineage [31], and others appear to have multilineage capabilities [35,39,40]. They are then influenced by various signals (only some of which have been characterized), which direct their migration out of the circulation and into tissues where they subsequently mature [41,42]. They display considerable variability both within and across tissues compared with other cell types [43].
Kit and stem cell factor — An important growth factor for mast cells is stem cell factor (SCF), which is constitutively produced in both a soluble and membrane-bound form by stromal cells, particularly endothelial cells and fibroblasts [44-46]. SCF is also called kit ligand (KL) or steel factor [44,47-50]. The surface receptor for SCF, the receptor tyrosine kinase kit (CD117) generated from the gene KIT, is expressed by hematopoietic stem cells and is maintained during myeloid differentiation. It is thus an early marker for mast cell precursors. Mast cells continue to express kit throughout the lifetime of the cell, unlike most other cells (including basophils), which lose this marker during their development and become unresponsive to SCF [1,35,51].
SCF and kit were previously believed to be critical for the development of mast cells, and this seems true for the appearance of the mature, tissue-resident mast cell. However, the maturation of mast cell precursors to pre-mast cells may not be totally dependent on kit, as evidenced by the survival of circulating mast cell progenitors in patients undergoing therapy with imatinib, a drug that inhibits signaling through kit and other tyrosine kinases [52]. This interpretation was supported by in vitro developmental studies and is consistent with development of immature but not mature cells in mice in the absence of SCF-kit signaling. Note that imatinib does not inhibit mutated KIT, in particular at the D816V position, and early expression of KIT on pre-mast cells may not be accessible to imatinib.
With the above noted limited exception, SCF has been shown in vitro to participate in nearly every stage of growth and differentiation of mast cells, including chemotaxis, adhesion, survival, proliferation, and differentiation [53]. This global influence, combined with the constitutive and widespread production of SCF, results in the ubiquitous presence of mast cells throughout the tissues [33].
Other growth and differentiation factors — Numerous other factors (in addition to SCF) have been shown to influence proliferation and/or differentiation of mast cells. Both human and mouse MCps respond in vitro to several of the T helper type 2 (Th2) cell cytokines, including interleukin (IL) 3, IL-4, IL-5, IL-6, IL-9, and IL-10, although responses to these cytokines are better studied for mouse mast cells than for human mast cells [1]. Defects in the gene for phosphatase and tensin homolog (PTEN) can also result in hyperproliferation and heightened allergic responses in mice, although the prevalence of these defects in humans has not been extensively studied [54].
Migration into tissues — The exit of mast cell precursors from the circulation and the accumulation of differentiated mast cells in various tissues depends upon the interaction with endothelial cells initially and then with various tissue factors via adhesion molecules, including integrins and immunoglobulin supergene family receptors [55-58]. As an example, murine bone marrow-derived mast cells (BMMCs) exposed to the matrix protein, vitronectin, will spontaneously adhere and increase their proliferation [59]. A more general discussion of leukocyte movement and trafficking can be found elsewhere. (See "Leukocyte-adhesion deficiency" and "Leukocyte-endothelial adhesion in the pathogenesis of inflammation".)
Based principally on studies in the mouse with some limited support from human investigations, homing of MCps is highly organ specific [56,60,61]. In the mouse, MCp expression of the integrin alpha-4-beta-7 directs migration of MCps into normal intestine and inflamed lung. Alpha-4-beta-7 recognizes mucosal addressin cell adhesion molecule 1 (MAdCAM-1) and vascular cell adhesion molecule 1 (VCAM-1, CD106), both of which are present on normal vascular endothelium in Peyer's patches and lamina propria, while only VCAM-1 is found on vascular epithelium in the lung. The expression of the IL-8 receptor on both MCps and the vascular endothelium directs the specific migration of the precursors to the intestinal mucosa [56,57]. These processes appear to occur constitutively, with MCps demonstrating a tissue half-life in the intestine of approximately one week. These mechanisms result in the accumulation of a large pool of MCps, especially after inflammation, that is poised to mature into effector mast cells [58,62].
In contrast to the intestine, the submucosa of the mouse lung contains few mast cells and MCps in the absence of inflammation. With allergic inflammation, a rapid (within three days) and large (>25-fold) influx of MCps occurs, directed by alpha-4-beta-1 and alpha-4-beta-7 integrins on the MCps and by VCAM-1 and CXC chemokine receptor 2 (CXCR2) on the endothelium [58,63]. Studies indicate that this large pool of MCps gives rise to the mast cells that are found associated with the bronchial epithelium in the mouse and in association with both bronchial epithelium and smooth muscle in the human with chronic inflammation, such as asthma [63]. Studies in the mouse suggest a tissue-dependent variable lifespan for these inflammation-induced mature cells of anywhere from one week to several months [64].
Chemoattractants — Mast cell chemotaxis has been studied predominantly in vitro and occurs in response to a variety of growth and differentiation factors, such as SCF and IL-3, and to numerous chemokines. Transforming growth factor (TGF) beta is among the most potent mast cell chemotactic factors, active at femtomolar concentrations in both mouse and human [65,66]. The C-C chemokines RANTES (regulated on activation normal T expressed and secreted, CCL5) and CCL2 or monocyte chemotactic protein 1 (MCP-1) cause directed migration of cultured human mast cells and mouse BMMCs on vitronectin and laminin [67,68]. Also, CCL3 or macrophage inflammatory protein 1 (MIP-1) alpha and CXCL4 or platelet factor 4 (PF-4) elicit migration of mouse BMMCs after Fc-epsilon-RI activation on laminin, vitronectin, and fibronectin [67]. CXCR2 controls the chemotaxis of a human mast cell line in response to IL-8 (CXCL8) [69]. The neurotransmitter serotonin, acting through a serotonin receptor, is chemotactic for human mast cells [70]. The chemoattractant signals mediating MCp recruitment to peripheral tissue in vivo are less well understood. The murine IL-8 homologs (CXCL1 and CXCL2) acting on the single IL-8 receptor in the mouse, CXCR2, control homing of MCps to the small intestine of the mouse as noted above. CXCR2 expression by MCp is not required for recruitment to the murine lung; however, CXCR2 knockout mice exhibit impaired pulmonary MCp recruitment due to an unexpected role for this receptor in mediating VCAM-1 induction in pulmonary endothelial cells [63].
Mature phenotypes — Most investigational work on mast cells has been performed in mouse models to enable more sophisticated analyses. Using these models, subtypes of mature mast cells have been identified, which differ in location, mediator production, granule contents (and therefore staining properties), and behavior upon activation [1]. The properties of two prominent subtypes found in the mouse are presented here. It is not certain to what degree these findings apply to human mast cells. There are many similarities, but there are also differences, some of which may be due to the fact that the mice are housed in pathogen-limited environments, unlike the human situation.
In the mouse intestine, two primary forms of mature mast cells have been identified: murine mucosal mast cells (mMMCs), which appear mostly with inflammation, and murine connective tissue mast cells (mCTMCs), which are constitutive in most tissues [71]. Murine lineage tracing studies indicate that these two forms arise at different developmental time points and from different progenitor origins. Two sequential waves of progenitors arising from the yolk sac and aorta-gonado-mesonephros (AGM) develop into mCTMC, while mMMCs develop from adult bone marrow-derived progenitors [72,73]. In the small intestine, these differ most dramatically in their expression of the secretory granule proteases with proteases 1 and 2 associated with mast cells in the mucosal epithelium and proteases 4, 5, 6, 7, and the carboxypeptidase associated with mast cells in submucosal sites. However, this difference is tissue dependent as this does not hold true in the mouse lung [74]. Differences in eicosanoid synthesis have also been noted, with the mMMC producing both cysteinyl leukotrienes as well as prostanoids, while the mCTMC produces principally prostanoids upon activation [1].
Similarly, in the human, the principal division has been based upon secretory granule contents. The mast cells whose granules contain mostly tryptase (MC-T) are more prominent in the mucosa, while those containing tryptase, chymase, and carboxypeptidase A3 (MC-TC) are more prominent in the submucosal and connective tissue sites. In addition, the MC-T is the cell type depleted in human immunodeficiency virus (HIV) 1 infection, indicating that it is T cell dependent like the mMMC [75]. Thus, the MC-T and MC-TC are comparable with mMMC and mCTMC, although, due to the plasticity of this cell and differences in the proteases between the two species, this is an oversimplification, and caution is advised in drawing too strong an analogy between the murine and human systems. As in the mouse, subsequent studies have identified other tissue-dependent phenotypes, such as an intestinal mast cell containing only chymase and labeled MCc [76]. Th2-associated inflammatory diseases can also alter mast cell protease expression, with intraepithelial MC-T containing both tryptase and carboxypeptidase A3 in bronchial epithelium in asthma [77], apical epithelium in nasal polyposis [78], and esophageal epithelium during eosinophilic esophagitis [79].
Transcriptomics and proteomics studies have indicated that the MC-T/MC-TC paradigm is also somewhat of an oversimplification. Within human nasal polyps, MC-T and MC-TC are not transcriptionally discrete cell types but rather exist as two ends to a transcriptional gradient, suggesting that they may arise from a common progenitor and polarize in response to microenvironmental signals [80,81]. The nasal polyp MC-TC were also found to be highly distinct from those within the skin at the transcript level. In human lung tissue, flow cytometry-based proteomics analysis has indicated a high degree of heterogeneity across the mast cell compartment, with surface expression gradients observed for at least 10 cell surface markers, none of which exhibited a bimodal distribution [82]. Thus, while classification of mast cells based on the presence or absence of chymase can be useful under certain circumstances, it vastly underestimates the true degree of human mast cell heterogeneity.
●Mucosal mast cells – MMCs in mice are found in the mucosal epithelial surfaces of the intestine and respiratory tract, typically in association with inflammation associated with Th2 responses. Intestinal infections and allergic diseases, such as allergic rhinitis and asthma, result in dramatic increases in the numbers of MMCs and, to a lesser extent, CTMCs at the involved sites [83-85].
As MMCs expand in number, they also differentiate in ways that are defined by the tissue microenvironment [86]. As an example, in murine Trichinella spiralis infection, the MMC population undergoes sequential changes in the secretory granule phenotype as it migrates through the lamina propria to an intraepithelial residence and then reverses its migration and phenotype with the resolution of infection [83]. Thus, the phenotype of these cells is dynamic and defined by the inflammatory perturbations at a tissue site, likely allowing this cell to play roles in both the induction/amplification phase and the resolution/healing phase of the response [83,86].
The development of MMCs is dependent on T cell-derived factors, such as IL-3 and IL-4, as evidenced by the selective absence of MMCs in athymic mice and studies in cytokine-deficient mice [87-90]. Similarly, patients with HIV and acquired immunodeficiency syndrome (AIDS) who have low CD4+ T cell counts are profoundly deficient in intestinal mast cells of the MC-T phenotype, illustrating the dependency of this human mast cells' phenotype on T cells [75].
●Connective tissue mast cells – CTMCs in mice are found in the submucosal connective tissues of the intestine and throughout the body in association with various other connective tissues. Their maturation is T cell independent in mice as normal numbers are seen in lymphocyte-deficient strains [33]. Also, their numbers do not increase as significantly in acute reactions as the mMMC in the intestine or the lung of mice following Th2-mediated inflammations, such as in helminthic infection or atopic diseases [83].
In humans, increased numbers of mast cells are noted in association with bronchial smooth muscle in patients with asthma and with the synovium in rheumatoid arthritis, while mast cells with the MC-TC phenotype can be found in bronchial epithelium in severe asthma [84,91-93].
As mentioned previously, mast cell populations within tissues can expand severalfold during various disease states, including the following [94]:
●Parasitic infection
●Mastocytosis
●Atopic diseases (including urticaria, eosinophilic esophagitis, acute allergic reactions, rhinitis, nasal polyposis, and asthma)
●Rheumatologic disease (rheumatoid arthritis, scleroderma)
●Nonparasitic infectious disease (tuberculosis and syphilis)
●Neoplastic disease (melanoma and intestinal neoplasms)
●Chronic diseases (chronic kidney disease, chronic liver disease, and osteoporosis)
CELLULAR IDENTIFICATION — Mast cells are normally round mononuclear cells, which exhibit phenotypic variation in cytoplasmic morphology. Cell diameter ranges up to 25 micrometers. A unilobed nucleus may be round or oval in shape and is typically eccentrically positioned.
Staining properties — The mast cell can be recognized by its numerous cytoplasmic granules, which may occupy the majority of the cell volume [6,95]. Poorly granulated mast cells (eg, immature progenitors) or mast cells that have recently degranulated if stained with Giemsa or toluidine blue will stain poorly, making them difficult to pick out in tissue sections and can cause them to be mistaken for monocytes. However, mast cells may be found using the more sensitive immunohistochemistry for tryptase.
The following staining techniques can be used to identify human mast cells:
●Toluidine blue – Mast cell granules stain purple with the basic dye toluidine blue. This property of staining purple upon application of a blue dye is referred to as "metachromatic staining" and is due to the presence of highly sulfated, anionic proteoglycans (eg, heparin) complexed with the various secretory granule proteases. Metachromatic staining is unique to mast cells and basophils.
Eosinophils are usually easily differentiated from mast cells. Eosinophils stain red with Giemsa and blue with toluidine blue, and eosinophils have a bilobed nucleus. However, one of the authors (MC) has seen a case of cutaneous mastocytoma that was initially thought to be an eosinophilic granuloma [96]. Staining with monoclonal antibodies that reliably identify mast cells is critical in such situations.
●Monoclonal antibodies – Monoclonal antibodies directed against the membrane receptors (kit and the high-affinity IgE receptor) and the granule proteases (tryptase, chymase, and mast cell carboxypeptidase A3) are useful in identifying mast cells [97-100]. However, the monoclonal antibody for tryptase will also stain basophils, although basophils are not normally located in the tissues [101]. Basophils contain much less tryptase, and the nuclear morphology of basophils and mast cells is different.
●Fluorescently conjugated avidin – Avidin conjugated with a fluorophore, such as fluorescein isothiocyanate (FITC), can be used histologically to fluorescently label the granules of mast cells containing tryptase, chymase, and carboxypeptidase A3 (MC-TC) but not mast cells whose granules contain mostly tryptase (MC-T), likely due to interactions with heparin within the mast cell granule [76].
Electron microscopy — Mast cells examined with electron microscopy show abundant cytoplasmic granules, ranging in size from 0.3 to 0.8 micrometers (picture 1). The cytoplasmic granules of mast cells contain macromolecular complexes of proteoglycans and proteases that exhibit discrete patterns on electron microscopy. These patterns are related to the type of protease expressed (picture 2).
●All granules of human mast cells contain trypsin-like proteases. In unstimulated MC-T, the secretory granules exhibit an ultrastructural pattern on electron microscopy that resembles scrolls viewed in cross-section. Histologically, the granules do not stain with safranin and will not stain after formalin fixation [53,102].
●Granules containing chymase and carboxypeptidase A3 have a grating or lattice ultrastructure and are found in mast cells with the MC-TC phenotype [102,103]. Mast cells with this type of granule predominate in the skin and intestinal submucosa. The mast cell-specific carboxypeptidase A3 is also selectively found in MC-TC cells (containing tryptase, chymase, and carboxypeptidase A3) that are associated with connective tissue locations [99].
●Mast cells also have numerous cytoplasmic projections called pseudopods that may interdigitate with other cells.
PHYSIOLOGIC ROLES — Primarily in mice, mast cells have been implicated in both physiologic and pathogenic processes. Mast cells are important in defense against some bacteria and viruses and contribute to defense against parasites [2-4,104,105]. They are key effector cells in both innate and acquired immunity and are capable of inducing and amplifying both types of responses [53,106]. Specifically, mast cells are capable of detecting microbial products through surface pattern recognition receptors, and they are involved in recruitment of other leukocytes, containment of bacterial infections, and tissue repair [2,53,105].
Innate immunity — Mast cells have emerged as important effector cells of the innate immune system [33,53,107]. (See "An overview of the innate immune system", section on 'Mast cells'.)
●Mast cells assist in innate defense against certain bacterial (and likely also viral) infections by releasing cytokines in response to bacterial or viral products. These products include lipopolysaccharide (LPS), peptidoglycan, and single- or double-stranded nucleic acids [108-115]. Activation by microbial products is mediated through Toll-like receptors (TLRs) on the mast cell surface [109,110] and also involves complement activation that may amplify mast cell activation [116]. (See "Toll-like receptors: Roles in disease and therapy".)
●A G-protein-coupled receptor has been described in mice and human mast cells, Mrgprb2/Mas-related G protein-coupled receptor X2 (MRGPRX2), which is responsible for secretagogue-induced histamine release and non-IgE-mediated reactions to quinolones, Hymenoptera mastoparan, and general anesthetics [117]. This receptor also mediates mast cell activation by the neuropeptide substance p, central to the development of experimental atopic dermatitis in mice, and pro-adrenomedullin peptide 9-20, regulating nonhistaminergic itch [118,119]. In humans, MRGPRX2 is highly expressed on skin MC-TC but is absent from MC-TC within nasal polyp tissue.
●In mice, mast cells have important antibacterial responses. Mast cell-deficient mice succumb to experimentally induced peritonitis, whereas normal mice can survive [3]. Reconstitution of the peritoneal mast cells in the mast cell-deficient mice restores the ability of these mice to withstand this insult. Humans do not have peritoneal mast cells, and it is unclear if there are clinical correlates in human disease.
●Mast cells may phagocytose bacteria, such as Salmonella typhi, under some circumstances [112-114].
●Mast cells degranulate upon exposure to some viruses and release various cytokines and chemotactic mediators in response to others, again suggesting a role in both early defense and recruitment of other effector cells to sites of infection [115,120-122].
●Mast cells produce antimicrobial peptides, such as cathelicidins, and can amplify complement activation, resulting in disruption of microbial membranes and lysis [123]. These may be important in defense against common bacteria, such as streptococci.
●The proteases synthesized and released by mast cells are able to degrade and thus protect against some toxins. This was demonstrated in a study in which normal and mast cell-deficient mice were injected with snake and honey bee venoms [124,125]. Mast cell-deficient mice were 10-fold more sensitive to the toxins' effects, and this was ameliorated by restoration of mast cells. Similar studies have been performed with venoms from scorpions and Gila monsters [126].
●Reperfusion injury results in an inflammatory response mediated by immunoglobulin M (IgM), complement, and mast cells. The mast cell secretory granule proteases have been implicated as critical mediators in this reaction [127].
Mast cell-derived cytokines are crucial to the early and effective recruitment of neutrophils and other leukocytes to sites of infection [111,128,129]. Specifically, mast cell-derived tumor necrosis factor (TNF) has been shown to be involved in neutrophil recruitment to sites of inflammation, as well as in dendritic cell migration to lymph nodes. The mast cell secretory granule proteases (tryptases specifically) can recruit both eosinophils and neutrophils [104,105,129]. The actions of these and other mast cell mediators are discussed separately. (See "Mast cell-derived mediators".)
Acquired immunity — Mast cells are thought to be important in defense against parasitic infections, although the mechanisms involved are not fully elucidated [87,88,130-133]. IgE antibody plays a role in the expulsion of some intestinal parasites in experimental animals. However, it does not account fully for the mast cell response [130,132,133].
Mast cell degranulation may also affect other cell types in ways that promote the development of a T helper type 2 (Th2) acquired immune response. In mice, stimuli that result in mast cell degranulation also enhance interleukin (IL) 4 generation by dendritic cells and suppress interferon (IFN) gamma production by T cells [134].
Other physiologic functions — Mast cells have been implicated in various physiologic and regenerative processes.
●The role of mast cells in triggering increased intestinal motility, bronchoconstriction, and epithelial sloughing may have protective effects in ridding the body's epithelial surfaces of invaders and infectious agents, although these responses are more commonly viewed as manifestations of allergic reactions [2,135].
●Mast cells stimulate fibroblast proliferation and collagen synthesis and are believed to play a role in "walling off" and limiting the spread of infections, as well as in wound healing and scar formation [136-139].
●The number of mast cells normally increases dramatically within uterine tissues during pregnancy [140]. It is proposed that this influx of mast cells may contribute to a strengthening of local immunity through the secretion of cytokines and unique proteases based upon the mouse [141], as well as influence the contractility of myometrial cells.
●Mast cells, together with T regulatory cells, may mediate allograft tolerance in mice and control inflammation in response to premalignant events in the intestine, suggesting a role for mast cells in immune surveillance [142,143].
●Mast cells release carboxypeptidase A3, which may be important in the degradation of angiotensin and generation of angiotensin II [144,145].
●Mast cell protease cleavage of the cytokine IL-33 significantly increases its bioactivity, which may be important for in vivo signal amplification [146].
●Mast cell chymase has been implicated in blood pressure and intestinal homeostasis. Mice lacking the human mast cell chymase homolog mMCP4 exhibited decreased cleavage of big endothelin-1 to endothelin-1 (1-31) in the blood and in the intestine, decreased basal permeability, and altered epithelial cell migrations and villus morphology [147,148].
Potentially detrimental functions
●Allergic diseases – Mast cells play a prominent and in some cases, a primary role in allergic responses, including anaphylaxis, urticaria, asthma, rhinitis, and atopic dermatitis [28,149-151]. (See 'Mast cells in allergy' below.)
●Mastocytosis – Mastocytosis is due to a mutation in KIT, resulting in chronic activation and clonal expansion of mast cells. The disorder may affect multiple organ systems or be confined to the skin. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)
●Atherosclerosis – Increased mast cell numbers have been noted for decades within human atherosclerotic lesions, although their functions within plaques were unclear [152]. Mouse models suggest that mast cells promote atherosclerotic changes through the release of proinflammatory cytokines and perhaps proteases [153,154].
●Autoimmune disease – Experiments employing a number of models of autoimmunity, including multiple sclerosis and rheumatoid arthritis, have implicated mast cells. In both instances, mast cell-deficient mice showed reduced pathology that was reversed upon reconstitution of the mast cells in the mice [155,156]. (See "Synovial pathology in rheumatoid arthritis".)
●Burn lesions – Mast cells in the skin are rapidly activated following thermal trauma, and the release of the proteases is critical to the development of the inflammatory response that exacerbates the damage caused by first- and second-degree burns [157].
Mast cells in allergy — Mast cells play a central role in the response to allergen challenge. The activation of mast cells results in both an early and a delayed phase of inflammation. The various chemical mediators released from mast cells during an allergic reaction are discussed separately. (See "Mast cell-derived mediators".)
Early-phase response — Following activation of cutaneous mast cells, the early phase of the response occurs within 10 minutes and resolves within one hour. Cutaneous allergen challenge in sensitized subjects (ie, those with IgE specific to the allergen) elicits an early-phase response characterized by a "wheal-and-flare." The "wheal" is a central area of pruritic skin edema, caused predominantly by histamine-mediated increased vasopermeability [158]. The "flare" is erythema due to local vasodilation, which spreads out from the central area due to an axonal reflex, likely mediated by neuropeptides. Histology demonstrates dermal edema, characterized by separation of collagen bundles and degranulated mast cells, without an inflammatory infiltrate. The early phase of the response may be even more rapid (ie, seconds) in mucosal mast cells (MMCs).
Late-phase response — The early-phase response is followed in some patients by a delayed phase, which involves cutaneous erythema, warmth, and induration. This phase begins at six to eight hours and resolves within 24 hours. Histology at this point demonstrates dermal edema with the influx of mononuclear cells, eosinophils, basophils, and neutrophils [159]. A similar biphasic clinical and histologic process occurs in the airways of some patients with asthma when challenged with specific antigen inhalation [151].
SUMMARY
●Anatomic locations – Mast cells are positioned as sentinels at sites that pathogens might invade the body (the dermis, gut mucosa and submucosa, conjunctiva, pulmonary alveoli, and airways). Dermal mast cells are often located in close proximity to blood vessels, nerves, and lymphatics. (See 'Anatomic locations' above.)
●Collection and culture – Human mast cells are difficult to collect and study. Immature forms pass transiently through the circulation and are difficult to distinguish from other cell types. Progenitors develop into mature mast cells in the tissues, which do not recirculate through the blood. For these and other technical reasons, mouse mast cells are often used in research, but findings from studies of mouse mast cells do not always apply to humans. (See 'Collection and culture' above.)
●Development – Mast cells arise from pluripotential CD34+ stem cells originating in the bone marrow and spleen and differentiate along the myeloid pathway. Stem cell factor (SCF or kit ligand [KL]) produced by stromal cells is critical for almost every stage of mast cell development and survival. The surface receptor for SCF is kit (CD117), which is expressed by many hematopoietic stem cells early in development but is later lost by all cell types except mast cells. Only mast cells remain responsive to SCF. (See 'Development' above.)
●Identification and staining – The mast cell can be recognized by its numerous cytoplasmic granules, which may occupy the majority of the cell volume. Mast cell granules stain purple with the basic dye toluidine blue, a property referred to as metachromatic staining. Monoclonal antibodies directed against the membrane receptors kit, the high-affinity immunoglobulin E (IgE) receptor, and granule proteases (tryptase, chymase, and mast cell carboxypeptidase A3) are useful in identifying mast cells. (See 'Cellular identification' above.)
●Roles in innate immunity – Mast cells participate in innate defense against certain bacterial and viral infections by releasing cytokines in response to lipopolysaccharide (LPS), peptidoglycan, and nucleic acids, which are recognized through Toll-like receptors (TLRs) on the mast cell surface. In response to these microbial products, mast cells secrete cytokines, activate complement, and recruit other effector cells to the site of invasion. (See 'Physiologic roles' above.)
●Roles in disease and health – Mast cells are critical effector cells in allergic responses, including anaphylaxis, urticaria, asthma, rhinitis, and atopic dermatitis. Mast cell mediators trigger increased intestinal motility, bronchoconstriction, and epithelial sloughing. These responses may have protective effects by ridding the body's epithelial surfaces of invaders and infectious agents when properly controlled. However, in excess, these responses are manifestations of allergic reactions. (See 'Physiologic roles' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Michael Gurish, PhD, who contributed to earlier versions of this topic review.
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