Your activity: 273 p.v.
your limit has been reached. plz Donate us to allow your ip full access, Email:

Mast cells: Surface receptors and signal transduction

Mast cells: Surface receptors and signal transduction
Mariana C Castells, MD, PhD
Lora Bankova, MD
Section Editor:
Sarbjit Saini, MD
Deputy Editor:
Anna M Feldweg, MD
Literature review current through: Nov 2022. | This topic last updated: Jan 21, 2021.

INTRODUCTION — Mast cells display a host of stimulatory and inhibitory surface receptors, allowing them to respond to a variety of stimuli in a modulated manner. The ultimate response of a cell to its environment is determined by the balance of stimulatory and inhibitory factors present at a given moment and acting on different receptors.

This topic review will discuss the activating and inhibitory receptors on mast cells and signal transduction mechanisms. The information in this review pertains to human mast cells whenever possible, and notation is made when data are derived purely from murine studies. Mast cell-derived mediators, as well as the development, identification, and physiologic roles of mast cells, are reviewed separately. (See "Mast cell-derived mediators" and "Mast cells: Development, identification, and physiologic roles".)

ACTIVATING RECEPTORS — Important stimulatory receptors on the surface of mast cells include the high-affinity immunoglobulin E (IgE) receptor, immunoglobulin G (IgG) receptors, toll-like receptors (TLRs), receptors for stem cell factor (SCF), complement proteins, cytokine receptors (eg, for the alarmins interleukin-33 [IL-33] and thymic stromal lymphopoietin [TSLP]), neuropeptides, and opioids. A G-coupled protein receptor that is important in anaphylactoid reactions, MRGPRX2, was identified in 2015 [1].

High affinity IgE receptor — Classical mast cell activation occurs through the high affinity immunoglobulin E (IgE) receptor, Fc-epsilon-RI. Activation occurs when adjacent receptors, occupied by receptor-bound IgE, are crosslinked by a multivalent antigen. This is a strong stimulus for degranulation and release of preformed mediators, as well as for de novo production and subsequent release of leukotrienes, prostaglandins, and cytokines, including numerous chemokines. (See "Mast cell-derived mediators".)

High and low valency or affinity antigens are able to trigger differential responses through Fc-epsilon-RI receptors. High affinity or high valency antigens trigger classic degranulation and cytokine responses with neutrophilic inflammation. In contrast, low valency or low affinity allergens may not trigger degranulation, but can still trigger production of chemokines that recruit macrophages and monocytes [2,3].

IgE is involved in defense against parasitic infection and in hypersensitivity reactions. It is estimated that there are usually >100,000 Fc-epsilon-RI receptors on the surface of each human mast cell, although the number can vary with activation state and the presence of circulating IgE [4-6]. As the transcript is stabilized by binding of monomeric IgE to the receptor, there is a greater number of receptors and hence capacity for binding serum IgE in atopic individuals. This likely accounts for this large range in the number of receptors per cell and the efficacy of therapy directed to reducing the serum titer of IgE [7-9]. (See 'Clinical applications' below.)

The fully functional form of the Fc-epsilon-RI receptor on mast cells and on basophils is a tetrameric structure consisting of one alpha chain, one beta chain, and two gamma chains [10,11]:

The alpha chain contains two extracellular domains that bind IgE with high affinity.

The beta chain transverses the membrane four times and may form an ion pore.

The two gamma chains, which are structurally homologous to the zeta chain of the T cell receptor, each have two cytoplasmic immunoreceptor tyrosine activation motifs (ITAMs) and mediate signal transduction.

Several other human cell types express a trimeric form of Fc-epsilon-RI, which lacks the beta chain. This is found on eosinophils, epithelial cells, and on antigen-presenting cells, such as dendritic cells, Langerhans cells, and monocytes and may be involved in the immune modulatory functions of these cells [10,12-16]. (See "Mast cells: Development, identification, and physiologic roles", section on 'Acquired immunity'.)

MRGPRX2 — This newly identified Mas-related G protein–coupled receptor may be responsible for reactions to quinolone medications, such as ciprofloxacin, icatibant, and general anesthetics, such as rocuronium, atracurium, and others with the central tetrahydroisoquinoline (THIQ) motif [1]. The extent of the expression of this receptor on human mast cells is not fully understood, although it could potentially explain anaphylactic reactions to these medications in which IgE antibodies have not been demonstrated. MRGPRX2 is also expressed on human basophils and eosinophils [17].

Studies in mice point to a role of the mouse ortholog of MRGPRX2 (Mrgprb2) in nonhistaminergic itch and in mast cell–sensory neuron interactions [18,19]. Whether MRGPRX2 mediates similar reactions in humans has not been established. However, a significant increase in number and percentage (45 versus 22 percent) of MRGPRX2 mast cells has been described in the skin of patients with chronic urticaria compared with that of nonatopic control subjects [20]. In addition, cutaneous mast cells of patients with chronic urticaria show increased reactivity to MRGPRX2 ligands [21].

Receptors for mechanical stimulation — Mast cell degranulation in response to mechanical stimulation was linked to signaling through the dermatan sulfate adhesion GPCR, ADGRE2. Mutations of ADGRE2 that render it "hyperactive" are associated with a vibratory urticaria phenotype [22,23]. (See "Physical (inducible) forms of urticaria", section on 'Vibratory angioedema and urticaria'.)

IgG receptors — Human mast cells also express receptors for immunoglobulin G (IgG), including Fc-gamma-RII-alpha and Fc-gamma-RIII, activating receptors that bind IgG3 most avidly [24,25]. These receptors allow activation of the cells by immune complexes that are either circulating or formed in situ. Human mast cells can also transiently express Fc-gamma-RI, another activating receptor [26].

Kit (stem cell factor receptor) — Mast cells express Kit, the receptor for stem cell factor (SCF), which is the critical growth factor for mast cell development. (See "Mast cells: Development, identification, and physiologic roles", section on 'Kit and stem cell factor'.)

For mature mast cells, SCF also serves as a chemotactic factor and can be a direct activator, causing degranulation and cysteinyl leukotriene production, and in conjunction with interleukin-10 (IL-10) and interleukin-1beta (IL-1beta), can be an inducer of prostanoid and cytokine production [27-33].

Alarmin receptors — Mast cells express the IL-33 receptor known as ST2, which is a member of the interleukin-1 receptor family as well as a receptor for the alarmin TSLP [34]. Both of these can be released from activated epithelium. The epithelium releases an alternatively spliced form of IL-33, which in combination with TSLP, activates mast cells. This pathway is likely important in various responses occurring at environmental interfaces. For instance, together with basophils, this pathway for mast cell activation has been implicated in driving the type 2 inflammation in some patients with asthma [35] and in patients with aspirin-exacerbated respiratory disease [36,37]. TSLP-mediated activation of mast cells triggers prostaglandin D2 (PGD2) production and likely contributes significantly to the non-IgE mediated aspirin induced reactions in patients with aspirin-exacerbated respiratory disease [38].

Complement receptors — Mast cells in human skin express receptors for both the anaphylatoxins, C3a and C5a, and release histamine in response to exposure to these complement fragments. These provide additional mechanisms in which immune complexes or microbes may activate mast cells that may occur via classical or alternative complement activation pathways. However, in contrast to activation through Fc-epsilon-RI, exocytosis by complement fragments is not associated with the generation of prostaglandins or leukotrienes. There is some variability in distribution of complement receptors, as some cardiac mast cells demonstrate a functional receptor for C5a (CD88) by immunofluorescence, whereas mast cells isolated from the human lung, uterus, or tonsils do not [39-42]. (See "Complement pathways", section on 'Classical pathway'.)

Toll-like receptors — Mast cells express a variety of toll-like receptors (TLRs), which are both surface and internal membrane-associated molecules in eukaryotic cells that detect and respond to microbial infection. The activation of mast cells through TLRs is an important mechanism through which mast cells serve as a bridge between the innate and adaptive immune systems. Using cultured human mast cell lines, these cells have been shown to express TLRs 1 through 9, although TLR8 was lost with continued culture [43-45].

Human mast cells also can be activated by many of the ligands specific to the different receptors (eg, peptidoglycans through TLR2, double-stranded RNA through TLR3, and lipopolysaccharide [LPS] through TLR4). In broad terms, mast cells respond to activation through TLR with the production of inflammatory cytokines, rather than degranulation, yet the responses to the different stimuli are distinct. Thus, double-stranded RNA induces expression of the type 1 interferons, but not tumor necrosis factor-alpha (TNF-alpha) or interleukin-6 (IL-6), while LPS induces expression of these two proinflammatory cytokines, but not degranulation as occurs following peptidoglycan stimulation [46,47]. A general discussion of TLRs is found elsewhere. (See "Toll-like receptors: Roles in disease and therapy".)

Receptors for neuropeptides and opioids — Neuropeptides, such as vasoactive intestinal polypeptide (VIP), substance P, and somatostatin, mediate secretory granule exocytosis from mast cells with little generation of lipid mediators [48-50]. The responses to these neuropeptides are mediated through pertussis-sensitive G proteins, with concomitant release of calcium from intracellular stores [51-53]. Mast cell activation by substance P is at least partially mediated through the newly identified receptor MRGPX2 [54].

Certain muscle relaxants, such as succinylcholine, tubocurarine, and atracurium, cause both skin and lung mast cells to release histamine, while opiates also cause histamine release from skin mast cells [55-57]. The latter underlies the common occurrence of pruritus and urticaria in response to opioid analgesics.

Platelet-activating factor receptor — Receptors for platelet-activating factor (PAF) have been identified on human mast cells cultured from the lung and from progenitors in peripheral blood [58]. PAF is known to be important in murine anaphylaxis, and preliminary data suggest that PAF plays a role in human anaphylaxis as well, particularly in amplification of the initial response. (See "Pathophysiology of anaphylaxis", section on 'Chemical mediators of anaphylaxis'.)

INHIBITORY RECEPTORS — Mast cells express several inhibitory receptors. While the functions of these are not fully understood, some have been shown to regulate mast cell-mediated events, including human mast cell activation, and in the mouse, mast cell-dependent inflammation [59,60]. Many of the inhibitory receptors contain immunoregulatory tyrosine inhibition motifs (ITIMs).

Examples of ITIM-associated receptors capable of suppressing mast cell activation are Fc-gamma-RIIb, CD300a, platelet-endothelial cell adhesion molecule 1 (PECAM-1), paired immunoglobulin-like receptor B (PIR-B), the c-lectin mast cell function-associated antigen (MAFA), sialic acid-binding immunoglobulin-like lectins (Siglecs), and leukocyte immunoglobulin-like receptor B4 (LILB4) [60,61]. PIR-B is a surface receptor expressed on both mast cells and macrophages and appears to regulate basal activation of both cells. Examples of ITIM-independent inhibitory receptors include the mast cell receptor for the glycoprotein CD200, the A2b adenosine receptor, and the transient receptor potential cation channel, subfamily M, member 4 (TRPM4) ion channel [60].

Siglecs — Sialic acid-binding immunoglobulin-like lectin (Siglec)-6 and Siglec-8 are expressed on mast cells and eosinophils, and therapeutic targeting of Siglec 8 is under investigation for treatment of diseases of mast cell expansion and activation [62,63].

Leukocyte immunoglobulin-like receptor 4 — Murine mast cells express leukocyte immunoglobulin-like receptor 4, subfamily B, member 4 (LILRB4), an inhibitory receptor with significant homology with the killer cell inhibitory receptors (KIR) found on natural killer (NK) cells [55,64,65]. This molecule was previously called gp49B1. (See "NK cell deficiency syndromes: Clinical manifestations and diagnosis".)

Mice deficient in LILRB4 have increased severity in local and systemic anaphylaxis, suggesting that this receptor has a "braking function" during mast cell activation [65,66].

CD200 receptor 1 — The CD200 R1 receptor, a member of the immunoglobulin supergene family that is expressed on myeloid cells, inhibits mast cell degranulation and cytokine secretion [67-69]. It does not contain an ITIM and may play a role in determining the cell's threshold for activation. In contrast, a related member of this family, CD200 R3, has been implicated in mast cell activation [70].

CD300a — CD300a is a type 1 transmembrane protein that contains three classical and one nonclassical ITIM in the intracellular cytoplasmic tail. It is expressed on both myeloid and lymphoid cells. Coligation of the high affinity immunoglobulin E (IgE) receptor and CD300a inhibits mast cell activation [71-74].

Beta-adrenoreceptor 2 — The beta-adrenoreceptor (beta-2) found on human lung mast cells is linked via a G protein to a cyclic AMP (cAMP)-dependent pathway of calcium mobilization [75]. Isolated human lung mast cells display inhibition of degranulation and eicosanoid generation after treatment with beta-agonists [76,77].

IgG receptors — The immunoglobulin G (IgG) receptor Fc-gamma-RIIb is an inhibitory receptor on the surface of mast cells. Fc-gamma-RIIb crosslinking has been shown to reduce IgE-mediated mast cell activation, and investigational therapies based on this mechanism have been reported [78,79].

Toll-like receptor 4 — Toll-like receptor 4 (TLR4) also binds a protein produced by parasitic roundworms, ES-62 [80]. Unlike the binding of TLR4 to lipopolysaccharide (LPS), however, ligation with ES-62 results in inhibition of activation of the cell through Fc-epsilon-RI, and therefore, TLR4 functions as an inhibitory receptor in this context [81]. Nematodes expressing this protein would be able to modulate the mast cell inflammatory response of the host to infection, thus preventing fulminant inflammation and demise of the host or expulsion of the parasite. Future therapies based upon analogs of ES-62 have been proposed. (See "Toll-like receptors: Roles in disease and therapy".)

SIGNAL TRANSDUCTION — Signal transduction pathways are intertwined webs of molecules, through which external information about ongoing events is transmitted to the internal workings of that cell in order to induce a specific effect. These pathways are complex, overlapping, and tightly controlled. The steps in the signal transduction pathway that results from crosslinking of two Fc-epsilon-RI receptors by multivalent antigen on the surface of a mast cell are described here as an example:

Crosslinking of the Fc-epsilon-RI receptor by polymeric/polyvalent antigens bound to specific immunoglobulin E (IgE) at the membrane initiates signal transduction. Specific IgE is bound to the alpha chain of the Fc-epsilon-RI, while the beta and gamma chains are critical for signal transduction. (See 'High affinity IgE receptor' above.)

Crosslinking of Fc-epsilon-RI leads to phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) of the cytoplasmic domain of both the beta and gamma subunits of the receptor complex [82]. The beta chain of Fc-epsilon-RI is constitutively associated with Lyn, a tyrosine kinase belonging to the Src family [82,83]. Tyrosine phosphorylation of the beta subunit activates Lyn [82]. Activated Lyn mediates recruitment of the nonreceptor tyrosine kinase Syk, which interacts via its SH2 domain with the phosphorylated ITAM on the gamma subunit of Fc-epsilon-RI [82,84,85]. Syk then stimulates sequences leading to the mitogen-activated protein kinase (MAPK) pathways and the protein kinase C (PKC) and Ca2+ dependent pathways [86].

Activation of the MAPK pathway has been linked to the downstream activation of cytosolic phospholipase A2 (cPLA2) in stimulated mast cells [87-90]. The enzyme cPLA2 translocates from a cytosolic to membrane compartment [91], where it cleaves arachidonic acid from phospholipids for the generation of leukotrienes and prostaglandins, as well as forming lyso-phosphatidylcholine, the precursor of platelet-activating factor (PAF).

Syk phosphorylation also causes activation of phosphatidylinositol-specific phospholipase C (PLCg1). The activated PLC cleaves phosphatidylinositol-derived inositol 4,5 bisphosphate (PIP2) to generate the second messengers diacylglycerol (DAG) and inositol 1,4,5 triphosphate (IP3) [92,93]. DAG activates protein kinase C with a consequent translocation to the plasma membrane.

PKC activation results in phosphorylation of numerous proteins including the myosin light chain, which is thought to contribute to exocytosis of mast cell granules and the activation of c-fos and c-jun, leading to enhanced transcription of immediate early genes [94,95]. IP3 acts at the endoplasmic reticulum to release calcium from intracellular stores and activates the calmodulin/calcineurin phosphatase pathway with resultant transcription of cytokine genes, such as interleukin-6 (IL-6), via the nuclear translocation of the transcription factor nuclear factor of activated T cells (NFAT) [96,97]. Subsequent influx of calcium through the membrane further augments mast cell degranulation [98].

Early activation events lead to the release of granule contents, arachidonic acid metabolites, and tumor necrosis factor-alpha (TNF-alpha) secretion. Late-phase events include the release of cytokines and chemokines, such as interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and newly-formed TNF-alpha. (See "Mast cell-derived mediators".)

CLINICAL APPLICATIONS — Activating and inhibitory receptors on mast cells and the signaling pathways used by these receptors can be manipulated to achieve specific clinical effects. The following are examples of therapeutic applications that have either already been realized or are in development:

The high affinity immunoglobulin E (IgE) receptor can be downregulated on the surface of mast cells by administration of the anti-IgE therapy omalizumab. This agent binds free IgE in the serum and tissues and clears it from circulation, resulting in a reduction in the number of Fc-epsilon-RI receptors present on mast cells (and basophils). Anti-IgE therapy is used in the treatment of allergic asthma. It has also been successfully administered to patients with Hymenoptera venom-induced anaphylaxis who require venom immunotherapy, but who have reactions to the injections, to improve the safety of the vaccination process. In the future, its use may be extended to other diseases in which IgE is part of the pathophysiology, including allergic rhinitis and anaphylaxis. The use of anti-IgE therapy in asthma and chronic idiopathic urticaria is reviewed in more detail separately. (See "Anti-IgE therapy".)

The receptor for stem cell factor (SCF), Kit, is a tyrosine kinase. PKC412 (midostaurin) is a tyrosine kinase inhibitor that inhibits Kit, including Kit with a specific D816V mutation, while imatinib (Gleevec) inhibits only wild-type Kit. Patients with aggressive forms of systemic mastocytosis have benefited from these drugs, providing evidence that activation of Kit is a fundamental part of the pathophysiology of the disease. (See "Advanced systemic mastocytosis: Management and prognosis", section on 'Midostaurin'.)

Analogs of the parasite product ES-62, an agonist of toll-like receptor 4 (TLR4), are in development. The action of ES-62 at TLR4 leads to inhibition of Fc-epsilon-RI. It is hoped that these agents could be used as immunomodulators to treat or prevent allergic and other inflammatory diseases [99,100]. (See "Toll-like receptors: Roles in disease and therapy", section on 'TLR-based therapies'.)

Fusion proteins composed of major allergenic proteins linked to agonists of inhibitory immunoglobulin G (IgG) receptors have been developed for the purposes of treating allergic disease. For example, the major cat allergen, Fel d 1, has been fused with Fc-gamma-I and is being studied for use in safer and more effective forms of immunotherapy [101].

Syk inhibitors have been studied to block signal transduction in mast cells and prevent activation at the time of allergen exposure, and their application in allergic rhinitis and asthma is under study. However, the potential side effects of blocking signal transduction are complex, due to the broad functions of Syk in T cells and other immune cells.


Mast cells display a host of stimulatory and inhibitory surface receptors, and the balance of signals arising from these receptors at a given moment determines the ultimate response of the cell. (See 'Introduction' above.)

Important stimulatory mast cell receptors include the high affinity immunoglobulin E (IgE) receptor, immunoglobulin G (IgG) receptors, toll-like receptors (TLRs), complement component receptors, and the receptor for stem cell factor (SCF). (See 'Activating receptors' above.)

Inhibitory receptors act to regulate and modulate mast cell function. Critical inhibitory receptors include leukocyte immunoglobulin-like receptor, subfamily B, member 4 (LILRB4) and CD200R1. (See 'Inhibitory receptors' above.)

Signal transduction pathways are complex and precisely controlled networks of molecules, through which information is transmitted from the cell surface to the inside of the cell to induce a specific effect. (See 'Signal transduction' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to an earlier version of this topic review.

The UpToDate editorial staff acknowledges Michael Gurish, PhD, now deceased, who contributed to an earlier version of this topic review.

  1. McNeil BD, Pundir P, Meeker S, et al. Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. Nature 2015; 519:237.
  2. Suzuki R, Leach S, Liu W, et al. Molecular editing of cellular responses by the high-affinity receptor for IgE. Science 2014; 343:1021.
  3. Uermösi C, Zabel F, Manolova V, et al. IgG-mediated down-regulation of IgE bound to mast cells: a potential novel mechanism of allergen-specific desensitization. Allergy 2014; 69:338.
  4. Havard S, Scola AM, Kay LJ, et al. Characterization of syk expression in human lung mast cells: relationship with function. Clin Exp Allergy 2011; 41:378.
  5. MacGlashan DW Jr, Schleimer RP, Peters SP, et al. Comparative studies of human basophils and mast cells. Fed Proc 1983; 42:2504.
  6. Conrad DH, Bazin H, Sehon AH, Froese A. Binding parameters of the interaction between rat IgE and rat mast cell receptors. J Immunol 1975; 114:1688.
  7. MacGlashan D Jr, McKenzie-White J, Chichester K, et al. In vitro regulation of FcepsilonRIalpha expression on human basophils by IgE antibody. Blood 1998; 91:1633.
  8. Yamaguchi M, Sayama K, Yano K, et al. IgE enhances Fc epsilon receptor I expression and IgE-dependent release of histamine and lipid mediators from human umbilical cord blood-derived mast cells: synergistic effect of IL-4 and IgE on human mast cell Fc epsilon receptor I expression and mediator release. J Immunol 1999; 162:5455.
  9. Milgrom H, Berger W, Nayak A, et al. Treatment of childhood asthma with anti-immunoglobulin E antibody (omalizumab). Pediatrics 2001; 108:E36.
  10. Kinet JP. The gamma-zeta dimers of Fc receptors as connectors to signal transduction. Curr Opin Immunol 1992; 4:43.
  11. Cambier JC. Antigen and Fc receptor signaling. The awesome power of the immunoreceptor tyrosine-based activation motif (ITAM). J Immunol 1995; 155:3281.
  12. Ishizaka K, Tomioka H, Ishizaka T. Mechanisms of passive sensitization. I. Presence of IgE and IgG molecules on human leukocytes. J Immunol 1970; 105:1459.
  13. Kinet JP. The high-affinity receptor for IgE. Curr Opin Immunol 1989- 1990; 2:499.
  14. Bieber T, de la Salle H, Wollenberg A, et al. Human epidermal Langerhans cells express the high affinity receptor for immunoglobulin E (Fc epsilon RI). J Exp Med 1992; 175:1285.
  15. Schwartz LB. Effector cells of anaphylaxis: mast cells and basophils. Novartis Found Symp 2004; 257:65.
  16. Grayson MH, Cheung D, Rohlfing MM, et al. Induction of high-affinity IgE receptor on lung dendritic cells during viral infection leads to mucous cell metaplasia. J Exp Med 2007; 204:2759.
  17. Wedi B, Gehring M, Kapp A. The pseudoallergen receptor MRGPRX2 on peripheral blood basophils and eosinophils: Expression and function. Allergy 2020; 75:2229.
  18. Meixiong J, Anderson M, Limjunyawong N, et al. Activation of Mast-Cell-Expressed Mas-Related G-Protein-Coupled Receptors Drives Non-histaminergic Itch. Immunity 2019; 50:1163.
  19. Serhan N, Basso L, Sibilano R, et al. House dust mites activate nociceptor-mast cell clusters to drive type 2 skin inflammation. Nat Immunol 2019; 20:1435.
  20. Fujisawa D, Kashiwakura J, Kita H, et al. Expression of Mas-related gene X2 on mast cells is upregulated in the skin of patients with severe chronic urticaria. J Allergy Clin Immunol 2014; 134:622.
  21. Shtessel M, Limjunyawong N, Oliver ET, et al. MRGPRX2 Activation Causes Increased Skin Reactivity in Patients with Chronic Spontaneous Urticaria. J Invest Dermatol 2021; 141:678.
  22. Boyden SE, Desai A, Cruse G, et al. Vibratory Urticaria Associated with a Missense Variant in ADGRE2. N Engl J Med 2016; 374:656.
  23. Olivera A, Beaven MA, Metcalfe DD. Mast cells signal their importance in health and disease. J Allergy Clin Immunol 2018; 142:381.
  24. Guo CB, Kagey-Sobotka A, Lichtenstein LM, Bochner BS. Immunophenotyping and functional analysis of purified human uterine mast cells. Blood 1992; 79:708.
  25. Okayama Y, Kirshenbaum AS, Metcalfe DD. Expression of a functional high-affinity IgG receptor, Fc gamma RI, on human mast cells: Up-regulation by IFN-gamma. J Immunol 2000; 164:4332.
  26. Woolhiser MR, Okayama Y, Gilfillan AM, Metcalfe DD. IgG-dependent activation of human mast cells following up-regulation of FcgammaRI by IFN-gamma. Eur J Immunol 2001; 31:3298.
  27. Meininger CJ, Yano H, Rottapel R, et al. The c-kit receptor ligand functions as a mast cell chemoattractant. Blood 1992; 79:958.
  28. Murakami M, Austen KF, Arm JP. The immediate phase of c-kit ligand stimulation of mouse bone marrow-derived mast cells elicits rapid leukotriene C4 generation through posttranslational activation of cytosolic phospholipase A2 and 5-lipoxygenase. J Exp Med 1995; 182:197.
  29. Murakami M, Matsumoto R, Austen KF, Arm JP. Prostaglandin endoperoxide synthase-1 and -2 couple to different transmembrane stimuli to generate prostaglandin D2 in mouse bone marrow-derived mast cells. J Biol Chem 1994; 269:22269.
  30. Lu-Kuo JM, Austen KF, Katz HR. Post-transcriptional stabilization by interleukin-1beta of interleukin-6 mRNA induced by c-kit ligand and interleukin-10 in mouse bone marrow-derived mast cells. J Biol Chem 1996; 271:22169.
  31. Bischoff SC, Dahinden CA. c-kit ligand: a unique potentiator of mediator release by human lung mast cells. J Exp Med 1992; 175:237.
  32. Costa JJ, Demetri GD, Harrist TJ, et al. Recombinant human stem cell factor (kit ligand) promotes human mast cell and melanocyte hyperplasia and functional activation in vivo. J Exp Med 1996; 183:2681.
  33. Feldweg AM, Friend DS, Zhou JS, et al. gp49B1 suppresses stem cell factor-induced mast cell activation-secretion and attendant inflammation in vivo. Eur J Immunol 2003; 33:2262.
  34. Allakhverdi Z, Smith DE, Comeau MR, Delespesse G. Cutting edge: The ST2 ligand IL-33 potently activates and drives maturation of human mast cells. J Immunol 2007; 179:2051.
  35. Gordon ED, Simpson LJ, Rios CL, et al. Alternative splicing of interleukin-33 and type 2 inflammation in asthma. Proc Natl Acad Sci U S A 2016; 113:8765.
  36. Liu T, Kanaoka Y, Barrett NA, et al. Aspirin-Exacerbated Respiratory Disease Involves a Cysteinyl Leukotriene-Driven IL-33-Mediated Mast Cell Activation Pathway. J Immunol 2015; 195:3537.
  37. Pan D, Buchheit KM, Samuchiwal SK, et al. COX-1 mediates IL-33-induced extracellular signal-regulated kinase activation in mast cells: Implications for aspirin sensitivity. J Allergy Clin Immunol 2019; 143:1047.
  38. Buchheit KM, Cahill KN, Katz HR, et al. Thymic stromal lymphopoietin controls prostaglandin D2 generation in patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 2016; 137:1566.
  39. Füreder W, Agis H, Willheim M, et al. Differential expression of complement receptors on human basophils and mast cells. Evidence for mast cell heterogeneity and CD88/C5aR expression on skin mast cells. J Immunol 1995; 155:3152.
  40. el-Lati SG, Dahinden CA, Church MK. Complement peptides C3a- and C5a-induced mediator release from dissociated human skin mast cells. J Invest Dermatol 1994; 102:803.
  41. Nilsson G, Johnell M, Hammer CH, et al. C3a and C5a are chemotaxins for human mast cells and act through distinct receptors via a pertussis toxin-sensitive signal transduction pathway. J Immunol 1996; 157:1693.
  42. Schulman ES, Post TJ, Henson PM, Giclas PC. Differential effects of the complement peptides, C5a and C5a des Arg on human basophil and lung mast cell histamine release. J Clin Invest 1988; 81:918.
  43. McCurdy JD, Olynych TJ, Maher LH, Marshall JS. Cutting edge: distinct Toll-like receptor 2 activators selectively induce different classes of mediator production from human mast cells. J Immunol 2003; 170:1625.
  44. Kulka M, Alexopoulou L, Flavell RA, Metcalfe DD. Activation of mast cells by double-stranded RNA: evidence for activation through Toll-like receptor 3. J Allergy Clin Immunol 2004; 114:174.
  45. Varadaradjalou S, Féger F, Thieblemont N, et al. Toll-like receptor 2 (TLR2) and TLR4 differentially activate human mast cells. Eur J Immunol 2003; 33:899.
  46. Marshall JS, Jawdat DM. Mast cells in innate immunity. J Allergy Clin Immunol 2004; 114:21.
  47. Marshall JS, McCurdy JD, Olynych T. Toll-like receptor-mediated activation of mast cells: implications for allergic disease? Int Arch Allergy Immunol 2003; 132:87.
  48. Church MK, et al. Functional heterogeneity of human mast cells. In: Mast cell and basophil differentiation and function in health and disease, Galli SJ, Austen KF (Eds), Raven Press, Raven Press 1989.
  49. Benyon RC, Lowman MA, Church MK. Human skin mast cells: their dispersion, purification, and secretory characterization. J Immunol 1987; 138:861.
  50. Church MK, el-Lati S, Caulfield JP. Neuropeptide-induced secretion from human skin mast cells. Int Arch Allergy Appl Immunol 1991; 94:310.
  51. Aridor M, Traub LM, Sagi-Eisenberg R. Exocytosis in mast cells by basic secretagogues: evidence for direct activation of GTP-binding proteins. J Cell Biol 1990; 111:909.
  52. Mousli M, Bronner C, Bueb JL, Landry Y. Evidence for the interaction of mast cell-degranulating peptide with pertussis toxin-sensitive G proteins in mast cells. Eur J Pharmacol 1991; 207:249.
  53. Tatemoto K, Nozaki Y, Tsuda R, et al. Immunoglobulin E-independent activation of mast cell is mediated by Mrg receptors. Biochem Biophys Res Commun 2006; 349:1322.
  54. Gaudenzio N, Sibilano R, Marichal T, et al. Different activation signals induce distinct mast cell degranulation strategies. J Clin Invest 2016; 126:3981.
  55. Wang LL, Mehta IK, LeBlanc PA, Yokoyama WM. Mouse natural killer cells express gp49B1, a structural homologue of human killer inhibitory receptors. J Immunol 1997; 158:13.
  56. Stellato C, de Paulis A, Cirillo R, et al. Heterogeneity of human mast cells and basophils in response to muscle relaxants. Anesthesiology 1991; 74:1078.
  57. Moss J, Rosow CE. Histamine release by narcotics and muscle relaxants in humans. Anesthesiology 1983; 59:330.
  58. Kajiwara N, Sasaki T, Bradding P, et al. Activation of human mast cells through the platelet-activating factor receptor. J Allergy Clin Immunol 2010; 125:1137.
  59. Katz HR. Inhibitory receptors and allergy. Curr Opin Immunol 2002; 14:698.
  60. Finkelman FD. Anaphylaxis: lessons from mouse models. J Allergy Clin Immunol 2007; 120:506.
  61. Yokoi H, Myers A, Matsumoto K, et al. Alteration and acquisition of Siglecs during in vitro maturation of CD34+ progenitors into human mast cells. Allergy 2006; 61:769.
  62. Duan S, Paulson JC. Siglecs as Immune Cell Checkpoints in Disease. Annu Rev Immunol 2020; 38:365.
  63. O'Sullivan JA, Chang AT, Youngblood BA, Bochner BS. Eosinophil and mast cell Siglecs: From biology to drug target. J Leukoc Biol 2020; 108:73.
  64. Daëron M, Malbec O, Latour S, et al. Regulation of high-affinity IgE receptor-mediated mast cell activation by murine low-affinity IgG receptors. J Clin Invest 1995; 95:577.
  65. Daheshia M, Friend DS, Grusby MJ, et al. Increased severity of local and systemic anaphylactic reactions in gp49B1-deficient mice. J Exp Med 2001; 194:227.
  66. Zhou JS, Friend DS, Lee DM, et al. gp49B1 deficiency is associated with increases in cytokine and chemokine production and severity of proliferative synovitis induced by anti-type II collagen mAb. Eur J Immunol 2005; 35:1530.
  67. Voehringer D, Rosen DB, Lanier LL, Locksley RM. CD200 receptor family members represent novel DAP12-associated activating receptors on basophils and mast cells. J Biol Chem 2004; 279:54117.
  68. Cherwinski HM, Murphy CA, Joyce BL, et al. The CD200 receptor is a novel and potent regulator of murine and human mast cell function. J Immunol 2005; 174:1348.
  69. Zhang S, Phillips JH. Identification of tyrosine residues crucial for CD200R-mediated inhibition of mast cell activation. J Leukoc Biol 2006; 79:363.
  70. Kojima T, Obata K, Mukai K, et al. Mast cells and basophils are selectively activated in vitro and in vivo through CD200R3 in an IgE-independent manner. J Immunol 2007; 179:7093.
  71. Bachelet I, Munitz A, Moretta A, et al. The inhibitory receptor IRp60 (CD300a) is expressed and functional on human mast cells. J Immunol 2005; 175:7989.
  72. Okoshi Y, Tahara-Hanaoka S, Nakahashi C, et al. Requirement of the tyrosines at residues 258 and 270 of MAIR-I in inhibitory effect on degranulation from basophilic leukemia RBL-2H3. Int Immunol 2005; 17:65.
  73. Simhadri VR, Andersen JF, Calvo E, et al. Human CD300a binds to phosphatidylethanolamine and phosphatidylserine, and modulates the phagocytosis of dead cells. Blood 2012; 119:2799.
  74. Nakahashi-Oda C, Tahara-Hanaoka S, Shoji M, et al. Apoptotic cells suppress mast cell inflammatory responses via the CD300a immunoreceptor. J Exp Med 2012; 209:1493.
  75. Chong LK, Morice AH, Yeo WW, et al. Functional desensitization of beta agonist responses in human lung mast cells. Am J Respir Cell Mol Biol 1995; 13:540.
  76. Church MK, Hiroi J. Inhibition of IgE-dependent histamine release from human dispersed lung mast cells by anti-allergic drugs and salbutamol. Br J Pharmacol 1987; 90:421.
  77. Okayama Y, Church MK. Comparison of the modulatory effect of ketotifen, sodium cromoglycate, procaterol and salbutamol in human skin, lung and tonsil mast cells. Int Arch Allergy Immunol 1992; 97:216.
  78. Zhu D, Kepley CL, Zhang K, et al. A chimeric human-cat fusion protein blocks cat-induced allergy. Nat Med 2005; 11:446.
  79. Mertsching E, Bafetti L, Hess H, et al. A mouse Fcgamma-Fcepsilon protein that inhibits mast cells through activation of FcgammaRIIB, SH2 domain-containing inositol phosphatase 1, and SH2 domain-containing protein tyrosine phosphatases. J Allergy Clin Immunol 2008; 121:441.
  80. Goodridge HS, Marshall FA, Else KJ, et al. Immunomodulation via novel use of TLR4 by the filarial nematode phosphorylcholine-containing secreted product, ES-62. J Immunol 2005; 174:284.
  81. Melendez AJ, Harnett MM, Pushparaj PN, et al. Inhibition of Fc epsilon RI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes. Nat Med 2007; 13:1375.
  82. Jouvin MH, Adamczewski M, Numerof R, et al. Differential control of the tyrosine kinases Lyn and Syk by the two signaling chains of the high affinity immunoglobulin E receptor. J Biol Chem 1994; 269:5918.
  83. Yamashita T, Mao SY, Metzger H. Aggregation of the high-affinity IgE receptor and enhanced activity of p53/56lyn protein-tyrosine kinase. Proc Natl Acad Sci U S A 1994; 91:11251.
  84. Wilson BS, Kapp N, Lee RJ, et al. Distinct functions of the Fc epsilon R1 gamma and beta subunits in the control of Fc epsilon R1-mediated tyrosine kinase activation and signaling responses in RBL-2H3 mast cells. J Biol Chem 1995; 270:4013.
  85. Oliver JM, Burg DL, Wilson BS, et al. Inhibition of mast cell Fc epsilon R1-mediated signaling and effector function by the Syk-selective inhibitor, piceatannol. J Biol Chem 1994; 269:29697.
  86. Kambayashi T, Koretzky GA. Proximal signaling events in Fc epsilon RI-mediated mast cell activation. J Allergy Clin Immunol 2007; 119:544.
  87. Blumer KJ, Johnson GL. Diversity in function and regulation of MAP kinase pathways. Trends Biochem Sci 1994; 19:236.
  88. Cano E, Mahadevan LC. Parallel signal processing among mammalian MAPKs. Trends Biochem Sci 1995; 20:117.
  89. Hirasawa N, Santini F, Beaven MA. Activation of the mitogen-activated protein kinase/cytosolic phospholipase A2 pathway in a rat mast cell line. Indications of different pathways for release of arachidonic acid and secretory granules. J Immunol 1995; 154:5391.
  90. Hirasawa N, Scharenberg A, Yamamura H, et al. A requirement for Syk in the activation of the microtubule-associated protein kinase/phospholipase A2 pathway by Fc epsilon R1 is not shared by a G protein-coupled receptor. J Biol Chem 1995; 270:10960.
  91. Glover S, de Carvalho MS, Bayburt T, et al. Translocation of the 85-kDa phospholipase A2 from cytosol to the nuclear envelope in rat basophilic leukemia cells stimulated with calcium ionophore or IgE/antigen. J Biol Chem 1995; 270:15359.
  92. Divecha N, Irvine RF. Phospholipid signaling. Cell 1995; 80:269.
  93. Fukamachi H, Kawakami Y, Takei M, et al. Association of protein-tyrosine kinase with phospholipase C-gamma 1 in bone marrow-derived mouse mast cells. Proc Natl Acad Sci U S A 1992; 89:9524.
  94. Lewin I, Jacob-Hirsch J, Zang ZC, et al. Aggregation of the Fc epsilon RI in mast cells induces the synthesis of Fos-interacting protein and increases its DNA binding-activity: the dependence on protein kinase C-beta. J Biol Chem 1996; 271:1514.
  95. Razin E, Szallasi Z, Kazanietz MG, et al. Protein kinases C-beta and C-epsilon link the mast cell high-affinity receptor for IgE to the expression of c-fos and c-jun. Proc Natl Acad Sci U S A 1994; 91:7722.
  96. Marquardt DL, Alongi JL, Walker LL. The phosphatidylinositol 3-kinase inhibitor wortmannin blocks mast cell exocytosis but not IL-6 production. J Immunol 1996; 156:1942.
  97. Fruman DA, Bierer BE, Benes JE, et al. The complex of FK506-binding protein 12 and FK506 inhibits calcineurin phosphatase activity and IgE activation-induced cytokine transcripts, but not exocytosis, in mouse mast cells. J Immunol 1995; 154:1846.
  98. Penner R, Matthews G, Neher E. Regulation of calcium influx by second messengers in rat mast cells. Nature 1988; 334:499.
  99. Erb KJ. Can helminths or helminth-derived products be used in humans to prevent or treat allergic diseases? Trends Immunol 2009; 30:75.
  100. Harnett MM, Melendez AJ, Harnett W. The therapeutic potential of the filarial nematode-derived immunodulator, ES-62 in inflammatory disease. Clin Exp Immunol 2010; 159:256.
  101. Zhang K, Zhu D, Kepley C, et al. Chimeric human fcgamma-allergen fusion proteins in the prevention of allergy. Immunol Allergy Clin North Am 2007; 27:93.
Topic 3981 Version 19.0