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The Journal of Immunology, 2005, 175: 4167-4173.
Copyright © 2005 by The American Association of Immunologists

BRIEF REVIEWS

Mast Cell Survival and Activation by IgE in the Absence of Antigen: A Consideration of the Biologic Mechanisms and Relevance1

Toshiaki Kawakami3 and Jiro Kitaura2

Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121


   Abstract
Top
 Abstract
Introduction
 IgE-induced mast cell survival...
 Heterogeneity of IgE molecules
 Models for IgE-induced receptor...
 Fc{epsilon}RI components and...
 Strength and duration of...
 Autocrine and paracrine...
 Signal transduction for IgE(-Ag)...
 In vivo effects of...
 Conclusions
 References
 
Mast cells are not only major effector cells in allergy and host defense against parasites and bacteria but also important cellular components in other immune responses. Recent studies on the effects of monomeric IgE on mast cell survival and activation have made an impact on our view of the IgE binding to its high-affinity receptors, Fc{epsilon}RI. Traditionally, IgE binding to Fc{epsilon}RI has been considered as a passive action of "sensitization" before receptor aggregation by Ag. However, recent studies indicate that at high concentrations some monoclonal IgEs have effects on mast cells similar to or identical to those induced by IgE+Ag stimulation. These effects may be due to induction of Fc{epsilon}RI aggregation by these IgEs in the absence of Ag. This review will synthesize recent findings of the heterogeneity of IgEs in their ability to induce survival and activation events, their mechanisms, the potential in vivo significance of IgE-Fc{epsilon}RI interactions, and the implications of the mouse studies to human diseases.


   Introduction
Top
 Abstract
 Introduction
IgE-induced mast cell survival...
 Heterogeneity of IgE molecules
 Models for IgE-induced receptor...
 Fc{epsilon}RI components and...
 Strength and duration of...
 Autocrine and paracrine...
 Signal transduction for IgE(-Ag)...
 In vivo effects of...
 Conclusions
 References
 
Mast cells reside close to the mucosal and epithelial interfaces with the environment and around blood vessels. A vast majority of mast cell studies have dealt with their predominant role in acute allergic reactions (immediate hypersensitivity) and more recently their roles in late-phase allergic reactions (1) and in the host defense against certain bacteria (2, 3) and parasites (4, 5). Beyond this traditional understanding, our knowledge of mast cell functions has recently been substantially expanded (6, 7) and now includes those in autoimmunity such as experimental allergic encephalomyelopathy and rheumatoid arthritis (8, 9), delayed-type hypersensitivity (10), angiogenesis (11), and congestive heart failure (12).

Fc{epsilon}RI expressed on murine mast cells consists of four subunits ({alpha}{beta}{gamma}2): an IgE-binding {alpha} subunit, a signal-amplifying, receptor-stabilizing {beta} subunit, and two disulfide-bonded {gamma} subunits that are the main signal transducer (13). Stimulation of IgE-sensitized mast cells with Ag (this mode of stimulation hereafter referred to as IgE+Ag) or anti-IgE Ab (referred to as IgE+anti-IgE) induces receptor aggregation or cross-linking. Aggregation of Fc{epsilon}RI leads to the activation of {beta} subunit-associated Lyn, a Src family protein tyrosine kinase (PTK).4 Activated Lyn phosphorylates tyrosine residues in the ITAMs in the cytoplasmic regions of {beta} and {gamma} subunits. Phosphorylated {beta} and {gamma} ITAMs recruit Lyn and Syk, respectively. Another Src family PTK, Fyn, was also shown to associate with Fc{epsilon}RI and to play a complementary role, particularly by activating PI3K (14). These PTKs phosphorylate numerous targets and activate several signaling pathways, including the PI3K, phospholipase C/Ca2+, and several MAPK pathways (15, 16). These signaling events lead to degranulation and cytokine and chemokine production. Chemicals (e.g., histamine and serotonin), lipids (leukotrienes and PGs), nucleotides (e.g., adenosine), and polypeptides (e.g., proteases, cytokines, and chemokines) released from activated mast cells are effector molecules that induce allergic or inflammatory reactions or modulate innate and adaptive immune responses (7, 17).


   IgE-induced mast cell survival and activation in the absence of Ag
Top
 Abstract
 Introduction
 IgE-induced mast cell survival...
Heterogeneity of IgE molecules
 Models for IgE-induced receptor...
 Fc{epsilon}RI components and...
 Strength and duration of...
 Autocrine and paracrine...
 Signal transduction for IgE(-Ag)...
 In vivo effects of...
 Conclusions
 References
 
One of the traditional views that have been widely accepted is on effects of IgE binding to the Fc{epsilon}RI. IgE binding was once thought of as a passive step of sensitization, which would keep mast cells at a "resting" state, before receptor aggregation with multivalent Ag (allergen) or anti-IgE. In stark contrast to this traditional view, it was shown that IgE binding to Fc{epsilon}RI in the absence of specific Ag (the stimulation mode referred to as IgE(-Ag)) engenders several biological outcomes in mast cells: IgE(-Ag) can induce up-regulation of cell surface expression of the receptor (i.e., Fc{epsilon}RI) (18, 19, 20), survival (21, 22), increase in histamine content (23), histamine release, leukotriene release, receptor internalization, DNA synthesis (24), increased responses to compound 48/80 and substance P (25), increase in F-actin content (26), membrane ruffling (27), mast cell adhesion to fibronectin (28), and migration (29). These events are almost all inducible by IgE+Ag or IgE+anti-IgE (Fig. 1). Importantly, these IgE(-Ag) effects are induced at high concentrations of IgE 2–3 logs more than required to sensitize a mast cell for Ag-dependent activation. Parenthetically, IgE was shown to augment IL-3-induced mast cell proliferation (30), but unfortunately, this finding in 1986 received little attention.



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  		FIGURE 1. Biological effects by various modes of stimulation via the Fc{epsilon}RI. Experiments using mouse BMMCs are summarized. Concentrations of stimuli are as follows: PC IgE (H1 DNP-{epsilon}-206) and HC IgE (SPE-7), 0.5 µg/ml (low) and 5 µg/ml (high); and IgE+Ag (DNP21-BSA), 1 ng/ml (low) and 100 ng/ml (high). Notice that biological events are listed in a rough order of occurrences and that receptor aggregation presumably occurs in all modes of stimulation, except for low PC IgE concentrations. -, not detected, -#, very weak; W, weak; W#, weak~moderate; S#, moderate~strong; and S, strong. References: receptor internalization (24 44 50 ); histamine release (14 21 22 24 26 27 43 44 50 ); leukotriene release (21 22 24 ); adhesion (28 56 ); IL-6 production (21 22 24 43 44 50 51 ); migration (29 ); histamine content (23 24 57 ); DNA synthesis (21 22 24 86 ); and survival (21 22 24 43 44 50 51 58 59 60 61 62 ). In Ref.60 , MC9 mouse mast cells were used. In Ref.62 , BMMCs were stimulated with anti-TNP IgE (hybridoma supernatants) and TNP4.8-BSA (1 µg/ml). However, it is not clear whether the used Ag concentration corresponds to weak or strong stimulus.

 
Earlier studies established that receptor aggregation induced by IgE+Ag or IgE+anti-IgE is required for mast cell activation (31), which is in line with receptor dimerization or oligomerization as the common mechanism for receptor-mediated cell activation, e.g., that by peptide growth factors (32, 33). A biophysical method termed time-resolved phosphorescence anisotropy measurement (that quantifies motions of phosphorescent dye-labeled membrane proteins in the nano- to microsecond range, thus assessing the size and rigidity of the membrane structures containing the labeled proteins) suggests that IgE(-Ag) also induces receptor aggregation (24). The enhancement in the affinity of binding an Ag-combining site of an IgE molecule to an epitope on another IgE was estimated by calculating the probability of finding as nearest neighbor a distinct receptor at distances between r0 and r0 +{Delta}r on a cell surface (34). This simulation (r0 = 75Å and {Delta}r = 30Å) predicted a significant probability (>0.4 or ~0.1, respectively, for cells with 3 x 105 (RBL-2H3 rat mast cells) or 5 x 104 (mouse bone marrow-derived mast cell (BMMC)) receptors per cell), with which IgE-IgE interactions (presumed Fc{epsilon}RI aggregations) take place on the cell surface at IgE concentrations > 1 µg/ml in the absence of Ag. These calculations match the experimental data obtained in different laboratories in that IgE effects on survival and activation are seen at ≥0.5 µg/ml IgE concentrations, and they are consistent with IgE(Ag)-mediated Fc{epsilon}RI aggregation suggested by the phosphorescence anisotropy data. By contrast, the same simulation predicts a ~104-fold lower probability of nearest neighbor (IgE-IgE) interactions in solution. Several studies suggested that survival and other activation effects were due to binding to Fc{epsilon}RI by monomeric, but not aggregate, IgE molecules in the IgE preparations. However, IgE(-Ag)-induced Fc{epsilon}RI aggregation will need to be confirmed by other methodologies.

Despite the rapid progress in this area, there are many issues to be resolved (Table I). It has never been absolutely shown if the very high amounts of IgE added under the culture conditions used do not self-aggregate. IgE effects, interpreted as due to monomeric IgE, would be in fact due to aggregated IgE within the culture or IgE sticking to plastic plates. Also, the cultured mast cells exposed to these high levels of IgE have not seen IgE during maturation. This is not what happens in vivo, where an individual IgE receptor expressed on the developing mast cell is immediately engaged by IgE. Furthermore, how would such a system with no Ag specificity mechanistically function in tissues?


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  		Table I. Outstanding questions to be addressed in future

 

   Heterogeneity of IgE molecules
Top
 Abstract
 Introduction
 IgE-induced mast cell survival...
 Heterogeneity of IgE molecules
Models for IgE-induced receptor...
 Fc{epsilon}RI components and...
 Strength and duration of...
 Autocrine and paracrine...
 Signal transduction for IgE(-Ag)...
 In vivo effects of...
 Conclusions
 References
 
Not all monoclonal IgE molecules can induce all the activation events listed above in the absence of Ag: IgEs display a wide spectrum in their ability to induce the production and secretion of IL-6 and TNF-{alpha} with highly cytokinergic (HC) IgEs at one extreme end and poorly cytokinergic (PC) IgEs at the other (24). Anisotropy data suggest that more extensive receptor aggregations take place with HC IgEs than with PC IgEs. Consistent with such differences in the extent of receptor aggregation, a strong HC IgE could induce all the tested activation events, whereas PC IgEs cause only a limited set of activation events and even for those to a lesser extent. Importantly, a mixture of seven different monoclonal IgEs exhibited survival effects (24), suggesting that polyclonal IgE should also have survival effects.


   Models for IgE-induced receptor aggregation
Top
 Abstract
 Introduction
 IgE-induced mast cell survival...
 Heterogeneity of IgE molecules
 Models for IgE-induced receptor...
Fc{epsilon}RI components and...
 Strength and duration of...
 Autocrine and paracrine...
 Signal transduction for IgE(-Ag)...
 In vivo effects of...
 Conclusions
 References
 
Despite this remarkable heterogeneity among IgE molecules, no information is available about differences among IgEs at molecular levels. Affinity of IgEs to Fc{epsilon}RI does not appear to be a determining factor of the differences between HC and PC IgEs, as a typical HC IgE, SPE-7, and a much weaker HC IgE, H1 DNP-{epsilon}-26, have similar reported affinities (KD = ~15 nM) (35, 36). The variable (V) regions of IgE molecules seem important for receptor aggregation and consequent survival and cytokine production, as monovalent hapten (for which the used IgE is specific) can inhibit IgE(-Ag)-induced receptor aggregation, survival, and cytokine production (24). Potentially related to the receptor aggregation mechanism and as a likely factor that determines the potency to induce receptor aggregation, a recent study showed that the SPE-7 Ab expressed as a recombinant single-chain Fv (VH-VL) molecule can adopt different Ag binding site conformations before Ag binding and that binding of different Ags can induce isomerization of the binding site, leading to high-affinity complexes with a deep or narrow binding site (37). Therefore, it is conceivable that IgEs can induce Fc{epsilon}RI aggregation in the absence of specific Ag when the Fab portion of a Fc{epsilon}RI-bound IgE molecule interacts with a neighboring Fc{epsilon}RI-bound IgE directly or indirectly via a third molecule whose epitopes are recognized by neighboring IgEs. Similar aggregation models via Ig domain-Ig domain interactions or Ig-X-Ig ("X" represents an unknown bridging molecule) interactions were proposed for pre-BCR (38).

Interestingly, a recent study described a molecule termed p28 in RBL-2H3 cells (39). This molecule, which cross-reacts with a mAb against phospholipid scramblase 1, is associated with ~50% of Fc{epsilon}RI in RBL-2H3 cells in the absence of IgE and dissociates from the receptor when the cells are incubated with a high concentration (20 µM) of IgEs. Therefore, p28 might be involved in sensing IgE binding. However, the identity and function of p28 remain to be revealed. Both IgE and Fc{epsilon}RI {alpha} subunit are glycoproteins. However, potential involvement of the carbohydrate moiety vs polypeptide backbone of IgE in receptor aggregation remains to be studied in future.

Another interesting feature of IgE(-Ag) effects is that at least some of them require the continuous, but not transient, presence of IgE, hence prolonged receptor aggregation: survival promotion by both HC and PC IgEs and proliferation by HC IgEs could be seen only in the presence of IgE but not after washing off IgE even after surface expression of Fc{epsilon}RI was dramatically increased by preincubation with IgE (21). Prolonged Fc{epsilon}RI aggregation was also suspected to be required for augmented proliferation of peritoneal mast cells, although this proliferation was induced in a semisolid culture by IgE+Ag in the presence of IL-3 (40).


   Fc{epsilon}RI components and membrane microenvironments required for IgE(-Ag) effects
Top
 Abstract
 Introduction
 IgE-induced mast cell survival...
 Heterogeneity of IgE molecules
 Models for IgE-induced receptor...
 Fc{epsilon}RI components and...
Strength and duration of...
 Autocrine and paracrine...
 Signal transduction for IgE(-Ag)...
 In vivo effects of...
 Conclusions
 References
 
IgE+Ag stimulation induces localization of the aggregated receptors to cholesterol/sphingolipid-rich plasma membrane domains termed lipid rafts (41, 42). Experimental disruption of lipid rafts suggests that localization of the receptor in lipid rafts is required for the activation of ERK induced by IgE(-Ag) stimulation and therefore for survival as well (see Strength and duration of Fc{epsilon}RI stimulation determine mast cell survival) (22). Among the obligate subunits ({alpha}, {beta}, and {gamma}) of the murine Fc{epsilon}RI, both {alpha} and {gamma} subunits were shown to be required for IgE(-Ag)-mediated survival (21, 43). Interestingly, the ITAM of {gamma} subunit, which is critical for IgE+Ag-induced mast cell degranulation and cytokine production and IgE(-Ag)-mediated survival, is not essential for IgE(-Ag)-mediated receptor up-regulation (43). Consistent with this but unlike degranulation or other activation events, receptor up-regulation induced by IgE(-Ag) does not require Lyn, Syk, or other PTKs (44). This phenomenon is due to the increased lifetime of the surface-resident receptors rather than to its increased synthesis and/or transport to the plasma membrane (18, 45, 46). Thus, this effect of IgE binding to the Fc{epsilon}RI is of a nature totally different from the other effects.


   Strength and duration of Fc{epsilon}RI stimulation determine mast cell survival
Top
 Abstract
 Introduction
 IgE-induced mast cell survival...
 Heterogeneity of IgE molecules
 Models for IgE-induced receptor...
 Fc{epsilon}RI components and...
 Strength and duration of...
Autocrine and paracrine...
 Signal transduction for IgE(-Ag)...
 In vivo effects of...
 Conclusions
 References
 
Mast cells die by apoptosis in the paucity of growth factors in vitro and in vivo. In vivo apoptosis was reported in mast cells that had been proliferated by repetitive injections of stem cell factor, following the cessation of the injections (47) and splenic mast cells during parasite infection (48). Survival-enhancing stimuli of Fc{epsilon}RI include IgE(-Ag), IgE+anti-IgE, and IgE+Ag (low Ag concentrations) (44). Importantly, a slow on-rate of IgE interaction with Fc{epsilon}RI together with prolonged activation of ERK matches with the required pattern of ERK activity for survival of T cells and other cell types (49). Consistent with this, relatively weak signals emanated from the {gamma} subunit were required for the survival of mast cells expressing CD8/{gamma} chimera in the genetic background of {gamma}–/–, compared with the signals required for degranulation (50). However, the duration of the {gamma} signals seems more essential for survival because sustained ERK activation, even strong enough to induce degranulation, could induce survival.


   Autocrine and paracrine mechanisms for mast cell survival and activation
Top
 Abstract
 Introduction
 IgE-induced mast cell survival...
 Heterogeneity of IgE molecules
 Models for IgE-induced receptor...
 Fc{epsilon}RI components and...
 Strength and duration of...
 Autocrine and paracrine...
Signal transduction for IgE(-Ag)...
 In vivo effects of...
 Conclusions
 References
 
Survival mechanisms elicited by IgE(-Ag) and IgE+Ag are not completely understood. At cellular levels, HC IgEs use an autocrine or paracrine mechanism at least in part by secreting a cytokine(s) that supports mast cell survival (22, 24). Kohno et al. (51) recently identified IL-3 as the predominant cytokine induced by HC IgEs that is responsible for the survival effects; survival effects were drastically reduced (but not abrogated) by neutralization of IL-3 or IL-3 deficiency. By contrast, PC IgEs do not support Fc{epsilon}RI{alpha}–/– mast cells in coculture with wild-type cells (24), indicating that PC IgEs do not induce secretion of survival-mediating cytokines. These data suggest that there are at least two different survival mechanisms evoked by IgE(-Ag) at cellular levels.

In addition to the predominant role of autocrine IL-3 for mast cell survival, recent data indicate that the mediators released from activated mast cells affect not only other cell types (e.g., neutrophil recruitment by mast cell-derived TNF-{alpha} in late-phase allergic responses (52)) but also themselves and neighboring mast cells in terms of scale and duration of several aspects of activation. Thus, recent studies demonstrated the importance of adenosine and sphingosine 1-phosphate acutely released by IgE+Ag in Ca2+ influx, degranulation, and chemotaxis to Ag (53, 54). Unlike degranulation that is completed within several minutes after the initiation of IgE+Ag stimulation, migration induced by IgE(-Ag), as well as IgE+Ag, is affected by many factors; in addition to sphingosine 1-phosphate, adenosine, leukotriene B4, and several chemokines (MIP-1{alpha}/CCL3, MIP-1{beta}/CCL4, MIP-2/CXCL1–3, MCP-1/CCL2, and RANTES/CCL5) contribute to the full migratory activity using both directional (chemotaxis) and nondirectional (chemokinesis) mechanisms; as these factors all use G protein-coupled receptors, this form of migration is dependent on PI3K{gamma} (29). Therefore, the PTK-based signaling pathways and G protein-coupled receptor-based signaling pathways seem to converge or cross-talk to enhance degranulation and migratory responses (and probably other activation events as well).


   Signal transduction for IgE(-Ag)- and IgE+Ag-induced survival and activation
Top
 Abstract
 Introduction
 IgE-induced mast cell survival...
 Heterogeneity of IgE molecules
 Models for IgE-induced receptor...
 Fc{epsilon}RI components and...
 Strength and duration of...
 Autocrine and paracrine...
 Signal transduction for IgE(-Ag)...
In vivo effects of...
 Conclusions
 References
 
Because both IgE(-Ag) and IgE+Ag engage the Fc{epsilon}RI, it would not be irrational to assume that similar, if not identical, signaling events are elicited by the two modes of Fc{epsilon}RI stimulations. Indeed, recent studies using pharmacological agents and mast cells derived from gene-targeted mice showed very similar signaling requirements for IgE(-Ag)- and IgE+Ag-induced biological outcomes (refer to Refs.15 , 16 , 55 for detailed reviews of IgE+Ag-induced signaling): degranulation induced by these stimuli depends on Syk; production of IL-6 and TNF-{alpha} also requires Syk; Fc{epsilon}RI internalization requires Lyn but not other Src family PTKs, Syk, or Btk; optimal adhesion via fibronectin requires Lyn and Syk but not Fyn; and migration toward HC IgEs or Ag depends heavily on Lyn and Syk and Fyn, PKC{beta}, PKC{epsilon}, and PKC{theta} to a lesser extent (24, 28, 29, 44, 56). However, quantitative differences were observed for the required signaling molecules in the IgE(-Ag)- and IgE+Ag-induced biological consequences: for instance, the Lyn requirement for HC IgE-induced adhesion is almost absolute, but the role of Lyn for IgE+Ag-induced adhesion is at best contributory (56). Qualitative differences were also observed between the two stimulation modes: concentrations of intracellular Ca2+ are increased transiently by HC IgEs (26, 27, 28). A recent study showed that Ca2+ responses induced by SPE-7 IgE are suppressed by SK&F 96365, a specific inhibitor of store-operated Ca2+ channel but not by broad-spectrum Ca2+ channel inhibitors, La3+ or Gd3+, whereas Ca2+ responses induced by IgE+Ag are suppressed by these three inhibitors (57). These results suggest that IgE(-Ag) and IgE+Ag induce Ca2+ influx by different mechanisms (Fig. 2).



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  		FIGURE 2. Comparison of signaling events induced by different modes of Fc{epsilon}RI stimulation. Data with mouse BMMCs are summarized. Concentrations of stimuli are as follows: PC IgE (H1 DNP-{epsilon}-206) and HC IgE (SPE-7), 0.5 µg/ml (low) and 5 µg/ml (high); IgE+Ag (DNP21-BSA), 1 ng/ml (low) and 100 ng/ml (high). -, not detected; -#, very weak; W, weak; W#, weak~moderate; S#, moderate~strong; and S, strong. References: Lyn kinase activity (14 21 22 23 24 44 ); Fc{epsilon}RI {beta} tyrosine phosphorylation (14 21 22 24 ); Syk kinase activity (14 21 22 24 43 44 50 ); increased Ca2+ flux (14 21 23 26 27 57 ); ERK activity (14 21 22 24 43 50 51 ); and p38 activity (14 21 22 24 ).

 
A recent study showed that Bcl-2 and Bim, anti- and proapoptotic members of the Bcl-2 family proteins, respectively, antagonizes and promotes mast cell apoptosis induced by growth factor withdrawal (58). The major survival pathway induced by IgE(-Ag) appears to be dissected into two consecutive events: the Fc{epsilon}RI-activated signaling pathway leading to autocrine secretion of IL-3 and then activation of IL-3R signaling pathways leading to survival (51). Although details still remain to be worked out, the initial signaling events seem to include the activation of Lyn and Syk (24) leading to the activation of ERK. Interestingly, however, Fyn, Gab2, PI3K p85, or Akt are not required for IgE(-Ag)-mediated survival (51). Downstream of IL-3R signaling, Stat5 was shown to be important for mast cell survival (59). Expression of Bcl-xL and Bcl-2 is induced in an IL-3-dependent manner. Importantly, Bcl-xL can support mast cell survival in IL-3–/– mast cells (51).

IgE+Ag stimulation can also enhance mast cell survival under certain conditions (44): IgE+Ag prevents apoptosis of MC9 mast cells by an autocrine mechanism, producing IL-3, IL-4, and GM-CSF (60). Although secretion of endogenous IL-3 and GM-CSF is not sufficient for MC9 survival, IL- 4 renders the cells reactive to these cytokines. IgE+Ag can induce enhanced expression of FLIP, a caspase-8 inhibitor, and consequently a resistance to Fas-induced apoptosis (61). An antiapoptotic member of the Bcl-2 family, A1, was shown to be important for the IgE+Ag-induced survival effects (62). IgE+Ag stimulation induces the expression of not only antiapoptotic proteins such as A1 and Bcl-xL but also proapoptotic proteins such as BimEL and BimL (58). However, it remains to be examined whether these proteins with opposing functions contribute to IgE(-Ag)-induced mast cell survival. An IL-3-independent pathway used by IgE(-Ag) remains enigmatic, but it requires Syk because no survival effects of mIgEs were seen in syk–/– cells (24).


   In vivo effects of IgE(-Ag) stimulation and their implications in diseases
Top
 Abstract
 Introduction
 IgE-induced mast cell survival...
 Heterogeneity of IgE molecules
 Models for IgE-induced receptor...
 Fc{epsilon}RI components and...
 Strength and duration of...
 Autocrine and paracrine...
 Signal transduction for IgE(-Ag)...
 In vivo effects of...
Conclusions
 References
 
IgE(-Ag) effects on survival and activation may not represent mere in vitro artifacts in mouse mast cells, although the definitive in vivo evidence for these phenomena has yet to come. However, there are several in vivo observations that support roles for IgE in mast cell survival and activation. Increased serum IgE levels in mice transplanted with IgE-producing hybridomas were correlated with increased mast cell numbers in some mucosal tissues (24). However, the presence of IgE is not required for the development of mast cells (63), and no increase in mast cell numbers was reported in IgE-transgenic mice (64). These results do not contradict the IgE(-Ag) effects on mast cell survival because relatively high concentrations of IgE are required for survival effects. These observations suggest that IgE levels do not determine the homeostasis of mast cell populations in vivo under physiological conditions. By contrast, IgE might play a critical role in maintaining mastocytosis during parasite infection. Infection with the parasitic helminth, Trichinella spiralis, elicits a vigorous IgE response and pronounced intestinal and splenic mastocytosis in wild-type mice. However, splenic mastocytosis was diminished in IgE–/– mice while similar levels of eosinophilia and jejunal mastocytosis occurred in wild-type and mutant mice (48). Mast cells in T. spiralis-infected mice migrate from the gut to the spleen and die there by apoptosis. Therefore, high-level IgEs seem essential to protect mast cells from apoptosis in the infected spleens. Furthermore, mucosal mastocytosis is impaired in IL-3–/– mice during nematode (Strongyloides venezuelensis) infection (5). These observations fit well with the IL-3 autocrine mechanism for IgE(-Ag)-induced mast cell survival. Therefore, under conditions where IgE may reach very high levels, e.g., parasite infection (53.3 µg/ml serum IgE in T. spiralis-infected mice (48)) and atopy (sometimes >100 µg/ml in NC/Nga mice (65)), tissue density of mast cells could be regulated in part by the survival (and proliferative) effects of IgE. However, the potential involvement of Ag, for which IgEs are specific, in the role for IgEs in enhancing mast cell survival has not been addressed in parasite infections, although much of the IgE that is produced in response to nematode infections is found not to be specific to the parasite (66). Additionally, contributions to mast cell survival by other factors, e.g., cytokines and chemokines, have not been known in the above parasite experiments.

A recent study showed that mast cell accumulation can be induced by epicutaneous application of HC IgEs and IgE+Ag (29). These results suggest that HC IgEs (in the absence of specific Ag) and IgE+Ag can induce accumulation of mast cells without prior inflammation. However, it is conceivable that, in allergic individuals, some inflammatory reactions such as the infiltration of helper T cells have occurred when IgE synthesis in B cells takes place at mucosal sites in response to Ag exposure (67, 68, 69, 70, 71, 72). Given the vast variety of proinflammatory mediators secreted from activated mast cells (73), IgE(-Ag)- and IgE+Ag-induced mast cell accumulation would amplify inflammatory reactions by recruiting other immune cells such as T cells, eosinophils, monocytes, and neutrophils: for instance, histamine plays an important role in the pathogenesis of atopic asthma by enhancing the secretion of Th2 cytokines and inhibiting the production of Th1 cytokines (74). Leukotriene B4 recruits T cells and myeloid cells (75, 76, 77), and mast cell-produced cytokines and chemokines can recruit T cells, eosinophils, monocytes, and neutrophils. CC chemokine transcripts coding for I-309/CCL1, MIP-1{alpha}/CCL3 MIP-1{beta}/CCL4, and MCP-3/CCL7 are among the most dramatically enhanced in IgE+Ag-stimulated mast cells (78). The ability of HC IgEs to attract mast cells suggests that this amplification of inflammation can last as long as local IgE synthesis continues even after the elimination of Ag. Therefore, IgEs in the presence as well as absence of allergen are implicated in mast cell accumulation at allergic tissue sites with local high IgE levels.

Importantly, IgE was shown to be essential for optimal sensitization in contact sensitivity but not for the elicitation phase, unlike mast cells, which are required for both the sensitization and elicitation phases (79). Contact sensitivity was markedly impaired in IgE–/– mice but was restored by either transfer of sensitized cells from wild-type mice or administration of hapten-irrelevant IgEs (including two HC IgEs) before sensitization. IgE was required for generating an appropriate cytokine milieu for immunization. IL-6, IL-1{beta}, and MCP-1/CCL2 (and weakly TNF-{alpha}) can replace IgE in sensitization. However, it is not clear in this study whether or how IgE-mast cell interactions are required for the oxazolone sensitization, whether specific endogenous Ag interacts with IgE, or whether PC IgEs can restore responses in IgE–/– mice.

Several studies indicate the ability of IgE to enhance mast cell and basophil function in both mouse and human cells (20, 80, 81). Together with the enhanced cell survival, a positive feedback-loop hypothesis was proposed to explain inflammatory situations often found in atopic diseases associated with high-serum IgE levels: {uparrow}IgE -> {uparrow}Fc{epsilon}RI, {uparrow}mast cells -> {uparrow}Ag-, IgE-, and Fc{epsilon}RI-dependent release of IL-4, IL-13, MIP-1{alpha}/CCL3, and so on -> {uparrow}IgE. Now, studies have been extended to human monoclonal IgEs: human umbilical-cord-blood-derived mast cells incubated with IgE synthesize and release I-309/CCL1 (a ligand for CCR8 responsible for chemoattraction of Th2 cells), GM-CSF, and MIP-1{alpha}/CCL3 (82).

The distinction between HC and PC IgEs is reminiscent of the dichotomy found in human IgE molecules in their ability to prime basophils for the stimulation with histamine-releasing factor, a cytokine produced by macrophages and platelets: basophils bound by IgEs (termed IgE+) derived from atopic patients, but not those (termed IgE–) from normal subjects, can release histamine and cytokines such as IL-4 and IL-13 in response to histamine-releasing factor (83, 84). Structural basis for the difference between IgE+ and IgE– is not known yet. Interestingly, unusual usages of VH regions have been noted in allergic individuals: VH5, one of the smallest gene families containing two members out of the total of 52 functional VH genes, is overrepresented in the IgE from allergic patients (85). These observations together indicate the structural and functional heterogeneity among human IgE molecules. Therefore, it is interesting to study the human IgE heterogeneity and its relevance to human atopic and other diseases.


   Conclusions
Top
 Abstract
 Introduction
 IgE-induced mast cell survival...
 Heterogeneity of IgE molecules
 Models for IgE-induced receptor...
 Fc{epsilon}RI components and...
 Strength and duration of...
 Autocrine and paracrine...
 Signal transduction for IgE(-Ag)...
 In vivo effects of...
 Conclusions
References
 
Although numerous unanswered issues still remain (Table I), IgE(-Ag) effects on mast cell survival and activation have been well established. Several reports summarized in the previous section also presage future directions. Particularly, translational research together with basic mechanistic studies should be encouraged. Such studies will lead to a better understanding and, hopefully, better treatment of asthma, other allergic diseases, and host responses to parasite infections. Additionally, we hope this review stimulate studies in related fields, e.g., studies on effects of IgG-Fc{gamma}Rs.


   Acknowledgments
 
We thank Ralph Kubo and two anonymous reviewers for critical reading of the manuscript.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This study was supported by Public Health Service Grants AI50209 from the National Institutes of Health (to T.K.). Back

2 Current address: Division of Cellular Therapy, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, Japan. Back

3 Address correspondence and reprint requests to Dr. Toshiaki Kawakami at La Jolla Institute of Allergy and Immunology, San Diego, CA 92121. E-mail address: toshi{at}liai.org Back

4 Abbreviations used in this paper: PTK, protein tyrosine kinase; BMMC, bone marrow-derived mast cell; HC, highly cytokinergic; PC, poorly cytokinergic. Back

Received for publication May 10, 2005. Accepted for publication August 4, 2005.


   References
Top
 Abstract
 Introduction
 IgE-induced mast cell survival...
 Heterogeneity of IgE molecules
 Models for IgE-induced receptor...
 Fc{epsilon}RI components and...
 Strength and duration of...
 Autocrine and paracrine...
 Signal transduction for IgE(-Ag)...
 In vivo effects of...
 Conclusions
 References
 

  1. Galli, S. J., M. Maurer, C. S. Lantz. 1999. Mast cells as sentinels of innate immunity. Curr. Opin. Immunol. 11:53.-59. [Medline]
  2. Malaviya, R., T. Ikeda, E. Ross, S. N. Abraham. 1996. Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNF-{alpha}. Nature 381:77.-80. [Medline]
  3. Echtenacher, B., D. N. Mannel, L. Hultner. 1996. Critical protective role of mast cells in a model of acute septic peritonitis. Nature 381:75.-77. [Medline]
  4. Matsuda, H., N. Watanabe, Y. Kiso, S. Hirota, H. Ushio, Y. Kannan, M. Azuma, H. Koyama, Y. Kitamura. 1990. Necessity of IgE antibodies and mast cells for manifestation of resistance against larval Haemaphysalis longicornis ticks in mice. J. Immunol. 144:259.-262. [Abstract]
  5. Lantz, C. S., J. Boesiger, C. H. Song, N. Mach, T. Kobayashi, R. C. Mulligan, Y. Nawa, G. Dranoff, S. J. Galli. 1998. Role for interleukin-3 in mast-cell and basophil development and in immunity to parasites. Nature 392:90.-93. [Medline]
  6. Gurish, M. F., K. F. Austen. 2001. The diverse roles of mast cells. J. Exp. Med. 194:F1.-F5. [Medline]
  7. Galli, S. J., S. Nakae, M. Tsai. 2005. Mast cells in the development of adaptive immune responses. Nat. Immunol. 6:135.-142. [Medline]
  8. Secor, V. H., W. E. Secor, C. A. Gutekunst, M. A. Brown. 2000. Mast cells are essential for early onset and severe disease in a murine model of multiple sclerosis. J. Exp. Med. 191:813.-822. [Abstract/Free Full Text]
  9. Lee, D. M., D. S. Friend, M. F. Gurish, C. Benoist, D. Mathis, M. B. Brenner. 2002. Mast cells: a cellular link between autoantibodies and inflammatory arthritis. Science 297:1689.-1692. [Abstract/Free Full Text]
  10. Biedermann, T., M. Kneilling, R. Mailhammer, K. Maier, C. A. Sander, G. Kollias, S. L. Kunkel, L. Hultner, M. Rocken. 2000. Mast cells control neutrophil recruitment during T cell-mediated delayed-type hypersensitivity reactions through tumor necrosis factor and macrophage inflammatory protein 2. J. Exp. Med. 192:1441.-1452. [Abstract/Free Full Text]
  11. Coussens, L. M., W. W. Raymond, G. Bergers, M. Laig-Webster, O. Behrendtsen, Z. Werb, G. H. Caughey, D. Hanahan. 1999. Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev. 13:1382.-1397. [Abstract/Free Full Text]
  12. Hara, M., K. Ono, M. W. Hwang, A. Iwasaki, M. Okada, K. Nakatani, S. Sasayama, A. Matsumori. 2002. Evidence for a role of mast cells in the evolution to congestive heart failure. J. Exp. Med. 195:375.-381. [Abstract/Free Full Text]
  13. Kinet, J. P.. 1999. The high-affinity IgE receptor (Fc{epsilon}RI): from physiology to pathology. Annu. Rev. Immunol. 17:931.-972. [Medline]
  14. Parravicini, V., M. Gadina, M. Kovarova, S. Odom, C. Gonzalez-Espinosa, Y. Furumoto, S. Saitoh, L. E. Samelson, J. J. O’Shea, J. Rivera. 2002. Fyn kinase initiates complementary signals required for IgE-dependent mast cell degranulation. Nat. Immunol. 3:741.-748. [Medline]
  15. Turner, H., J. P. Kinet. 1999. Signalling through the high-affinity IgE receptor Fc{epsilon}RI. Nature 402:B24.-B30. [Medline]
  16. Kawakami, T., S. J. Galli. 2002. Regulation of mast-cell and basophil function and survival by IgE. Nat. Rev. Immunol. 2:773.-786. [Medline]
  17. Wedemeyer, J., M. Tsai, S. J. Galli. 2000. Roles of mast cells and basophils in innate and acquired immunity. Curr. Opin. Immunol. 12:624.-631. [Medline]
  18. Furuichi, K., J. Rivera, C. Isersky. 1985. The receptor for immunoglobulin E on rat basophilic leukemia cells: effect of ligand binding on receptor expression. Proc. Natl. Acad. Sci. USA 82:1522.-1525. [Abstract/Free Full Text]
  19. Hsu, C., D. MacGlashan, Jr. 1996. IgE antibody up-regulates high affinity IgE binding on murine bone marrow-derived mast cells. Immunol. Lett. 52:129.-134. [Medline]
  20. Yamaguchi, M., C. S. Lantz, H. C. Oettgen, I. M. Katona, T. Fleming, I. Miyajima, J. P. Kinet, S. J. Galli. 1997. IgE enhances mouse mast cell Fc{epsilon}RI expression in vitro and in vivo: evidence for a novel amplification mechanism in IgE-dependent reactions. J. Exp. Med. 185:663.-672. [Abstract/Free Full Text]
  21. Asai, K., J. Kitaura, Y. Kawakami, N. Yamagata, M. Tsai, D. P. Carbone, F. T. Liu, S. J. Galli, T. Kawakami. 2001. Regulation of mast cell survival by IgE. Immunity 14:791.-800. [Medline]
  22. Kalesnikoff, J., M. Huber, V. Lam, J. E. Damen, J. Zhang, R. P. Siraganian, G. Krystal. 2001. Monomeric IgE stimulates signaling pathways in mast cells that lead to cytokine production and cell survival. Immunity 14:801.-811. [Medline]
  23. Tanaka, S., Y. Takasu, S. Mikura, N. Satoh, A. Ichikawa. 2002. Antigen-independent induction of histamine synthesis by immunoglobulin E in mouse bone marrow-derived mast cells. J. Exp. Med. 196:229.-235. [Abstract/Free Full Text]
  24. Kitaura, J., J. Song, M. Tsai, K. Asai, M. Maeda-Yamamoto, A. Mocsai, Y. Kawakami, F. T. Liu, C. A. Lowell, B. G. Barisas, S. J. Galli, T. Kawakami. 2003. Evidence that IgE molecules mediate a spectrum of effects on mast cell survival and activation via aggregation of the Fc{epsilon}RI. Proc. Natl. Acad. Sci. USA 100:12911.-12916. [Abstract/Free Full Text]
  25. Yamada, N., H. Matsushima, Y. Tagaya, S. Shimada, S. I. Katz. 2003. Generation of a large number of connective tissue type mast cells by culture of murine fetal skin cells. J. Invest. Dermatol. 121:1425.-1432. [Medline]
  26. Oka, T., M. Hori, A. Tanaka, H. Matsuda, H. Karaki, H. Ozaki. 2004. IgE alone-induced actin assembly modifies calcium signaling and degranulation in RBL-2H3 mast cells. Am. J. Physiol. 286:C256.-C263.
  27. Pandey, V., S. Mihara, A. Fensome-Green, S. Bolsover, S. Cockcroft. 2004. Monomeric IgE stimulates NFAT translocation into the nucleus, a rise in cytosol Ca2+, degranulation, and membrane ruffling in the cultured rat basophilic leukemia-2H3 mast cell line. J. Immunol. 172:4048.-4058. [Abstract/Free Full Text]
  28. Lam, V., J. Kalesnikoff, C. W. Lee, V. Hernandez-Hansen, B. S. Wilson, J. M. Oliver, G. Krystal. 2003. IgE alone stimulates mast cell adhesion to fibronectin via pathways similar to those used by IgE + antigen but distinct from those used by Steel factor. Blood 102:1405.-1413. [Abstract/Free Full Text]
  29. Kitaura, J., T. Kinoshita, M. Matsumoto, S. Chung, Y. Kawakami, M. Leitges, D. Wu, C. A. Lowell, T. Kawakami. 2005. IgE- and IgE+Ag-mediated mast cell migration in an autocrine/paracrine fashion. Blood 105:3222.-3229. [Abstract/Free Full Text]
  30. Kawanishi, H.. 1986. Role of IgE as a mast cell development co-factor in the differentiation of murine gut-associated mast cells in vitro. Eur. J. Immunol. 16:689.-692. [Medline]
  31. Beaven, M. A., H. Metzger. 1993. Signal transduction by Fc receptors: the Fc{epsilon}RI case. Immunol. Today 14:222.-226. [Medline]
  32. Ullrich, A., J. Schlessinger. 1990. Signal transduction by receptors with tyrosine kinase activity. Cell 61:203.-212. [Medline]
  33. Heldin, C. H.. 1995. Dimerization of cell surface receptors in signal transduction. Cell 80:213.-223. [Medline]
  34. Schweitzer-Stenner, R., I. Pecht. 2005. Cutting edge: death of a dogma or enforcing the artificial: monomeric IgE binding may initiate mast cell response by inducing its receptor aggregation. J. Immunol. 174:4461.-4464. [Abstract/Free Full Text]
  35. Liu, F. T., J. W. Bohn, E. L. Ferry, H. Yamamoto, C. A. Molinaro, L. A. Sherman, N. R. Klinman, D. H. Katz. 1980. Monoclonal dinitrophenyl-specific murine IgE antibody: preparation, isolation, and characterization. J. Immunol. 124:2728.-2737. [Medline]
  36. Eshhar, Z., M. Ofarim, T. Waks. 1980. Generation of hybridomas secreting murine reaginic antibodies of anti-DNP specificity. J. Immunol. 124:775.-780. [Abstract]
  37. James, L. C., P. Roversi, D. S. Tawfik. 2003. Antibody multispecificity mediated by conformational diversity. Science 299:1362.-1367. [Abstract/Free Full Text]
  38. Ohnishi, K., F. Melchers. 2003. The nonimmunoglobulin portion of {lambda}5 mediates cell-autonomous pre-B cell receptor signaling. Nat. Immunol. 4:849.-856. [Medline]
  39. Charles, N., R. C. Monteiro, M. Benhamou. 2004. p28, a novel IgE receptor-associated protein, is a sensor of receptor occupation by its ligand in mast cells. J. Biol. Chem. 279:12312.-12318. [Abstract/Free Full Text]
  40. Takagi, M., T. Nakahata, K. Koike, T. Kobayashi, K. Tsuji, S. Kojima, T. Hirano, A. Miyajima, K. Arai, T. Akabane. 1989. Stimulation of connective tissue-type mast cell proliferation by cross-linking of cell-bound IgE. J. Exp. Med. 170:233.-244-244. [Abstract/Free Full Text]
  41. Field, K. A., D. Holowka, B. Baird. 1995. Fc{epsilon}RI-mediated recruitment of p53/56lyn to detergent-resistant membrane domains accompanies cellular signaling. Proc. Natl. Acad. Sci. USA 92:9201.-9205. [Abstract/Free Full Text]
  42. Field, K. A., D. Holowka, B. Baird. 1997. Compartmentalized activation of the high affinity immunoglobulin E receptor within membrane domains. J. Biol. Chem. 272:4276.-4280. [Abstract/Free Full Text]
  43. Sakurai, D., S. Yamasaki, K. Arase, S. Y. Park, H. Arase, A. Konno, T. Saito. 2004. Fc{epsilon}RI{gamma}-ITAM is differentially required for mast cell function in vivo. J. Immunol. 172:2374.-2381. [Abstract/Free Full Text]
  44. Kitaura, J., W. Xiao, M. Maeda-Yamamoto, Y. Kawakami, C. A. Lowell, T. Kawakami. 2004. Early divergence of Fc{epsilon} receptor I signals for receptor up-regulation and internalization from degranulation, cytokine production, and survival. J. Immunol. 173:4317.-4323. [Abstract/Free Full Text]
  45. Borkowski, T. A., M. H. Jouvin, S. Y. Lin, J. P. Kinet. 2001. Minimal requirements for IgE-mediated regulation of surface Fc{epsilon}RI. J. Immunol. 167:1290.-1296. [Abstract/Free Full Text]
  46. Kubo, S., K. Matsuoka, C. Taya, F. Kitamura, T. Takai, H. Yonekawa, H. Karasuyama. 2001. Drastic up-regulation of Fc{epsilon}ri on mast cells is induced by IgE binding through stabilization and accumulation of Fc{epsilon}ri on the cell surface. J. Immunol. 167:3427.-3434. [Abstract/Free Full Text]
  47. Iemura, A., M. Tsai, A. Ando, B. K. Wershil, S. J. Galli. 1994. The c-kit ligand, stem cell factor, promotes mast cell survival by suppressing apoptosis. Am. J. Pathol. 144:321.-328. [Abstract]
  48. Gurish, M. F., P. J. Bryce, H. Tao, A. B. Kisselgof, E. M. Thornton, H. R. Miller, D. S. Friend, H. C. Oettgen. 2004. IgE enhances parasite clearance and regulates mast cell responses in mice infected with Trichinella spiralis. J. Immunol. 172:1139.-1145. [Abstract/Free Full Text]
  49. Werlen, G., B. Hausmann, D. Naeher, E. Palmer. 2003. Signaling life and death in the thymus: timing is everything. Science 299:1859.-1863. [Abstract/Free Full Text]
  50. Yamasaki, S., E. Ishikawa, M. Kohno, T. Saito. 2004. The quantity and duration of FcR{gamma} signals determine mast cell degranulation and survival. Blood 103:3093.-3101. [Abstract/Free Full Text]
  51. Kohno, M., S. Yamasaki, V. L. Tybulewicz, T. Saito. 2005. Rapid and large amount of autocrine IL-3 production is responsible for mast cell survival by IgE in the absence of antigen. Blood 105:2059.-2065. [Abstract/Free Full Text]
  52. Wershil, B. K., Z. S. Wang, J. R. Gordon, S. J. Galli. 1991. Recruitment of neutrophils during IgE-dependent cutaneous late phase reactions in the mouse is mast cell-dependent: partial inhibition of the reaction with antiserum against tumor necrosis factor {alpha}. J. Clin. Invest. 87:446.-453.
  53. Laffargue, M., R. Calvez, P. Finan, A. Trifilieff, M. Barbier, F. Altruda, E. Hirsch, M. P. Wymann. 2002. Phosphoinositide 3-kinase {gamma} is an essential amplifier of mast cell function. Immunity 16:441.-451. [Medline]
  54. Jolly, P. S., M. Bektas, A. Olivera, C. Gonzalez-Espinosa, R. L. Proia, J. Rivera, S. Milstien, S. Spiegel. 2004. Transactivation of sphingosine-1-phosphate receptors by Fcvar{epsilon}RI triggering is required for normal mast cell degranulation and chemotaxis. J. Exp. Med. 199:959.-970. [Abstract/Free Full Text]
  55. Siraganian, R. P.. 2003. Mast cell signal transduction from the high-affinity IgE receptor. Curr. Opin. Immunol. 15:639.-646. [Medline]
  56. Kitaura, J., K. Eto, T. Kinoshita, Y. Kawakami, M. Leitges, C. A. Lowell, T. Kawakami. 2005. Regulation of highly cytokinergic IgE-induced mast cell adhesion by Src, Syk, Tec, and protein kinase C family kinases. J. Immunol. 174:4495.-4504. [Abstract/Free Full Text]
  57. Tanaka, S., S. Mikura, E. Hashimoto, Y. Sugimoto, A. Ichikawa. 2005. Ca2+ influx-mediated histamine synthesis and IL-6 release in mast cells activated by monomeric IgE. Eur. J. Immunol. 35:460.-468. [Medline]
  58. Alfredsson, J., H. Puthalakath, H. Martin, A. Strasser, G. Nilsson. 2005. Proapoptotic Bcl-2 family member Bim is involved in the control of mast cell survival and is induced together with Bcl-xL upon IgE-receptor activation. Cell Death Differ. 12:136.-144. [Medline]
  59. Shelburne, C. P., M. E. McCoy, R. Piekorz, V. Sexl, K. H. Roh, S. M. Jacobs-Helber, S. R. Gillespie, D. P. Bailey, P. Mirmonsef, M. N. Mann, et al 2003. Stat5 expression is critical for mast cell development and survival. Blood 102:1290.-1297. [Abstract/Free Full Text]
  60. Yoshikawa, H., Y. Nakajima, K. Tasaka. 1999. Glucocorticoid suppresses autocrine survival of mast cells by inhibiting IL-4 production and ICAM-1 expression. J. Immunol. 162:6162.-6170. [Abstract/Free Full Text]
  61. Yoshikawa, H., Y. Nakajima, K. Tasaka. 2000. Enhanced expression of Fas-associated death domain-like IL-1-converting enzyme (FLICE)-inhibitory protein induces resistance to Fas-mediated apoptosis in activated mast cells. J. Immunol. 165:6262.-6269. [Abstract/Free Full Text]
  62. Xiang, Z., A. A. Ahmed, C. Moller, K. Nakayama, S. Hatakeyama, G. Nilsson. 2001. Essential role of the prosurvival bcl-2 homologue A1 in mast cell survival after allergic activation. J. Exp. Med. 194:1561.-1569. [Abstract/Free Full Text]
  63. Oettgen, H. C., T. R. Martin, A. Wynshaw-Boris, C. Deng, J. M. Drazen, P. Leder. 1994. Active anaphylaxis in IgE-deficient mice. Nature 370:367.-370. [Medline]
  64. Matsuoka, K., C. Taya, S. Kubo, N. Toyama-Sorimachi, F. Kitamura, C. Ra, H. Yonekawa, H. Karasuyama. 1999. Establishment of antigen-specific IgE transgenic mice to study pathological and immunobiological roles of IgE in vivo. Int. Immunol. 11:987.-994. [Abstract/Free Full Text]
  65. Matsuda, H., N. Watanabe, G. P. Geba, J. Sperl, M. Tsudzuki, J. Hiroi, M. Matsumoto, H. Ushio, S. Saito, P. W. Askenase, C. Ra. 1997. Development of atopic dermatitis-like skin lesion with IgE hyperproduction in NC/Nga mice. Int. Immunol. 9:461.-466. [Abstract/Free Full Text]
  66. Pritchard, D. I., C. Hewitt, R. Moqbel. 1997. The relationship between immunological responsiveness controlled by T helper 2 lymphocytes and infections with parasitic helminths. Parasitology 115:(Suppl.):S33.-S44.
  67. Cameron, L. A., S. R. Durham, M. R. Jacobson, K. Masuyama, S. Juliusson, H. J. Gould, O. Lowhagen, E. M. Minshall, Q. A. Hamid. 1998. Expression of IL-4, C{epsilon} RNA, and I{epsilon} RNA in the nasal mucosa of patients with seasonal rhinitis: effect of topical corticosteroids. J. Allergy Clin. Immunol. 101:330.-336. [Medline]
  68. Coker, H. A., S. R. Durham, H. J. Gould. 2003. Local somatic hypermutation and class switch recombination in the nasal mucosa of allergic rhinitis patients. J. Immunol. 171:5602.-5610. [Abstract/Free Full Text]
  69. Durham, S. R., H. J. Gould, C. P. Thienes, M. R. Jacobson, K. Masuyama, S. Rak, O. Lowhagen, E. Schotman, L. Cameron, Q. A. Hamid. 1997. Expression of epsilon germ-line gene transcripts and mRNA for the epsilon heavy chain of IgE in nasal B cells and the effects of topical corticosteroid. Eur. J. Immunol. 27:2899.-2906. [Medline]
  70. Smurthwaite, L., S. N. Walker, D. R. Wilson, D. S. Birch, T. G. Merrett, S. R. Durham, H. J. Gould. 2001. Persistent IgE synthesis in the nasal mucosa of hay fever patients. Eur. J. Immunol. 31:3422.-3431. [Medline]
  71. Snow, R. E., R. Djukanovic, F. K. Stevenson. 1999. Analysis of immunoglobulin E VH transcripts in a bronchial biopsy of an asthmatic patient confirms bias towards VH5, and indicates local clonal expansion, somatic mutation and isotype switch events. Immunology 98:646.-651. [Medline]
  72. Ying, S., M. Humbert, Q. Meng, R. Pfister, G. Menz, H. J. Gould, A. B. Kay, S. R. Durham. 2001. Local expression of epsilon germline gene transcripts and RNA for the epsilon heavy chain of IgE in the bronchial mucosa in atopic and nonatopic asthma. J. Allergy Clin. Immunol. 107:686.-692. [Medline]
  73. Galli, S. J., J. J. Costa. 1995. Mast-cell-leukocyte cytokine cascades in allergic inflammation. Allergy 50:851.-862. [Medline]
  74. Packard, K. A., M. M. Khan. 2003. Effects of histamine on Th1/Th2 cytokine balance. Int. Immunopharmacol. 3:909.-920. [Medline]
  75. Goodarzi, K., M. Goodarzi, A. M. Tager, A. D. Luster, U. H. von Andrian. 2003. Leukotriene B4 and BLT1 control cytotoxic effector T cell recruitment to inflamed tissues. Nat. Immunol. 4:965.-973. [Medline]
  76. Ott, V. L., J. C. Cambier, J. Kappler, P. Marrack, B. J. Swanson. 2003. Mast cell-dependent migration of effector CD8+ T cells through production of leukotriene B4. Nat. Immunol. 4:974.-981. [Medline]
  77. Tager, A. M., S. K. Bromley, B. D. Medoff, S. A. Islam, S. D. Bercury, E. B. Friedrich, A. D. Carafone, R. E. Gerszten, A. D. Luster. 2003. Leukotriene B4 receptor BLT1 mediates early effector T cell recruitment. Nat. Immunol. 4:982.-990. [Medline]
  78. Nakajima, T., N. Inagaki, H. Tanaka, A. Tanaka, M. Yoshikawa, M. Tamari, K. Hasegawa, K. Matsumoto, H. Tachimoto, M. Ebisawa, et al 2002. Marked increase in CC chemokine gene expression in both human and mouse mast cell transcriptomes following Fc{epsilon} receptor I cross-linking: an interspecies comparison. Blood 100:3861.-3868. [Abstract/Free Full Text]
  79. Bryce, P. J., M. L. Miller, I. Miyajima, M. Tsai, S. J. Galli, H. C. Oettgen. 2004. Immune sensitization in the skin is enhanced by antigen-independent effects of IgE. Immunity 20:381.-392. [Medline]
  80. Yano, K., M. Yamaguchi, F. de Mora, C. S. Lantz, J. H. Butterfield, J. J. Costa, S. J. Galli. 1997. Production of macrophage inflammatory protein-1{alpha} by human mast cells: increased anti-IgE-dependent secretion after IgE-dependent enhancement of mast cell IgE-binding ability. Lab. Invest. 77:185.-193. [Medline]
  81. Yamaguchi, M., K. Sayama, K. Yano, C. S. Lantz, N. Noben-Trauth, C. Ra, J. J. Costa, S. J. Galli. 1999. 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. 162:5455.-5465. [Abstract/Free Full Text]
  82. Gilchrest, H., B. Cheewatrakoolpong, M. Billah, R. W. Egan, J. C. Anthes, S. Greenfeder. 2003. Human cord blood-derived mast cells synthesize and release I-309 in response to IgE. Life Sci. 73:2571.-2581. [Medline]
  83. MacDonald, S. M., L. M. Lichtenstein, D. Proud, M. Plaut, R. M. Naclerio, D. W. MacGlashan, A. Kagey-Sobotka. 1987. Studies of IgE-dependent histamine releasing factors: heterogeneity of IgE. J. Immunol. 139:506.-512. [Abstract]
  84. Schroeder, J. T., L. M. Lichtenstein, S. M. MacDonald. 1996. An immunoglobulin E-dependent recombinant histamine-releasing factor induces interleukin-4 secretion from human basophils. J. Exp. Med. 183:1265.-1270. [Abstract/Free Full Text]
  85. Gould, H. J., B. J. Sutton, A. J. Beavil, R. L. Beavil, N. McCloskey, H. A. Coker, D. Fear, L. Smurthwaite. 2003. The biology of IGE and the basis of allergic disease. Annu. Rev. Immunol. 21:579.-628. [Medline]
  86. Plaut, M., J. H. Pierce, C. J. Watson, J. Hanley-Hyde, R. P. Nordan, W. E. Paul. 1989. Mast cell lines produce lymphokines in response to cross-linkage of Fc{epsilon}RI or to calcium ionophores. Nature 339:64.-67. [Medline]



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Blood, August 15, 2008; 112(4): 946 - 956.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
J.-i. Kashiwakura, W. Xiao, J. Kitaura, Y. Kawakami, M. Maeda-Yamamoto, J. R. Pfeiffer, B. S. Wilson, U. Blank, and T. Kawakami
Pivotal Advance: IgE accelerates in vitro development of mast cells and modifies their phenotype
J. Leukoc. Biol., August 1, 2008; 84(2): 357 - 367.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
H. F. Rosenberg
The many faces of IgE: an interview with Dr. Toshiaki Kawakami
J. Leukoc. Biol., August 1, 2008; 84(2): 368 - 370.
[Full Text] [PDF]

Home page
 J. Immunol.Home page
E. Shumilina, R. S. Lam, F. Wolbing, N. Matzner, I. M. Zemtsova, M. Sobiesiak, H. Mahmud, U. Sausbier, T. Biedermann, P. Ruth, et al.
Blunted IgE-Mediated Activation of Mast Cells in Mice Lacking the Ca2+-Activated K+ Channel KCa3.1
J. Immunol., June 15, 2008; 180(12): 8040 - 8047.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
Y. Yamanishi, J. Kitaura, K. Izawa, T. Matsuoka, T. Oki, Y. Lu, F. Shibata, S. Yamazaki, H. Kumagai, H. Nakajima, et al.
Analysis of mouse LMIR5/CLM-7 as an activating receptor: differential regulation of LMIR5/CLM-7 in mouse versus human cells
Blood, January 15, 2008; 111(2): 688 - 698.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
L. H. Ho, T. Ohno, K. Oboki, N. Kajiwara, H. Suto, M. Iikura, Y. Okayama, S. Akira, H. Saito, S. J. Galli, et al.
IL-33 induces IL-13 production by mouse mast cells independently of IgE-Fc{epsilon}RI signals
J. Leukoc. Biol., December 1, 2007; 82(6): 1481 - 1490.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
K. Izawa, J. Kitaura, Y. Yamanishi, T. Matsuoka, T. Oki, F. Shibata, H. Kumagai, H. Nakajima, M. Maeda-Yamamoto, J. P. Hauchins, et al.
Functional Analysis of Activating Receptor LMIR4 as a Counterpart of Inhibitory Receptor LMIR3
J. Biol. Chem., June 22, 2007; 282(25): 17997 - 18008.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
S. Yamasaki, E. Ishikawa, M. Sakuma, O. Kanagawa, A. M. Cheng, B. Malissen, and T. Saito
LAT and NTAL Mediate Immunoglobulin E-Induced Sustained Extracellular Signal-Regulated Kinase Activation Critical for Mast Cell Survival
Mol. Cell. Biol., June 15, 2007; 27(12): 4406 - 4415.
[Abstract] [Full Text] [PDF]

Home page
 Am J Trop Med HygHome page
L. M. GANLEY-LEAL, P. N. M. MWINZI, C. B. CETRE-SOSSAH, J. ANDOVE, A. W. HIGHTOWER, D. M. S. KARANJA, D. G. COLLEY, and W. E. SECOR
HIGHER PERCENTAGES OF CIRCULATING MAST CELL PRECURSORS CORRELATE WITH SUSCEPTIBILITY TO REINFECTION WITH SCHISTOSOMA MANSONI
Am J Trop Med Hyg, December 1, 2006; 75(6): 1053 - 1057.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
R. Geoffrey, S. Jia, A. E. Kwitek, J. Woodliff, S. Ghosh, A. Lernmark, X. Wang, and M. J. Hessner
Evidence of a Functional Role for Mast Cells in the Development of Type 1 Diabetes Mellitus in the BioBreeding Rat
J. Immunol., November 15, 2006; 177(10): 7275 - 7286.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. J. Demarest, J. Hopp, J. Chung, K. Hathaway, E. Mertsching, X. Cao, J. George, K. Miatkowski, M. J. LaBarre, M. Shields, et al.
An Intermediate pH Unfolding Transition Abrogates the Ability of IgE to Interact with Its High Affinity Receptor Fc{epsilon}RI{alpha}
J. Biol. Chem., October 13, 2006; 281(41): 30755 - 30767.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
C. M. Udell, L. A. Samayawardhena, Y. Kawakami, T. Kawakami, and A. W. B. Craig
Fer and Fps/Fes Participate in a Lyn-dependent Pathway from Fc{epsilon}RI to Platelet-Endothelial Cell Adhesion Molecule 1 to Limit Mast Cell Activation
J. Biol. Chem., July 28, 2006; 281(30): 20949 - 20957.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. Zhu, I. Rhee, Y. Liu, and W. Zhang
Negative Regulation of Fc{epsilon}RI-mediated Signaling and Mast Cell Function by the Adaptor Protein LAX
J. Biol. Chem., July 7, 2006; 281(27): 18408 - 18413.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
B. A. Olenchock, R. Guo, M. A. Silverman, J. N. Wu, J. H. Carpenter, G. A. Koretzky, and X.-P. Zhong
Impaired degranulation but enhanced cytokine production after Fc{varepsilon}RI stimulation of diacylglycerol kinase {zeta}-deficient mast cells
J. Exp. Med., June 12, 2006; 203(6): 1471 - 1480.
[Abstract] [Full Text] [PDF]

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