Signal Transduction in Mast Cells and Basophils, 1999
... determined, but one inter-esting observation is that phorbol myristate acetate (PMA) treatmen... more ... determined, but one inter-esting observation is that phorbol myristate acetate (PMA) treatment followed by per-meabilization and extensive washing of the RBL-2H3 cells allows depletion of all isozymes with the exception of£(P. Germano and J. Rivera, unpublished observation ...
The first step in immunoreceptor signaling is represented by ligand-dependent receptor aggregatio... more The first step in immunoreceptor signaling is represented by ligand-dependent receptor aggregation, followed by receptor phosphorylation mediated by tyrosine kinases of the Src family. Recently, sphingolipid-and cholesterol-rich plasma membrane microdomains, called lipid rafts, have been identified and proposed to function as platforms where signal transduction molecules may interact with the aggregated immunoreceptors.
Mast cells are important effectors in innate and adaptive immune responses. They contain numerous... more Mast cells are important effectors in innate and adaptive immune responses. They contain numerous secretory granules filled with inflammatory mediators in their cytoplasm. Exocytosis of granular content does not take place until the cell receives an appropriate stimulus such as the aggregation of IgE antibody bound to high-affinity IgE receptors by specific antigen. This process is therefore referred to as regulated exocytosis. A characteristic of mast cell exocytosis is that it does not involve release of a few individual granules, but rather, a large fraction of the granular content is released due to compound exocytosis, implicating the occurrence of granule-to-granule and granule-to-plasma membrane fusion. This unit describes assays that measure the release of granular content from mast cells. They include in vitro colorimetric-, radiolabel-, or antibody detection-based assays for substances stored in the granules. Given that animal models for basophil and mast cell activation are being used with increasing frequency, the unit also includes protocols to measure exocytosis of mast cell granule content in vivo.
Mast cell activation via the high-affinity immunoglobulin (Ig) E receptor Fc RI is a topic of ext... more Mast cell activation via the high-affinity immunoglobulin (Ig) E receptor Fc RI is a topic of extensive investigation with therapeutic potential in allergic disease. The protein tyrosine kinases Fyn, Lyn, and Syk are intimately linked with the early events initiated by allergen-mediated aggregation of IgE-occupied Fc RI. Fyn and Lyn initiate signaling events that are organized by adaptor molecules, which compartmentalize and coordinate the activity of activated protein and lipid kinases and phospholipases to generate lipid products essential for signal amplification and mast cell function. Fyn and Lyn counter-regulate phosphatidylinositol 3-OH kinase (PI3K), controlling the produced amount of phosphatidylinositol (3,4,5)-trisphosphate (PIP 3 ), a key regulator of mast cell degranulation. Fyn and Lyn also activate sphingosine kinases (SphK), which generate sphingosine-1-phosphate (S1P), thus contributing to mast cell chemotaxis and degranulation. Here, we summarize the current knowledge and future challenges and directions.
Mast cell degranulation and de novo cytokine production is a consequence of antigen-aggregation o... more Mast cell degranulation and de novo cytokine production is a consequence of antigen-aggregation of the immunoglobulin E (IgE)-occupied high affinity receptor for IgE (Fc RI). Herein, we report that lymphokines that promote allergic inflammation, like MCP-1, were potently induced at low antigen (Ag) concentrations or at low receptor occupancy with IgE whereas some that down-regulate this response, like interleukin (IL)-10, required high receptor occupancy. Weak stimulation of mast cells caused minimal degranulation whereas a half-maximal secretory response was observed for chemokines and, with the exception of TNF-␣ , a weaker cytokine secretory response was observed. The medium from weakly stimulated mast cells elicited a monocyte/macrophage chemotactic response similar to that observed at high receptor occupancy. Weak stimulation also favored the phosphorylation of Gab2 and p38MAPK, while LAT and ERK2 phosphorylation was induced by a stronger stimulus. Gab2-deficient mast cells were severely impaired in chemokine mRNA induction whereas LAT-deficient mast cells showed a more pronounced defect in cytokines. These findings demonstrate that perturbation of small numbers of IgE receptors on mast cells favors certain signals that contribute to a lymphokine response that can mediate allergic inflammation.
The Fc epsilonRI-dependent activation of nuclear factor (NF)kappaB is key for mast-cell cytokine ... more The Fc epsilonRI-dependent activation of nuclear factor (NF)kappaB is key for mast-cell cytokine production. The CARMA1-Bcl10-Malt1 adaptor complex regulates NFkappaB activation by antigen receptors in lymphocytes. A recent study reveals that the Bcl10-Malt1 complex promotes mast-cell interleukin-6 and tumor necrosis factor production, independent of degranulation, eicosanoid secretion or survival. The new findings place this complex at the forefront in discriminating between signals required for cytokine production and those required for mast-cell degranulation and eicosanoid production.
The hematopoietic cell-specific protein Vav1 is a substrate of tyrosine kinases activated followi... more The hematopoietic cell-specific protein Vav1 is a substrate of tyrosine kinases activated following engagement of many receptors, including FcRI. Vav1-deficient mice contain normal numbers of mast cells but respond more weakly than their normal counterparts to a passive systemic anaphylaxis challenge. Vav1deficient bone marrow-derived mast cells also exhibited reduced degranulation and cytokine production, although tyrosine phosphorylation of FcRI, Syk, and LAT (linker for activation of T cells) was normal. In contrast, tyrosine phosphorylation of phospholipase C␥1 (PLC␥1) and PLC␥2 and calcium mobilization were markedly inhibited. Reconstitution of deficient mast cells with Vav1 restored normal tyrosine phosphorylation of PLC␥1 and PLC␥2 and calcium responses. Thus, Vav1 is essential to FcRI-mediated activation of PLC␥ and calcium mobilization in mast cells. In addition to its known role as an activator of Rac1 GTPases, these findings demonstrate a novel function for Vav1 as a regulator of PLC␥-activated calcium signals.
Recent advances in understanding the physiological role of mast cells (MCs) point to an important... more Recent advances in understanding the physiological role of mast cells (MCs) point to an important regulatory role for these cells in adaptive immunity. MCs express a diverse array of molecules that can promote their interaction with T cells as well as with other immune cells. New evidence demonstrates that mast cells can directly and indirectly communicate with T cells. They can control both effector and regulatory T cell responses and their activity can in turn be modulated by these interactions. Here we briefly summarize these advances and discuss some of the major challenges in understanding the communication of MCs and T cells.
Mast cell mediator release represents a pivotal event in the initiation of inflammatory reactions... more Mast cell mediator release represents a pivotal event in the initiation of inflammatory reactions associated with allergic disorders. These responses follow antigen-mediated aggregation of immunoglobulin E (IgE)-occupied high affinity receptors for IgE (FcεRI) on the mast cell surface,a response which can be further enhanced following stem cell factor-induced ligation of the mast cell growth factor receptor KIT. Activation of tyrosine kinases is central to the ability of both FcεRI and KIT to transmit downstream signaling events required for the regulation of mast cell activation. Whereas KIT possesses inherent tyrosine kinase activity, FcεRI requires the recruitment of Src family tyrosine kinases and Syk to control the early receptor-proximal signaling events. The signaling pathways propagated by these tyrosine kinases can be further upregulated by the Tec kinase Bruton's tyrosine kinase (Btk) and downregulated by the actions of the tyrosine Src homology 2 domain-containing phosphatase 1 (SHP1) and SHP2. In this review, we discuss the regulation and role of specific members of this tyrosine kinase network in KIT and FcεRImediated mast cell activation.
IgE-dependent activation of mast cells is central to the allergic response. The engagement of IgE... more IgE-dependent activation of mast cells is central to the allergic response. The engagement of IgE-occupied receptors initiates a series of molecular events that cause the release of preformed, and de novo synthesis of, allergic mediators. Recent investigations demonstrate a critical role for non-enzymatic proteins that facilitate the activation and coordination of biochemical signals required for mast cell activation. Among these LAT, SLP-76 and Gab2 are critically important as adapters that facilitate events initiated by IgE receptor-dependent activation of Src family protein tyrosine kinases, Lyn and Fyn. An evaluation of the role of these adapters points to complementary but independent steps in early signaling and the possibility that preference for one or another adaptor complex may result in selective mast cell responses.
The mast cell is a central player in allergy and asthma. Activation of these cells induces the re... more The mast cell is a central player in allergy and asthma. Activation of these cells induces the release of preformed inflammatory mediators localized in specialized granules and the de novo synthesis and secretion of cytokines, chemokines, and eicosanoids. The balance of engaging inhibitory and activatory cell-surface receptors on mast cells determines whether the cell becomes active on encountering a challenge. However, recent evidence suggests that, once activated, a mast cell's response is further regulated by the balance of both positive and negative intracellular molecular events that extend well beyond the traditional role of kinases and phosphatases. These functional responses are also carefully governed by other protein and lipid mediators that determine the rate and extent of the response. Molecules that have adaptor functions, modulate lipids, and provide synergistic signals add to the regulatory complexity. Considerable information has been obtained from the study of the high-affinity receptor for IgE (FcɛRI), and thus it is the major focus of this review. The unifying theme is that the regulatory steps mentioned herein are required for promoting effective responses while protecting against unwanted inflammatory responses.
Mast cells (MCs) are able to secrete the contents of preformed cytoplasmic secretory granules (SG... more Mast cells (MCs) are able to secrete the contents of preformed cytoplasmic secretory granules (SGs) on encountering certain stimulants. For MCs, this process is fundamental to their role in innate and acquired immunity. Immunological adaptation through the production of IgE antibodies, to normally innocuous substances, has kidnapped the MC exocytotic response to cause allergic disease. Thus, understanding the molecular events in IgE-dependent MC exocytosis holds promise for therapeutic intervention. Recent advances, in deciphering the coupling of the high affinity IgE receptor (FcεRI) to the secretory machinery, promote a new paradigm of the molecular coordination of MC exocytosis. A clearer picture of the link between FcεRI stimulation and SG exocytosis is emerging.
The linker molecule LAT is a substrate of the tyrosine kinases activated following TCR engagement... more The linker molecule LAT is a substrate of the tyrosine kinases activated following TCR engagement of T cells. LAT is also expressed in platelets, NK, and mast cells. Although LAT-deficient mice contain normal numbers of mast cells, we found that LAT-deficient mice were resistant to IgE-mediated passive systemic anaphylaxis. LAT-deficient bone marrow–derived mast cells (BMMC) showed normal growth and development. Whereas tyrosine phosphorylation of FcεRI, Syk, and Vav was intact in LAT-deficient BMMCs following FcεRI engagement, tyrosine phosphorylation of SLP-76, PLC-γ1, and PLC-γ2 and calcium mobilization were dramatically reduced. LAT-deficient BMMCs also exhibited profound defects in activation of MAPK, degranulation, and cytokine production after FcεRI cross-linking. These results show that LAT plays a critical role in FcεRI-mediated signaling in mast cells.
FcεRI also uses a Fyn kinase-dependent pathway that does not require Lyn kinase or the adapter LA... more FcεRI also uses a Fyn kinase-dependent pathway that does not require Lyn kinase or the adapter LAT for its initiation, but is necessary for mast cell degranulation. Lyn-deficiency enhanced Fyndependent signals and degranulation, but inhibited the calcium response. Fyn-deficiency impaired degranulation, whereas Lyn-mediated signaling and calcium was normal.Thus, FcεRI-dependent mast cell degranulation involves cross-talk between Fyn and Lyn kinases.
IgE-dependent activation of mast cells is central to the allergic response. The engagement of IgE... more IgE-dependent activation of mast cells is central to the allergic response. The engagement of IgE-occupied receptors initiates a series of molecular events that cause the release of preformed, and de novo synthesis of, allergic mediators. Recent investigations demonstrate a critical role for non-enzymatic proteins that facilitate the activation and coordination of biochemical signals required for mast cell activation. Among these
Mast cells are central to allergic disease. Their immediate (exocytosis of granule-stored allergi... more Mast cells are central to allergic disease. Their immediate (exocytosis of granule-stored allergic-mediators) and delayed (de novo synthesis of inflammatory mediators) response to an allergen underlies the symptoms seen in acute; and chronic allergic disease. Thus, intervention in the allergen-mediated activation of mast cells is a long sought after goal in the treatment and management of allergic disease. The recent gain in deciphering the molecular mechanisms underlying immunoglobulin E (IgE)-mediated mast cell activation has provided optimism for the development of new therapeutic strategies. Among the most promising is the use of humanized anti-IgE antibodies that inhibit binding of IgE to its high affinity receptor (FcepsilonRI) on the mast cell. Other strategies target molecules proximal to FcepsilonRI, whose activities are central in mast cell activation. One such molecule, Syk kinase, has been targeted by various approaches including a small molecule inhibitor that specifically abrogates mast cell degranulation. More recently, various molecules that function to promote protein-protein interactions (adapters) were demonstrated as essential to mast cell degranulation and cytokine production. It remains to be seen if these molecules hold therapeutic promise for disease intervention. Additional studies identifying molecules required for mast cell granule fusion and content exocytosis also bodes well for discovery of new therapeutic targets. While our understanding of IgE-mediated mast cell activation is still at its inception, the modest success in identifying molecules essential to this process affords some confidence for better treatment of allergic disease.
Signal Transduction in Mast Cells and Basophils, 1999
... determined, but one inter-esting observation is that phorbol myristate acetate (PMA) treatmen... more ... determined, but one inter-esting observation is that phorbol myristate acetate (PMA) treatment followed by per-meabilization and extensive washing of the RBL-2H3 cells allows depletion of all isozymes with the exception of£(P. Germano and J. Rivera, unpublished observation ...
The first step in immunoreceptor signaling is represented by ligand-dependent receptor aggregatio... more The first step in immunoreceptor signaling is represented by ligand-dependent receptor aggregation, followed by receptor phosphorylation mediated by tyrosine kinases of the Src family. Recently, sphingolipid-and cholesterol-rich plasma membrane microdomains, called lipid rafts, have been identified and proposed to function as platforms where signal transduction molecules may interact with the aggregated immunoreceptors.
Mast cells are important effectors in innate and adaptive immune responses. They contain numerous... more Mast cells are important effectors in innate and adaptive immune responses. They contain numerous secretory granules filled with inflammatory mediators in their cytoplasm. Exocytosis of granular content does not take place until the cell receives an appropriate stimulus such as the aggregation of IgE antibody bound to high-affinity IgE receptors by specific antigen. This process is therefore referred to as regulated exocytosis. A characteristic of mast cell exocytosis is that it does not involve release of a few individual granules, but rather, a large fraction of the granular content is released due to compound exocytosis, implicating the occurrence of granule-to-granule and granule-to-plasma membrane fusion. This unit describes assays that measure the release of granular content from mast cells. They include in vitro colorimetric-, radiolabel-, or antibody detection-based assays for substances stored in the granules. Given that animal models for basophil and mast cell activation are being used with increasing frequency, the unit also includes protocols to measure exocytosis of mast cell granule content in vivo.
Mast cell activation via the high-affinity immunoglobulin (Ig) E receptor Fc RI is a topic of ext... more Mast cell activation via the high-affinity immunoglobulin (Ig) E receptor Fc RI is a topic of extensive investigation with therapeutic potential in allergic disease. The protein tyrosine kinases Fyn, Lyn, and Syk are intimately linked with the early events initiated by allergen-mediated aggregation of IgE-occupied Fc RI. Fyn and Lyn initiate signaling events that are organized by adaptor molecules, which compartmentalize and coordinate the activity of activated protein and lipid kinases and phospholipases to generate lipid products essential for signal amplification and mast cell function. Fyn and Lyn counter-regulate phosphatidylinositol 3-OH kinase (PI3K), controlling the produced amount of phosphatidylinositol (3,4,5)-trisphosphate (PIP 3 ), a key regulator of mast cell degranulation. Fyn and Lyn also activate sphingosine kinases (SphK), which generate sphingosine-1-phosphate (S1P), thus contributing to mast cell chemotaxis and degranulation. Here, we summarize the current knowledge and future challenges and directions.
Mast cell degranulation and de novo cytokine production is a consequence of antigen-aggregation o... more Mast cell degranulation and de novo cytokine production is a consequence of antigen-aggregation of the immunoglobulin E (IgE)-occupied high affinity receptor for IgE (Fc RI). Herein, we report that lymphokines that promote allergic inflammation, like MCP-1, were potently induced at low antigen (Ag) concentrations or at low receptor occupancy with IgE whereas some that down-regulate this response, like interleukin (IL)-10, required high receptor occupancy. Weak stimulation of mast cells caused minimal degranulation whereas a half-maximal secretory response was observed for chemokines and, with the exception of TNF-␣ , a weaker cytokine secretory response was observed. The medium from weakly stimulated mast cells elicited a monocyte/macrophage chemotactic response similar to that observed at high receptor occupancy. Weak stimulation also favored the phosphorylation of Gab2 and p38MAPK, while LAT and ERK2 phosphorylation was induced by a stronger stimulus. Gab2-deficient mast cells were severely impaired in chemokine mRNA induction whereas LAT-deficient mast cells showed a more pronounced defect in cytokines. These findings demonstrate that perturbation of small numbers of IgE receptors on mast cells favors certain signals that contribute to a lymphokine response that can mediate allergic inflammation.
The Fc epsilonRI-dependent activation of nuclear factor (NF)kappaB is key for mast-cell cytokine ... more The Fc epsilonRI-dependent activation of nuclear factor (NF)kappaB is key for mast-cell cytokine production. The CARMA1-Bcl10-Malt1 adaptor complex regulates NFkappaB activation by antigen receptors in lymphocytes. A recent study reveals that the Bcl10-Malt1 complex promotes mast-cell interleukin-6 and tumor necrosis factor production, independent of degranulation, eicosanoid secretion or survival. The new findings place this complex at the forefront in discriminating between signals required for cytokine production and those required for mast-cell degranulation and eicosanoid production.
The hematopoietic cell-specific protein Vav1 is a substrate of tyrosine kinases activated followi... more The hematopoietic cell-specific protein Vav1 is a substrate of tyrosine kinases activated following engagement of many receptors, including FcRI. Vav1-deficient mice contain normal numbers of mast cells but respond more weakly than their normal counterparts to a passive systemic anaphylaxis challenge. Vav1deficient bone marrow-derived mast cells also exhibited reduced degranulation and cytokine production, although tyrosine phosphorylation of FcRI, Syk, and LAT (linker for activation of T cells) was normal. In contrast, tyrosine phosphorylation of phospholipase C␥1 (PLC␥1) and PLC␥2 and calcium mobilization were markedly inhibited. Reconstitution of deficient mast cells with Vav1 restored normal tyrosine phosphorylation of PLC␥1 and PLC␥2 and calcium responses. Thus, Vav1 is essential to FcRI-mediated activation of PLC␥ and calcium mobilization in mast cells. In addition to its known role as an activator of Rac1 GTPases, these findings demonstrate a novel function for Vav1 as a regulator of PLC␥-activated calcium signals.
Recent advances in understanding the physiological role of mast cells (MCs) point to an important... more Recent advances in understanding the physiological role of mast cells (MCs) point to an important regulatory role for these cells in adaptive immunity. MCs express a diverse array of molecules that can promote their interaction with T cells as well as with other immune cells. New evidence demonstrates that mast cells can directly and indirectly communicate with T cells. They can control both effector and regulatory T cell responses and their activity can in turn be modulated by these interactions. Here we briefly summarize these advances and discuss some of the major challenges in understanding the communication of MCs and T cells.
Mast cell mediator release represents a pivotal event in the initiation of inflammatory reactions... more Mast cell mediator release represents a pivotal event in the initiation of inflammatory reactions associated with allergic disorders. These responses follow antigen-mediated aggregation of immunoglobulin E (IgE)-occupied high affinity receptors for IgE (FcεRI) on the mast cell surface,a response which can be further enhanced following stem cell factor-induced ligation of the mast cell growth factor receptor KIT. Activation of tyrosine kinases is central to the ability of both FcεRI and KIT to transmit downstream signaling events required for the regulation of mast cell activation. Whereas KIT possesses inherent tyrosine kinase activity, FcεRI requires the recruitment of Src family tyrosine kinases and Syk to control the early receptor-proximal signaling events. The signaling pathways propagated by these tyrosine kinases can be further upregulated by the Tec kinase Bruton's tyrosine kinase (Btk) and downregulated by the actions of the tyrosine Src homology 2 domain-containing phosphatase 1 (SHP1) and SHP2. In this review, we discuss the regulation and role of specific members of this tyrosine kinase network in KIT and FcεRImediated mast cell activation.
IgE-dependent activation of mast cells is central to the allergic response. The engagement of IgE... more IgE-dependent activation of mast cells is central to the allergic response. The engagement of IgE-occupied receptors initiates a series of molecular events that cause the release of preformed, and de novo synthesis of, allergic mediators. Recent investigations demonstrate a critical role for non-enzymatic proteins that facilitate the activation and coordination of biochemical signals required for mast cell activation. Among these LAT, SLP-76 and Gab2 are critically important as adapters that facilitate events initiated by IgE receptor-dependent activation of Src family protein tyrosine kinases, Lyn and Fyn. An evaluation of the role of these adapters points to complementary but independent steps in early signaling and the possibility that preference for one or another adaptor complex may result in selective mast cell responses.
The mast cell is a central player in allergy and asthma. Activation of these cells induces the re... more The mast cell is a central player in allergy and asthma. Activation of these cells induces the release of preformed inflammatory mediators localized in specialized granules and the de novo synthesis and secretion of cytokines, chemokines, and eicosanoids. The balance of engaging inhibitory and activatory cell-surface receptors on mast cells determines whether the cell becomes active on encountering a challenge. However, recent evidence suggests that, once activated, a mast cell's response is further regulated by the balance of both positive and negative intracellular molecular events that extend well beyond the traditional role of kinases and phosphatases. These functional responses are also carefully governed by other protein and lipid mediators that determine the rate and extent of the response. Molecules that have adaptor functions, modulate lipids, and provide synergistic signals add to the regulatory complexity. Considerable information has been obtained from the study of the high-affinity receptor for IgE (FcɛRI), and thus it is the major focus of this review. The unifying theme is that the regulatory steps mentioned herein are required for promoting effective responses while protecting against unwanted inflammatory responses.
Mast cells (MCs) are able to secrete the contents of preformed cytoplasmic secretory granules (SG... more Mast cells (MCs) are able to secrete the contents of preformed cytoplasmic secretory granules (SGs) on encountering certain stimulants. For MCs, this process is fundamental to their role in innate and acquired immunity. Immunological adaptation through the production of IgE antibodies, to normally innocuous substances, has kidnapped the MC exocytotic response to cause allergic disease. Thus, understanding the molecular events in IgE-dependent MC exocytosis holds promise for therapeutic intervention. Recent advances, in deciphering the coupling of the high affinity IgE receptor (FcεRI) to the secretory machinery, promote a new paradigm of the molecular coordination of MC exocytosis. A clearer picture of the link between FcεRI stimulation and SG exocytosis is emerging.
The linker molecule LAT is a substrate of the tyrosine kinases activated following TCR engagement... more The linker molecule LAT is a substrate of the tyrosine kinases activated following TCR engagement of T cells. LAT is also expressed in platelets, NK, and mast cells. Although LAT-deficient mice contain normal numbers of mast cells, we found that LAT-deficient mice were resistant to IgE-mediated passive systemic anaphylaxis. LAT-deficient bone marrow–derived mast cells (BMMC) showed normal growth and development. Whereas tyrosine phosphorylation of FcεRI, Syk, and Vav was intact in LAT-deficient BMMCs following FcεRI engagement, tyrosine phosphorylation of SLP-76, PLC-γ1, and PLC-γ2 and calcium mobilization were dramatically reduced. LAT-deficient BMMCs also exhibited profound defects in activation of MAPK, degranulation, and cytokine production after FcεRI cross-linking. These results show that LAT plays a critical role in FcεRI-mediated signaling in mast cells.
FcεRI also uses a Fyn kinase-dependent pathway that does not require Lyn kinase or the adapter LA... more FcεRI also uses a Fyn kinase-dependent pathway that does not require Lyn kinase or the adapter LAT for its initiation, but is necessary for mast cell degranulation. Lyn-deficiency enhanced Fyndependent signals and degranulation, but inhibited the calcium response. Fyn-deficiency impaired degranulation, whereas Lyn-mediated signaling and calcium was normal.Thus, FcεRI-dependent mast cell degranulation involves cross-talk between Fyn and Lyn kinases.
IgE-dependent activation of mast cells is central to the allergic response. The engagement of IgE... more IgE-dependent activation of mast cells is central to the allergic response. The engagement of IgE-occupied receptors initiates a series of molecular events that cause the release of preformed, and de novo synthesis of, allergic mediators. Recent investigations demonstrate a critical role for non-enzymatic proteins that facilitate the activation and coordination of biochemical signals required for mast cell activation. Among these
Mast cells are central to allergic disease. Their immediate (exocytosis of granule-stored allergi... more Mast cells are central to allergic disease. Their immediate (exocytosis of granule-stored allergic-mediators) and delayed (de novo synthesis of inflammatory mediators) response to an allergen underlies the symptoms seen in acute; and chronic allergic disease. Thus, intervention in the allergen-mediated activation of mast cells is a long sought after goal in the treatment and management of allergic disease. The recent gain in deciphering the molecular mechanisms underlying immunoglobulin E (IgE)-mediated mast cell activation has provided optimism for the development of new therapeutic strategies. Among the most promising is the use of humanized anti-IgE antibodies that inhibit binding of IgE to its high affinity receptor (FcepsilonRI) on the mast cell. Other strategies target molecules proximal to FcepsilonRI, whose activities are central in mast cell activation. One such molecule, Syk kinase, has been targeted by various approaches including a small molecule inhibitor that specifically abrogates mast cell degranulation. More recently, various molecules that function to promote protein-protein interactions (adapters) were demonstrated as essential to mast cell degranulation and cytokine production. It remains to be seen if these molecules hold therapeutic promise for disease intervention. Additional studies identifying molecules required for mast cell granule fusion and content exocytosis also bodes well for discovery of new therapeutic targets. While our understanding of IgE-mediated mast cell activation is still at its inception, the modest success in identifying molecules essential to this process affords some confidence for better treatment of allergic disease.
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