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Stephen J Galli - One of the best experts on this subject based on the ideXlab platform.
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new developments in Mast Cell biology
Nature Immunology, 2008Co-Authors: Janet Kalesnikoff, Stephen J GalliAbstract:Mast Cells can function as effector and immunoregulatory Cells in immunoglobulin E-associated allergic disorders, as well as in certain innate and adaptive immune responses. This review focuses on exciting new developments in the field of Mast Cell biology published in the past year. We highlight advances in the understanding of FcvarepsilonRI-mediated signaling and Mast Cell-activation events, as well as in the use of genetic models to study Mast Cell function in vivo. Finally, we discuss newly identified functions for Mast Cells or individual Mast Cell products, such as proteases and interleukin 10, in host defense, cardiovascular disease and tumor biology and in settings in which Mast Cells have anti-inflammatory or immunosuppressive functions.
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new developments in Mast Cell biology
Nature Immunology, 2008Co-Authors: Janet Kalesnikoff, Stephen J GalliAbstract:Mast Cells can function as effector and immunoregulatory Cells in immunoglobulin E–associated allergic disorders, as well as in certain innate and adaptive immune responses. This review focuses on exciting new developments in the field of Mast Cell biology published in the past year. We highlight advances in the understanding of FcɛRI-mediated signaling and Mast Cell–activation events, as well as in the use of genetic models to study Mast Cell function in vivo. Finally, we discuss newly identified functions for Mast Cells or individual Mast Cell products, such as proteases and interleukin 10, in host defense, cardiovascular disease and tumor biology and in settings in which Mast Cells have anti-inflammatory or immunosuppressive functions.
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Mast Cell deficient w sash c kit mutant kitw sh w sh mice as a model for investigating Mast Cell biology in vivo
American Journal of Pathology, 2005Co-Authors: Michele A Grimbaldeston, Chingcheng Chen, Mindy Tsai, Adrian M Piliponsky, Stephen J GalliAbstract:Mice carrying certain mutations in the white spotting (W) locus (ie, c-kit) exhibit reduced c-kit tyrosine kinase-dependent signaling that results in Mast Cell deficiency and other phenotypic abnormalities. The c-kit mutations in KitW/W-v mice impair melanogenesis and result in anemia, sterility, and markedly reduced levels of tissue Mast Cells. In contrast, KitW-sh/W-sh mice, bearing the W-sash (Wsh) inversion mutation, have Mast Cell deficiency but lack anemia and sterility. We report that adult KitW-sh/W-sh mice had a profound deficiency in Mast Cells in all tissues examined but normal levels of major classes of other differentiated hematopoietic and lymphoid Cells. Unlike KitW/W-v mice, KitW-sh/W-sh mice had normal numbers of TCRγδ intraepithelial lymphocytes in the intestines and did not exhibit a high incidence of idiopathic dermatitis, ulcers, or squamous papillomas of the stomach, but like KitW/W-v mice, they lacked interstitial Cells of Cajal in the gut and exhibited bile reflux into the stomach. Systemic or local reconstitution of Mast Cell populations was achieved in nonirradiated adult KitW-sh/W-sh mice by intravenous, intraperitoneal, or intradermal injection of wild-type bone marrow-derived cultured Mast Cells but not by transplantation of wild-type bone marrow Cells. Thus, KitW-sh/W-sh mice represent a useful model for Mast Cell research, especially for analyzing Mast Cell function in vivo.
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identification of Mast Cell progenitors in adult mice
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Chingcheng Chen, Michele A Grimbaldeston, Mindy Tsai, Irving L Weissman, Stephen J GalliAbstract:It is well known that Mast Cells are derived from hematopoietic stem Cells. However, in adult hematopoiesis, a committed Mast Cell progenitor has not yet been identified in any species, nor is it clear at what point during adult hematopoiesis commitment to the Mast Cell lineage occurs. We identified a Cell population in adult mouse bone marrow, characterized as Lin-c-Kit+Sca-1--Ly6c-FceRIα-CD27-β7+T1/ST2+, that gives rise only to Mast Cells in culture and that can reconstitute the Mast Cell compartment when transferred into c-kit mutant Mast Cell-deficient mice. In addition, our experiments strongly suggest that these adult Mast Cell progenitors are derived directly from multipotential progenitors instead of, as previously proposed, common myeloid progenitors or granulocyte/macrophage progenitors.
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Mast Cell and basophil development
Current Opinion in Hematology, 1994Co-Authors: Stephen J Galli, Ilan HammelAbstract:: Mast Cells and basophils express certain remarkable similarities in mediator content, histochemical characteristics, and function. Yet a large body of evidence now indicates that the Mast Cell and basophil lineages are distinct. Stem Cell factor, the ligand for the receptor encoded by c-kit, is a major growth factor for Mast Cells in both rodent and primate species, and can modulate Mast Cell secretory function. Moreover, abnormalities affecting the stem Cell factor receptor or stem Cell factor might contribute to some cases of Mastocytosis or Mast Cell neoplasms. By contrast, basophils can develop independently of stem Cell factor, and are not as sensitive as Mast Cells to the effects of stem Cell factor on mediator secretion. In addition, the cytokine interleukin-3 greatly augments the production of human basophils, but has little or no growth promoting activity for human Mast Cells.
Gunnar Pejler - One of the best experts on this subject based on the ideXlab platform.
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novel aspects of Mast Cell and basophil function highlights from the 9th meeting of the european Mast Cell and basophil research network embrn a marcus wallenberg symposium
Allergy, 2020Co-Authors: Jenny Hallgren, Gunnar Pejler, Gunnar Nilsson, Lars Hellman, Marcus Maurer, Sara Wernersson, Magnus AbrinkAbstract:Novel aspects of Mast Cell and basophil function : Highlights from the 9th meeting of the European Mast Cell and Basophil Research Network (EMBRN)-A Marcus Wallenberg Symposium.
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biology of Mast Cell tryptase
FEBS Journal, 2006Co-Authors: Jenny Hallgren, Gunnar PejlerAbstract:In 1960, a trypsin-like activity was found in Mast Cells [Glenner GG & Cohen LA (1960) Nature185, 846–847] and this activity is now commonly referred to as ‘tryptase’. Over the years, much knowledge about Mast Cell tryptase has been gathered, and a recent (18 January 2006) PubMed search for the keywords ‘tryptase + Mast Cell*’ retrieved 1661 articles. However, still very little is known about its true biological function. For example, the true physiological substrate(s) for Mast Cell tryptase has not been identified, and the potential role of tryptase in Mast Cell-related disease is not understood. Mast Cell tryptase has several unique features, with perhaps the most remarkable being its organization into a tetrameric state with all of the active sites oriented towards a narrow central pore and its consequent complete resistance towards endogenous macromolecular protease inhibitors. Much effort has been invested to elucidate these properties of tryptase. In this review we summarize the current knowledge of Mast Cell tryptase, including novel insights into its possible biological functions and mechanisms of regulation.
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biology of Mast Cell tryptase an inflammatory mediator
FEBS Journal, 2006Co-Authors: Jenny Hallgren, Gunnar PejlerAbstract:In 1960, a trypsin-like activity was found in Mast Cells [Glenner GG & Cohen LA (1960) Nature 185, 846-847] and this activity is now commonly referred to as 'tryptase'. Over the years, much knowledge about Mast Cell tryptase has been gathered, and a recent (18 January 2006) PubMed search for the keywords 'tryptase + Mast Cell*' retrieved 1661 articles. However, still very little is known about its true biological function. For example, the true physiological substrate(s) for Mast Cell tryptase has not been identified, and the potential role of tryptase in Mast Cell-related disease is not understood. Mast Cell tryptase has several unique features, with perhaps the most remarkable being its organization into a tetrameric state with all of the active sites oriented towards a narrow central pore and its consequent complete resistance towards endogenous macromolecular protease inhibitors. Much effort has been invested to elucidate these properties of tryptase. In this review we summarize the current knowledge of Mast Cell tryptase, including novel insights into its possible biological functions and mechanisms of regulation.
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Mast Cell cathepsins c and s control levels of carboxypeptidase a and the chymase mouse Mast Cell protease 5
Biological Chemistry, 2003Co-Authors: Frida Henningsson, George H Caughey, Paul J Wolters, Harold A Chapman, Gunnar PejlerAbstract:Carboxypeptidase A (CPA) is a metalloprotease, residing in the Mast Cell secretory granules together with chymases and tryptases. Little information is available with respect to the mechanisms that maintain or regulate the levels of stored proteases in the Mast Cell secretory granules. In this study we examined whether cathepsins C and S may be involved in the control of the levels of Mast Cell proteases. Mast Cells cultured from bone marrow of cathepsin C- or S-null mice expressed higher levels of CPA protein and activity than Cells from wild-type mice. Similar increases in protein were observed for the mouse chymase, Mast Cell protease-5 (mMCP-5), but not for the tryptase, mMCP-6. Steady-state levels of CPA and mMCP-5 mRNA were similar in wild-type and cathepsin C-null Mast Cells, indicating that post-transcriptional mechanisms explain the observed cathepsin C-dependence of CPA and mMCP-5 expression. The present study thus indicates novel roles for cathepsins C and S in regulating the levels of stored proteases in the Mast Cell secretory granules.
Alasdair M. Gilfillan - One of the best experts on this subject based on the ideXlab platform.
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targeting the kit activating switch control pocket a novel mechanism to inhibit neoplastic Mast Cell proliferation and Mast Cell activation
Leukemia, 2013Co-Authors: Yun Bai, Dean D. Metcalfe, Geethani Bandara, Eunice Ching Chan, Irina Maric, Olga Simakova, Sachini N Bandara, Scott Wise, Daniel L Flynn, Alasdair M. GilfillanAbstract:Targeting the KIT activating switch control pocket: a novel mechanism to inhibit neoplastic Mast Cell proliferation and Mast Cell activation
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measuring Mast Cell mediator release
Current protocols in immunology, 2010Co-Authors: Hye Sun Kuehn, Madeleine Radinger, Alasdair M. GilfillanAbstract:Mediators released from activated Mast Cells are responsible for the allergic inflammatory reactions associated with disease states such as anaphylaxis and atopy. These mediators are released as a consequence of immediate degranulation and phospholipid metabolism, upon Mast Cell activation, followed by delayed cytokine gene expression. Thus, techniques that monitor indices of these events in Mast Cell culture systems, in association with biochemical analysis of parameters of Cell signaling, are critical to our understanding of the molecular mechanisms regulating Mast Cell-mediated disease. Furthermore, these systems can be adapted for high throughput screens to identify potential inhibitors of Mast Cell activation which may provide potential leads for novel therapies for these diseases. In this unit, we describe approaches which can be readily used or adapted for a variety of rodent and human Mast Cell culture systems for the determination of degranulation, phospholipid-derived inflammatory mediator production, and cytokine generation.
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the tyrosine kinase network regulating Mast Cell activation
Immunological Reviews, 2009Co-Authors: Alasdair M. Gilfillan, Juan RiveraAbstract: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 (Fc epsilon RI) 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 (CD117). Activation of tyrosine kinases is central to the ability of both Fc epsilon RI and KIT to transmit downstream signaling events required for the regulation of Mast Cell activation. Whereas KIT possesses inherent tyrosine kinase activity, Fc epsilon RI 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 and downregulated by the actions of the tyrosine Src homology 2 domain-containing phosphatase 1 (SHP-1) and SHP-2. In this review, we discuss the regulation and role of specific members of this tyrosine kinase network in KIT and Fc epsilon RI-mediated Mast Cell activation.
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Mechanisms of Mast Cell signaling in anaphylaxis
Journal of Allergy and Clinical Immunology, 2009Co-Authors: Dean D. Metcalfe, Richard D. Peavy, Alasdair M. GilfillanAbstract:The recent development of a consensus definition and proposed diagnostic criteria for anaphylaxis offers promise for research efforts and a better understanding of the epidemiology and pathogenesis of this enigmatic and life-threatening disease. This review examines basic principles and recent research advances in the mechanisms of Mast Cell signaling believed to underlie anaphylaxis. The unfolding complexity of Mast Cell signaling suggests that the system is sensitive to regulation by any of several individual signaling pathways and intermediates and that complementary pathways regulate Mast Cell activation by amplified signals. The signaling events underlying anaphylactic reactions have largely been identified through experiments in genetically modified mice and supported by biochemical studies of Mast Cells derived from these mice. These studies have revealed that signaling pathways exist to both upregulate and downregulate Mast Cell responses. In this review we will thus describe the key molecular players in these pathways in the context of anaphylaxis.
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generation isolation and maintenance of rodent Mast Cells and Mast Cell lines
Current protocols in immunology, 2006Co-Authors: Bettina M Jensen, Emily J Swindle, Shoko Iwaki, Alasdair M. GilfillanAbstract:Antigen-mediated Mast Cell activation is a pivotal step in the initiation of allergic disorders including anaphylaxis and atopy. To date, studies aimed at investigating the mechanisms regulating these responses, and studies designed to identifying potential ways to prevent them, have primarily been conducted in rodent Mast Cells. However, to understand how these responses pertain to human disease, and to investigate and develop novel therapies for the treatment of human Mast Cell-driven disease, human Mast Cell models may have greater relevance. Recently, a number of systems have been developed which allow investigators to readily obtain sufficient quantities of human Mast Cells to conduct these studies. These Mast Cells release the appropriate suite of inflammatory mediators in response to known Mast Cell activators including antigen. These systems have also been employed to examine the signaling events regulating these responses. Proof of principle studies have also demonstrated utility of these systems for the identification of potential inhibitors of Mast Cell activation and growth. In this unit, we describe techniques for the development and culture of human Mast Cells from their progenitors and the culture of human Mast Cell lines. The relative merits and drawbacks of each model are also described.
Jenny Hallgren - One of the best experts on this subject based on the ideXlab platform.
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novel aspects of Mast Cell and basophil function highlights from the 9th meeting of the european Mast Cell and basophil research network embrn a marcus wallenberg symposium
Allergy, 2020Co-Authors: Jenny Hallgren, Gunnar Pejler, Gunnar Nilsson, Lars Hellman, Marcus Maurer, Sara Wernersson, Magnus AbrinkAbstract:Novel aspects of Mast Cell and basophil function : Highlights from the 9th meeting of the European Mast Cell and Basophil Research Network (EMBRN)-A Marcus Wallenberg Symposium.
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Mast Cell progenitors: Origin, development and migration to tissues
Molecular Immunology, 2015Co-Authors: Joakim S. Dahlin, Jenny HallgrenAbstract:Mast Cells in tissues are developed from Mast Cell progenitors emerging from the bone marrow in a process highly regulated by transcription factors. Through the advancement of the multicolor flow cytometry technique, the Mast Cell progenitor population in the mouse has been characterized in terms of surface markers. However, only Cell populations with enriched Mast Cell capability have been described in human. In naïve mice, the peripheral tissues have a constitutive pool of Mast Cell progenitors. Upon infections in the gut and in allergic inflammation in the lung, the local Mast Cell progenitor numbers increase tremendously. This review focuses on the origin and development of Mast Cell progenitors. Furthermore, the evidences for Cells and molecules that govern the migration of these Cells in mice in vivo are described.
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biology of Mast Cell tryptase
FEBS Journal, 2006Co-Authors: Jenny Hallgren, Gunnar PejlerAbstract:In 1960, a trypsin-like activity was found in Mast Cells [Glenner GG & Cohen LA (1960) Nature185, 846–847] and this activity is now commonly referred to as ‘tryptase’. Over the years, much knowledge about Mast Cell tryptase has been gathered, and a recent (18 January 2006) PubMed search for the keywords ‘tryptase + Mast Cell*’ retrieved 1661 articles. However, still very little is known about its true biological function. For example, the true physiological substrate(s) for Mast Cell tryptase has not been identified, and the potential role of tryptase in Mast Cell-related disease is not understood. Mast Cell tryptase has several unique features, with perhaps the most remarkable being its organization into a tetrameric state with all of the active sites oriented towards a narrow central pore and its consequent complete resistance towards endogenous macromolecular protease inhibitors. Much effort has been invested to elucidate these properties of tryptase. In this review we summarize the current knowledge of Mast Cell tryptase, including novel insights into its possible biological functions and mechanisms of regulation.
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biology of Mast Cell tryptase an inflammatory mediator
FEBS Journal, 2006Co-Authors: Jenny Hallgren, Gunnar PejlerAbstract:In 1960, a trypsin-like activity was found in Mast Cells [Glenner GG & Cohen LA (1960) Nature 185, 846-847] and this activity is now commonly referred to as 'tryptase'. Over the years, much knowledge about Mast Cell tryptase has been gathered, and a recent (18 January 2006) PubMed search for the keywords 'tryptase + Mast Cell*' retrieved 1661 articles. However, still very little is known about its true biological function. For example, the true physiological substrate(s) for Mast Cell tryptase has not been identified, and the potential role of tryptase in Mast Cell-related disease is not understood. Mast Cell tryptase has several unique features, with perhaps the most remarkable being its organization into a tetrameric state with all of the active sites oriented towards a narrow central pore and its consequent complete resistance towards endogenous macromolecular protease inhibitors. Much effort has been invested to elucidate these properties of tryptase. In this review we summarize the current knowledge of Mast Cell tryptase, including novel insights into its possible biological functions and mechanisms of regulation.
Cem Akin - One of the best experts on this subject based on the ideXlab platform.
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idiopathic anaphylaxis a form of Mast Cell activation syndrome
The Journal of Allergy and Clinical Immunology: In Practice, 2020Co-Authors: Cem Akin, Matthew P Giannetti, Mariana CastellsAbstract:Idiopathic anaphylaxis is a condition caused by paroxysmal episodes of sudden-onset multiorgan involvement variably including laryngeal edema, urticaria, bronchoconstriction, dyspnea, hypoxia, abdominal pain, nausea, vomiting, diarrhea, and hypotension. Rarely, the episodes can lead to cardiovascular collapse and death in the absence of a clear trigger, especially in the presence of other cardiovascular comorbidities. Elevated Mast Cell mediators such as tryptase and histamine have been reported during episodes, and Mast Cells are considered the primary Cells responsible for driving anaphylaxis in humans. Basophils also secrete histamine and LTC4 when activated and theoretically can contribute to symptoms. As our understanding of Mast Cell disorders continue to grow, the classification for these disorders evolves. The purpose of this article was 2-fold: to review the epidemiology, clinical manifestations, and diagnosis of idiopathic anaphylaxis and to discuss the classification of idiopathic anaphylaxis within the broader context of Mast Cell activation disorders.
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Mast Cell activation syndromes.
The Journal of allergy and clinical immunology, 2017Co-Authors: Cem AkinAbstract:Mast Cell activation is common and possibly necessary for maintenance of survival. Disordered Mast Cell activation occurs when Mast Cells are pathologically overproduced or if their activation is out of proportion to the perceived threat to homeostasis. Mast Cell activation syndrome refers to a group of disorders with diverse causes presenting with episodic multisystem symptoms as the result of Mast Cell mediator release. Despite introduction of diagnostic criteria and some advances in treatment in the last decade, many areas of Mast Cell activation syndrome are in need of research. This article reviews our current knowledge about the various types of Mast Cell activation disorders, their treatment, and areas of uncertainty in need of future investigation.
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levels of Mast Cell growth factors in plasma and in suction skin blister fluid in adults with Mastocytosis correlation with dermal Mast Cell numbers and Mast Cell tryptase
The Journal of Allergy and Clinical Immunology, 2002Co-Authors: Knut Brockow, Cem Akin, Mary M Huber, Linda M Scott, Lawrence B Schwartz, Dean D. MetcalfeAbstract:Abstract Background: Mast-Cell accumulation has been observed in the skin and other organs of patients with systemic indolent Mastocytosis (SM). The basis for this pathologic increase is not fully understood. Objective: We sought to determine levels of Mast-Cell growth factors in the skin and plasma of patients with SM, patients with atopic dermatitis (AD), and healthy individuals and to correlate these levels to dermal Mast-Cell numbers and levels of Mast-Cell tryptase. Methods: Skin suction blister fluid and plasma levels of stem-Cell factor, IL-3, IL-4, IL-6, vascular endothelial growth factor, and total Mast-Cell tryptase were analyzed by means of ELISA. The number of Mast Cells was determined in a biopsy section taken from adjacent skin. Results: Mast-Cell numbers in the dermis were higher in patients with SM compared with numbers in patients with AD ( P P P P P P P P Conclusion: Because elevated levels of IL-6 could contribute to the fever, fatigue, and osteoporosis observed in patients with SM and because IL-6 is antiapoptotic for Mast Cells, IL-6 could potentiate the biologic consequences of this disease. (J Allergy Clin Immunol 2002;109:82-8.)
