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PubMed1993

Induction of human IgE synthesis in B cells by mast cells and basophils.

Immunoglobulin E (IgE) is central to the induction of allergic diseases through its binding to the high-affinity receptor (Fc epsilon R1) on mast cells and basophils. Crosslinking by allergens of the bound IgE leads to the release of various inflammatory mediators. IgE production by B cells requires a physical interaction with T cells, involving a number of surface adhesion molecules, as well as the soluble factors interleukin-4 (IL-4) and IL-13 (ref. 5) produced by T cells, basophils and mast cells. Here we report that, in the presence of IL-4, mast and basophilic cell lines can provide the cell contact signals that are required for IgE synthesis. The human cell lines HMC-1 (mast) and KU812 (basophilic) both express the ligand for CD40 (CD40L) which is shown to be responsible for the IgE production. Moreover, freshly isolated purified human lung mast cells and blood basophils are also shown to express CD40L and to induce IgE production. This evidence suggests that mast cells and basophils may therefore play a key role in allergy not only by producing inflammatory mediators, but also by directly regulating IgE production independently of T cells.

Animals↗
PubMed2003

Prolonged effect of the tricyclic antidepressant, mianserin on the serotonin and histamine content of young rats' white blood cells and mast cells. A case of late-imprinting.

Perinatal encounter of a hormone and its developing target receptor sets the receptor-hormone-signal transduction complex for life (hormonal imprinting). In this critical period excess of the appropriate hormone or foreign molecules able to bind the receptor can cause faulty imprinting with life-long consequences. At present the imprinter effect of a molecule bound by receptor was studied in female rats at weaning. Histamine and serotonin content of blood lymphocytes and peritoneal cells (lymphocytes, mast cells and the monocyte-granulocyte-macrophage group) was measured by flow cytometry three weeks after three days treatment of three-week-old rats with the histamine and serotonin antagonist tricyclic antidepressant, mianserin. The histamine content was dramatically elevated in each cell type except blood lymphocytes. The serotonin content was also elevated in peritoneal mast cells and decreased in peritoneal lymphocytes. Considering that the measurement was done three weeks after treatment, the results call attention to the long-lasting effect of a molecule acting at receptorial level.

Animals↗
PubMed1991

The growth and differentiation of mast cells.

Mast cells (MCs) are local immune cells involved in host defense mechanisms and allergic response. They usually develop from MC committed progenitor cells which in turn are derived from uncommitted hemopoietic stem cells. MC precursors are supposed to develop in the bone marrow (bm) cavities as well as in extramedullary tissues. MC precursor cells also have the potential to circulate in the blood stream. After homing in the tissues they give rise to mature MCs. Recruitment and differentiation as well as terminal maturation of MCs is regulated by a complex network of factors. Two major arms of control have been delineated based on in vitro studies and experimental animal models. The first involves the response of the progenitor cells to growth inducing cytokines, such as IL-3. This type of control promotes the generation of MC precursor cells. The second arm of control involves the microenvironmental network interacting with the MC progenitors. It consists of both stroma cell- and immune cell-derived differentiation factors and the direct interaction of cells. It may be important for homing of MC progenitors during embryogenesis and probably throughout life. The stromal component also determines terminal differentiation towards a particular type of MCs and also supports in vitro development of MCs in long term cultures. Growth and function of the mature MCs in the various tissues may be triggered by additional factors including the interactions of MCs with other leukocytes and nerve cells. The coupling of MC activation processes with subsequent proliferation may be a triggering factor in allergic disease. This article attempts to provide a synthesis of current knowledge on MC development.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2026

Mast Cells Selectively Deliver Extracellular Vesicle-Encapsulated mRNA to Colorectal Cancer Cells.

Mast cells (MCs), a type of granulocytic immune cell, exert contrasting effects on tumorigenesis. The anti- or pro-tumorigenic activity of MCs depends on the cancer type, tumor microenvironment, and MC localization within the tumor. Consequently, their role remains controversial and poorly understood across multiple cancer types, including colorectal cancer (CRC). Most proposed mechanisms underlying MC activity in CRC have focused on MC secretion of biological factors. In this study, we demonstrated that MCs transfer extracellular vesicles containing mRNAs and proteins to CRC cells. This process occurs through a tightly regulated mechanism that requires direct cell-cell contact, calcium signaling, and integrin-mediated interactions. Such requirements resemble aspects of immunological synapses observed between lymphocytes and cancer cells. The novel mode of intercellular communication between MCs and cancer cells described here may help refine our understanding of MC functions in cancer biology.

Mast Cells↗
PubMed2003

Toll receptors modulate allergic responses: interaction with dendritic cells, T cells and mast cells.

PURPOSE OF REVIEW: The discovery of Toll-like receptors has generated much interest in understanding the impact of innate immunity on adaptive immune responses, including allergic diseases. RECENT FINDINGS: Recent studies suggest that Toll-like receptor pathways may mediate interactions between dendritic cells, T lymphocytes and mast cells, thus modulating allergic immune responses. Toll-like receptor signaling triggers dendritic cell maturation, which primes naive T lymphocytes towards specific T helper cell types 1 and 2 immune responses. Although a T helper cell type 1/2 balance may be important in modulating allergic responses, T regulatory cells that suppress certain immune responses may be critical in immune regulation. SUMMARY: With the identification of different subsets of dendritic cells and the discovery of Toll-like receptors on T regulatory cells and mast cells, the manipulation of Toll-like receptor signaling may lead to novel therapeutic options in allergic diseases.

Dendritic Cells↗
PubMed2000

MEKK2 gene disruption causes loss of cytokine production in response to IgE and c-Kit ligand stimulation of ES cell-derived mast cells.

Ligation of the high-affinity IgE receptor (FcepsilonRI) or of c-Kit stimulates cytokine production in mast cells. We show that MEK kinase 2 (MEKK2), a MAPK kinase kinase (MAP3K) that regulates the JNK and ERK5 pathways, is required for cytokine production in embryonic stem (ES) cell-derived mast cells (ESMC). Targeted disruption of the MEKK2 or MEKK1 gene was used to abolish expression of the respective kinases in ESMC. Transcription of specific cytokines in response to IgE or c-Kit ligand was markedly reduced in MEKK2(-/-) ESMC relative to wild-type ESMC. Cytokine production in MEKK1(-/-) ESMC was similar to that of wild-type ESMC, demonstrating the specificity of MEKK2 in signaling cytokine gene regulation. MEKK2(-/-) ESMC also lost receptor-mediated stimulation of JNK. In contrast, JNK activation in response to UV irradiation was normal, showing that MEKK2 is required for receptor signaling but not for cellular stress responses. MEKK2 is the first MAP3K shown to be required for mast cell tyrosine kinase receptor signaling controlling cytokine gene expression.

Animals↗
PubMed1987

Localization of mucosal mast cells in W/Wv mice after reconstitution with bone marrow cells or cultured mast cells, and its relation to the protective capacity to Strongyloides ratti infection.

Localization of mast cells in the intestinal epithelium, villous lamina propria and basal lamina propria of mast cell-deficient WBB6F1 (W/Wv) mice reconstituted with either bone marrow cells or with cultured mast cells (BMMC) was compared to that of mast cell-sufficient C57BL/6 or C57BL/6-bgj/bgj (beige) mice after infection with Strongyloides ratti. In mast cell-sufficient C57BL/6 or beige mice, the maximum number of intestinal mucosal mast cells (MMC) was more than 160 MMC/10 villus crypt units (VCU) and more than 90% of MMC were located in the intestinal epithelium. When W/Wv mice were reconstituted with bone marrow cells of beige mice, worm expulsion was hastened and the MMC response became comparable to that of mast cell-sufficient mice in terms of cell numbers and their intra-epithelial localization. On the other hand, when W/Wv mice were reconstituted with BMMC of beige mice, only a few donor type MMC were detected in the intestine. The proportion of intra-epithelial MMC was lower than that of mast cell-sufficient mice or of marrow-reconstituted W/Wv mice. Even repeated injection of BMMC could not fully restore the number of intra-epithelial MMC to the level of that observed in mast cell-sufficient mice. Since mast cell-growth factor-producing activity of W/Wv mice was comparable to that of mast cell-sufficient mice, the ineffectiveness of BMMC-transfer in restoring protective activity or MMC responses in W/Wv mice seems to be attributed to the functional immaturity or inactivity of BMMC.

Animals↗
PubMed2000

Natural killer cells and mast cells from gp49B null mutant mice are functional.

Immune responses are controlled by a combination of positive and negative cellular signals. Effector cells in the immune system express inhibitory receptors that serve to limit effector cell expansion and to protect the host from autoreactivity. gp49B is a receptor of unknown function that is expressed on activated mast cells and natural killer (NK) cells and whose cytoplasmic tail endows it with inhibitory potential. To gain insight into the function of gp49B in mice, we disrupted the gp49B gene by homologous recombination. gp49B(0) mice were born at expected ratios, were healthy and fertile, and displayed normal long-term survival rates. gp49B(0) mice showed no defect in NK or mast cell development. Furthermore, NK and mast cells from the gp49B(0) mice showed activation properties in vitro similar to those of cells isolated from wild-type mice. Therefore, gp49B is not critical for the development, expansion, and maturation of mast cells and NK cells in vivo. The healthy status of gp49B(0) mice makes them suitable for testing the role of gp49B in immune responses to infectious agents.

Animals↗
PubMed2002

T cells and mast cells as a major source of interleukin-13 in atopic dermatitis.

BACKGROUND: Interleukin (IL)-13 is a T-cell-derived cytokine that shares several functions with IL-4, including the induction of immunoglobulin E synthesis. Recent studies suggest that cytokines expressed locally in the skin play several critical roles in atopic dermatitis (AD), however, little is known about the role of IL-13 in AD lesions. OBJECTIVES: The present study was designed to characterize the involvement of IL-13 in AD in the skin and peripheral blood mononuclear cells (PBMC). METHODS: Using lesional and nonlesional skin from adult AD patients and normal skin from healthy volunteers, we performed RT-PCR, in situ RT and immunostaining to determine the IL-13 expression at the mRNA and protein levels. The actual numbers of IL-13 expressing cells in biopsy specimens were counted under the microscope. IL-13 mRNA expression in PBMC from AD patients and healthy volunteers was examined by RT-PCR analysis. RESULTS: IL-13 mRNA expression was detected by RT-PCR in lesional and nonlesional skin and in PBMC from AD patients, but not in normal skin or PBMC from healthy volunteers. In AD lesional skin, numerous IL-13 mRNA-positive cells were demonstrated by in situ RT, and similar numbers of IL-13-positive cells were also detected immunohistochemically. Smaller numbers of IL-13-positive cells were observed in AD nonlesional skin and in normal skin. The differences in the numbers of IL-13-expressing cells between lesional and nonlesional skin were statistically significant. Double immunostaining revealed that IL-13 was produced in approximately 40% of T cells and 20% of mast cells in AD lesional skin, suggesting that T cells and mast cells are major sources of IL-13 in AD lesions. CONCLUSION: IL-13 may play a local as well as a systemic role in the development of AD lesions.

Adult↗
PubMed2005

Mast cell tryptase in mast cell granules enhances MCP-1 and interleukin-8 production in human endothelial cells.

OBJECTIVE: Recent studies have highlighted the pathogenetic importance of chronic inflammation in cardiovascular disorders such as congestive heart failure and atherosclerosis. Mast cells release a wide variety of immune mediators that may initiate inflammatory responses, whereas endothelial cells (ECs) play a prominent role in the pathogenesis of cardiovascular diseases by secreting cytokines. The purpose of this study was to clarify the role of mast cells as an activator of ECs. METHODS AND RESULTS: ECs harvested from human umbilical cord veins were stimulated with mast cell granules (MCGs) prepared from sonicated human leukemic mast cells. The supernatants and total RNA from cells were collected. Levels of interleukin (IL)-1beta, tumor necrosis factor-alpha, and granulocyte colony-stimulating factor remained unchanged up to 24 hours. In contrast, levels of monocyte chemoattractant protein-1 (MCP-1) and IL-8 increased significantly within 6 hours. Northern blot analysis revealed an increase in MCP-1 and IL-8 mRNA expression in MCG-treated ECs. Induction of these chemokines was attenuated by antitryptase neutralizing antibody. Furthermore, MCP-1 and IL-8 were induced in ECs by incubation with human mast cell tryptase, but not with chymase. CONCLUSIONS: These results indicate that the production of MCP-1 and IL-8 in ECs was induced by MCG and amplified by tryptase.

Cells, Cultured↗
PubMed1987

Mediators of human mast cells and human mast cell subsets.

Although a great deal has been learned about the mediators produced by mast cells, the ultimate biologic function(s) of mast cell remains a mystery. Histamine, LTC4, PAF, and possibly tryptase (C3a generation) all enhance vasopermeability. Mediators with anticoagulant activities such as heparin and tryptase (fibrinogenolysis) and antithrombotic activity, PGD2, would appear to facilitate dispersion in tissues of the plasma ultrafiltrate brought there by the subgroup of mediators that enhance vasopermeability. In contrast, PAF causes platelet aggregation and chymase may cause arteriolar vasoconstriction (decreasing the volume of plasma reaching venules) by generation of angiotensin II. Assessment of any differential production of mediators by different types of mast cells will be of obvious importance in sorting out the physiologic responses to mast cell activation as well as the pathophysiology of allergic reactions.

Arachidonic Acid↗
PubMed2006

Mast cells: ontogeny, homing, and recruitment of a unique innate effector cell.

Mast cells (MCs) are found principally in peripheral tissues yet are of bone marrow origin. Recent studies in mice trace the MC lineage from the common myeloid progenitor through the granulocyte-macrophage progenitor in the bone marrow to a committed MC progenitor (MCP). Additionally, at least in the mouse, a bipotent basophil-MC progenitor has been identified in the spleen, suggesting a physiologic role for this organ in MC development. MCPs are especially abundant in the mouse intestine, likely ensuring the capacity for a rapid expansion of MCs in the intestinal epithelium during the effector response to helminth infection and perhaps providing a pool of committed cells capable of redistribution to other tissues. Migration of MCPs to the intestine is constitutive and controlled by alpha chemokine receptor 2 and alpha4beta7 integrins expressed on the MCPs, with the latter integrin interacting with endothelial vascular cell adhesion molecule 1 and mucosal addressin cell adhesion molecule 1. In contrast, normal mouse lung tissue contains few MCPs and MCs, and these cellular reservoirs are not affected by the lack of alpha chemokine receptor 2 or alpha4beta7 integrin. Nonetheless, robust recruitment of MCPs to the lung occurs during experimentally induced allergic pulmonary inflammation and requires alpha4beta7 and alpha4beta1 integrins interacting with vascular cell adhesion molecule 1 but not with mucosal addressin cell adhesion molecule 1. Thus although MCs are present in all organs, the pathways responsible for the trafficking of MCPs from the circulation are organ specific and include both constitutive and inducible systems, ensuring both resident MCs and the potential for incremental recruitment in accord with the requirements of the immune response. These findings in mice await confirmation in human subjects.

Animals↗
PubMed1981

Nature of the thymus dependency of mucosal mast cells. III. Mucosal mast cells in nude mice and nude rats, in B rats and in a child with the Di George syndrome.

Mucosal mast cells have been examined in the small intestinal mucosae of nude mice and nude rats, B rats and a child with the DiGeorge syndrome. In all three species, mast cells were present in normal numbers despite the athymic status of the nude mice and nude rats, the vestigial nature of the thymus in the child, and the functionally T lymphocyte-deprived status of the B rats. Connective tissue mast cells were also plentiful in skins and tongues of the nude mice and the child with thymic aplasia. It is concluded that normally neither population of mast cells has a obligatory dependence on the thymus or T lymphocytes for its differentiation, but that mucosal mast cells, under certain conditions of rapid hyperplasia, require an inductive influence provided by T lymphocytes.

Animals↗
PubMed1987

Specificity of a mouse monoclonal antibody raised against acute myeloid leukaemia cells for mast cells in human mucosal and connective tissues.

A mouse monoclonal antibody raised against acute myeloid leukaemia cells (YB5.B8 monoclonal antibody; Gadd, S. J. and Ashman, L. K. (1985): Leukaemia Res. 9, 1329-1336) has been found by an indirect immunoperoxidase technique to bind to scattered cells in frozen sections from a number of human tissues. They have been identified as mast cells in fixed sections of skin, tonsil and duodenum by simultaneous staining of glycosaminoglycan with Alcian blue in 0.7 N HCl. The antibody does not distinguish mast cells in mucosal tissues from those in connective tissue, although the level of expression by cells at both sites appears to be heterogeneous. With the exception of low affinity binding to B lymphocytes, no other bone marrow-derived cells were found to bind the antibody. In particular, basophils and eosinophils were not stained, suggesting that they are not related closely to mast cells and that the antigen detected by YB5.B8 monoclonal antibody is not an IgE Fc receptor. Therefore, among all mature haemopoietic lineages, the antibody is specific for mast cells.

Animals↗
PubMed2000

Mucosal defense against gastrointestinal nematodes: responses of mucosal mast cells and mouse mast cell protease 1 during primary strongyloides venezuelensis infection in FcRgamma-knockout mice.

A possible role for the gamma subunit of immunoglobulin Fc receptors (FcR) in mucosal defenses against intestinal nematode parasites was studied using age-matched FcRgamma-knockout (FcRgamma(-/-)) and wild-type (FcRgamma(+/+)) C57BL/6 mice. Mice were infected subcutaneously with 3,000 infective larvae of Strongyloides venezuelensis, and the degree of infection was monitored by daily fecal egg counts and adult worm recovery on days 8 and 13 postinfection. Mucosal mast cell (MMC) responses were assayed by in situ intestinal mast cell counts in stained histological sections of the jejunum and by measuring mouse mast cell protease 1 (MMCP-1) release in serum using sandwich enzyme-linked immunosorbent assay. FcRgamma(-/-) mice had significantly higher egg counts (P<0.01) and numbers of adult worms (P<0.05) than FcRgamma(+/+) mice, but mastocytosis and serum MMCP-1 release were comparable. It was concluded that MMCP-1 release may be spontaneous, does not depend on mast cell degranulation via the FcRgamma signaling system, and appears to play no role in the expulsion of S. venezuelensis. The delay in worm expulsion in the FcRgamma(-/-) mice might be related to inability of the MMC to degranulate and release effector molecules other than MMCP-1, since FcRgamma deletion abrogates mast cell degranulative responses.

Animals↗
PubMed1994

Mast cells and fibroblasts: two interacting cells.

Mast cell (MC) fibroblast interactions may have a role in health and disease. We analyzed the relationships between these cells by utilizing our in vitro model in which mucosal (MMC) and connective tissue (CTMC) type MC were cocultured long-term with different fibroblasts. Mouse 3T3 fibroblasts were used to provide a normal microenvironment for MC, while fibroblasts derived from mouse with chronic graft-versus-host disease (cGVHD) provided a fibrotic one. We found that both 3T3 and cGVHD fibroblasts maintain CTMC viability, phenotype and functional activity. When MMC were cocultured with 3T3 or cGVHD fibroblasts, they changed their phenotype towards that of CTMC. On the other hand, MCs were found to affect fibroblast properties. Coculture of MMC on 3T3 monolayers was shown to increase Forsmann antigen production and collagen synthesis and stimulate fibroblast proliferation. Resting CTMC or CTMC activated by anaphylactic stimuli induced 3T3 and cGVHD fibroblasts to proliferate more. In addition, CTMC activation increased collagen production by 3T3 fibroblasts. In conclusion, fibroblasts were found to regulate MC survival and differentiation, whereas MCs were shown to affect the biochemical properties of fibroblasts, which can lead to fibrosis.

3T3 Cells↗
PubMed2003

Tetrahydrobiopterin, a critical factor in the production and role of nitric oxide in mast cells.

Mast cells (MC) are biologically potent, ubiquitously distributed immune cells with fundamental roles in host integrity and disease. MC diversity and function is regulated by exogenous nitric oxide; however, the production and function of endogenously produced NO in MC is enigmatic. We used rat peritoneal MC (PMC) as an in vivo model to examine intracellular NO production. Live cell confocal analysis of PMC using the NO-sensitive probe diaminofluorescein showed distinct patterns of intracellular NO formation with either antigen (Ag)/IgE (short term) or interferon-gamma (IFN-gamma) (long term). Ag/IgE-induced NO production is preceded by increased intracellular Ca2+, implying constitutive nitric-oxide synthase (NOS) activity. NO formation inhibits MC degranulation. NOS has obligate requirements for tetrahydrobiopterin (BH4), a product of GTP-cyclohydrolase I (CHI), IFN-gamma-stimulated PMC increased CHI mRNA, protein, and enzymatic activity, while decreasing CHI feedback regulatory protein mRNA, causing sustained NO production. Treatment with the CHI inhibitor, 2,4-diamino-6-hydroxypyrimidine, inhibited NO in both IFN-gamma and Ag/IgE systems, increasing MC degranulation. Reconstitution with the exogenous BH4 substrate, sepiapterin, restored NO formation and inhibited exocytosis. Thus, Ag/IgE and IFN-gamma induced intracellular NO plays a key role in MC mediator release, and alterations in NOS activity via BH4 availability may be critical to the heterogeneous responsiveness of MC.

Animals↗
PubMed1984

Mast cell mediators with emphasis on intestinal mast cells.

Mast cells occur throughout most tissues although they are more prevalent in areas which come into contact with the external environment such as the skin, lungs, and gastrointestinal tract. The physiologic role of this cell is not known; however, it has a recognized pathophysiologic role as an effector cell in immediate hypersensitivity reactions. Such mast cells, when activated by either immunologic or non-immunologic stimuli, both release and generate chemical mediators such as histamine and leukotrienes which then act on surrounding tissues. Depending upon the site of mast cell degranulation, a variety of clinical findings ensue. For example, mast cell degranulation in the lungs may lead to wheezing, while mast cell degranulation in the gastrointestinal tract may lead to vomiting and diarrhea. It is now recognized that not all mast cells are identical. The best example of this mast cell heterogeneity is found in the gastrointestinal tract. There is evidence that certain gastrointestinal mast cells both contain and generate mediators either distinct from or differing in quantity from those of mast cells found at other sites. Such observations suggest that a knowledge of these differences is required to understand gastrointestinal diseases in which mast cell activation plays a part.

Aging↗