Mast cells have mainly been studied in the setting of allergic disease, but the importance of mast cells for host defence against several pathogens has now been well established. The location of mast cells, which are found closely associated with blood vessels, allows them to have a crucial sentinel role in host defence. The mast cell has a unique 'armamentarium' of receptor systems and mediators for responding to pathogen-associated signals. Studies of this intriguing immune-effector cell provide important insights into the complex mechanisms by which appropriate innate and acquired immune responses are initiated.

Mast-cell responses to pathogens

The biology of stem cell factor and its receptor C-kit.

The versatile role of mast cells in allergy, in innate immune responses and in the regulation of tissue homeostasis is well recognized. However, it is often not made clear that most mast-cell data derive solely from experiments in mice or rats, species that obviously never suffer from allergic and most other mast-cell-associated human diseases. Data on human mast cells are limited, and the mast-cell source and species from which findings derive are frequently not indicated in the titles and summaries of research publications. This Review summarizes recent data on human mast cells, discusses differences with murine mast cells, and describes new tools to study this increasingly meaningful cell type in humans.

Role of mast cells in allergic and non-allergic immune responses: comparison of human and murine data

That mast cells and allergic mechanisms play at least some role in bronchial asthma has been suggested for at least 75 years [92]. The incidence of these mechanisms in a cross section of all asthmatics [31, 77], and the importance of allergic mechanisms as compared with neural mechanisms is controversial, however, and has been discussed and debated for at least as long [16, 113].

/pdf/mast-cells-and-basophils-2suvtsp6l8.pdf

Mast cells and basophils.

Mast cells are hematopoietic cells that reside in virtually all vascularized tissues and that represent potential sources of a wide variety of biologically active secreted products, including diverse cytokines and growth factors. There is strong evidence for important non-redundant roles of mast cells in many types of innate or adaptive immune responses, including making important contributions to immediate and chronic IgE-associated allergic disorders and enhancing host resistance to certain venoms and parasites. However, mast cells have been proposed to influence many other biological processes, including responses to bacteria and virus, angiogenesis, wound healing, fibrosis, autoimmune and metabolic disorders, and cancer. The potential functions of mast cells in many of these settings is thought to reflect their ability to secrete, upon appropriate activation by a range of immune or non-immune stimuli, a broad spectrum of cytokines (including many chemokines) and growth factors, with potential autocrine, paracrine, local, and systemic effects. In this review, we summarize the evidence indicating which cytokines and growth factors can be produced by various populations of rodent and human mast cells in response to particular immune or non-immune stimuli, and comment on the proven or potential roles of such mast cell products in health and disease.

Mast cells as sources of cytokines, chemokines, and growth factors.

To establish the method for generating a large number of mature human mast cells, we cultured cord blood mononuclear cells (CBMC) in several conditions in the presence of Steel factor (SF). Among several cytokines tested, IL-6 enhanced SF-dependent mast cell growth from purified CD34+ cells for more than 8 wk in culture. When CBMC were cultured instead of CD34+ cells, IL-6 enhanced the mast cell development in the presence but not in the absence of PGE2. PGE2 enhanced the SF- and IL-6-dependent development of mast cells from CBMC probably by blocking granulocyte-macrophage CSF (GM-CSF) secretion from accessory cells, because 1) PGE2, or anti-GM-CSF enhanced the mast cell development induced by SF and IL-6 from CBMC, but not from CD34+ cells; 2) GM-CSF inhibited the enhancing effect of IL-6 on the mast cell development from CD34+ cells; and 3) PGE2 inhibited GM-CSF secretion from CBMC. The mast cells cultured in the presence of SF, IL-6, and PGE2 for >10 wk were 99% pure, and seemed to be functionally mature, because 1) they contained 5.62 micrograms of histamine and 3.46 micrograms of tryptase per 10(6) cells; and 2) when sensitized with human IgE and then challenged with anti-human IgE, the cells released a variety of mediators such as histamine, and an increase in intracellular Ca2+ was found in advance of the activation of membrane movement by using a confocal laser-scanning microscope. Electron-microscopic analysis revealed that some of the cultured mast cells are morphologically mature since they filled with scroll granules and contained crystal granules.

Selective growth of human mast cells induced by Steel factor, IL-6, and prostaglandin E2 from cord blood mononuclear cells.

Characterization of Mast Cell-Committed Progenitors Present in Human Umbilical Cord Blood

Iconographies supplémentaires de l'article : Genetic polymorphism regulating ORM1-like 3 ( Saccharomyces cerevisiae ) expression is associated with childhood atopic asthma in a Japanese population

Background The mast cell is one of the important cells in the pathogenesis of allergic disorders. However, isolating human mast cells is a laborious procedure. Recently, cultured human mast cells raised from umbilical cord blood cells have become available. It is necessary to examine whether these cells are useful in investigating the role of mast cells in human diseases. Objective The phenotype of mast cells depends on their anatomical sites. To examine which phenotype of mast cells these cultured mast cells most closely resemble, their ability to release was investigated. Methods The mast cells were raised from human umbilical cord blood cells in the presence of stem cell factor and interleukin-6. To determine the mast cell subtypes, the mast cells were immunocytochemically stained for tryptase and chymase. The cultured mast cells were then stimulated with various secretagogues, and histamine release was measured by a fluorometric technique using high-performance liquid chromatography. Results The immunocytochemical staining for mast cell proteases revealed that virtually all cells contained tryptase, the definitive marker of mast cells, and that about a quarter of the cells contained chymase. Anti-IgE effectively stimulated these mast cells to release histamine in a dose-dependent, time-dependent manner. The release was completed in about 30 min. One of the non-specific stimuli, calcium ionophore A23187, also induced histamine release in a dose-dependent, time-dependent manner. In contrast, compound 48/80 and substance P failed to induce histamine release from these cells. Conclusion Cultured human mast cells resemble lung mast cells in their ability to release histamine. They will help in studying the functional properties of human mast cells and may contribute to clarifying the pathophysiology of human allergic diseases.

Characteristics of histamine release from cultured human mast cells.

BACKGROUND: Transforming growth factor (TGF)-beta plays an important role in the regulation of airway inflammation and remodelling in asthma. Recent studies suggest that TGF-beta(2) is a predominant isoform expressed in severe asthma and it is also associated with airway remodelling. OBJECTIVE: To determine whether the polymorphisms in TGF-beta(2) are associated with childhood atopic bronchial asthma in a Japanese population. METHODS: We identified a total of eight polymorphisms and characterized the linkage disequilibrium (LD) mapping of the gene. Three variants in the promoter and 3'UTR were genotyped, and we conducted an association study of TGF-beta(2) (childhood atopic asthma n=297, normal controls n=555). An association analysis of these variants and an expression and functional analysis were performed. RESULTS: 3'UTR 94862T >A was found to be significantly associated with the risk of childhood atopic asthma (P=0.00041). The -109-->ACAA ins promoter variant was also associated with the risk of childhood atopic asthma (P=0.0037). TGF-beta(2) expression was observed in both the normal and asthmatic bronchial epithelium, and both real-time PCR and an ELISA showed a significant basal and TGF-beta(1)-induced TGF-beta(2) expression in the bronchial epithelial cell line BEAS2B. Furthermore, the promoter variant -109-->ACAA ins increased the TGF-beta(2) promoter-reporter activity in BEAS2B cells. CONCLUSIONS: Our data suggest that TGF-beta(2) may therefore be involved in the development of childhood atopic asthma by means of functional genetic polymorphism. The polymorphisms in TGF-beta(2) may become important information for asthma susceptibility in children.

M. Ebisawa

Papers

Selective growth of human mast cells induced by Steel factor, IL-6, and prostaglandin E2 from cord blood mononuclear cells.

Characterization of Mast Cell-Committed Progenitors Present in Human Umbilical Cord Blood

Iconographies supplémentaires de l'article : Genetic polymorphism regulating ORM1-like 3 ( Saccharomyces cerevisiae ) expression is associated with childhood atopic asthma in a Japanese population

Characteristics of histamine release from cultured human mast cells.

Transforming growth factor-β2 polymorphisms are associated with childhood atopic asthma