Monomeric IgE and mast cell development, survival and function.
ABSTRACT Mast cells play a major role in allergy and anaphylaxis, as well as a protective role in immunity against bacteria and venoms (innate immunity) and T-cell activation (acquired immunity).1,2 It was long thought that two steps are essential to mast cell activation. The first step (sensitization) occurs when antigen-specific IgE binds to its high-affinity IgE receptor (FcεRI) expressed on the surface of mast cells. The second step occurs when antigen (Ag) or anti-IgE binds antigen-specific IgE antibodies bound to FcεRI present on the mast cell surface (this mode of stimulation hereafter referred to as IgE+Ag or IgE+anti-IgE stimulation, respectively).Conventional wisdom has been that monomeric IgE plays only an initial, passive role in mast cell activation. However, recent findings have shown that IgE binding to its receptor FcεRI can mediate mast cell activation events even in the absence of antigen (this mode of stimulation hereafter referred to as IgE(-Ag) stimulation). Different subtypes of monomeric IgEs act via IgE(-Ag) stimulation to elicit varied effects on mast cells function, survival and differentiation. This chapter will describe the role of monomeric IgE molecules in allergic reaction, the various effects and mechanisms of action of IgE(-Ag) stimulation on mast cells and what possible developments may arise from this knowledge in the future. Since mast cells are involved in a variety of pathologic and protective responses, understanding the role that monomeric IgE plays in mast cell function, survival and differentiation will hopefully lead to better understanding and treatment of asthma and other allergic diseases, as well as improved understanding of host response to infections.
- SourceAvailable from: Toshiaki Kawakami[Show abstract] [Hide abstract]
ABSTRACT: Monomeric IgE molecules, when bound to the high-affinity receptor, exhibit a vast heterogeneity in their ability to induce survival promotion and cytokine production in mast cells. At one end of this spectrum, highly cytokinergic (HC) IgEs can induce potent survival promotion, degranulation, cytokine production, migration, etc., whereas at the other end, poorly cytokinergic (PC) IgEs can do so inefficiently. In this study, we investigated whether IgEs recognize autoantigens and whether IgEs' binding of autoantigens correlates with difference s in HC versus PC properties. Enzyme-linked immunosorbent assays were performed to test whether IgEs bind antigens. Histamine-releasing factor in human sera was quantified by western blotting. Cultured mast cells derived from human cord blood were used to test the effects of human sera on cytokine production. Most (7/8) of mouse monoclonal HC IgEs exhibited polyreactivity to double-stranded DNA (dsDNA), single-stranded DNA (ssDNA), β-galactosidase, thyroglobulin and/or histamine-releasing factor. By contrast, mouse PC IgEs failed to react with these antigens. A human monoclonal HC IgE also showed polyreactivity to histamine-releasing factor, dsDNA and ssDNA. Interestingly, sera from atopic dermatitis patients showed increased reactivity to ssDNA and β-galactosidase and increased levels of histamine-releasing factor. Some atopic dermatitis patients, but not healthy individuals, had substantial serum levels of HRF-reactive IgE. Sera from atopic dermatitis patients with high titers of DNA-reactive IgE could induce several fold more IL-8 secretion in human mast cells than sera from healthy individuals. The results show that most HC, but not PC, IgEs exhibit polyreactivity to autoantigens, supporting the autoimmune mechanism in the pathogenesis of atopic dermatitis.Allergy, asthma & immunology research 11/2012; 4(6):332-40. · 2.65 Impact Factor
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ABSTRACT: Mast cells are crucial effector cells evoking immune responses against bacterial pathogens. The positioning of mast cells at the host-environment interface, and the multitude of pathogen-recognition receptors and preformed mediator granules make these cells potentially the earliest to respond to an invading pathogen. In this review, the authors summarize the receptors used by mast cells to recognize invading bacteria and discuss the function of immune mediators released by mast cells in control of bacterial infection. The interaction of mast cells with other immune cells, including macrophages, dendritic cells and T cells, to induce protective immunity is highlighted. The authors also discuss mast cell-based vaccine strategies and the potential application in control of bacterial disease.Expert Review of Clinical Immunology 02/2013; 9(2):129-38. · 2.89 Impact Factor
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ABSTRACT: While gene knockout technology can reveal the roles of proteins in cellular functions, including in mast cells, fetal death due to gene manipulation frequently interrupts experimental analysis. We generated mast cells from mouse fetal liver (FLMC), and compared the fundamental functions of FLMC with those of bone marrow-derived mouse mast cells (BMMC). Under electron microscopy, numerous small and electron-dense granules were observed in FLMC. In FLMC, the expression levels of a subunit of the FcεRI receptor and degranulation by IgE cross-linking were comparable with BMMC. By flow cytometry we observed surface expression of c-Kit prior to that of FcεRI on FLMC, although on BMMC the expression of c-Kit came after FcεRI. The surface expression levels of Sca-1 and c-Kit, a marker of putative mast cell precursors, were slightly different between bone marrow cells and fetal liver cells, suggesting that differentiation stage or cell type are not necessarily equivalent between both lineages. Moreover, this indicates that phenotypically similar mast cells may not have undergone an identical process of differentiation. By comprehensive analysis using the next generation sequencer, the same frequency of gene expression was observed for 98.6% of all transcripts in both cell types. These results indicate that FLMC could represent a new and useful tool for exploring mast cell differentiation, and may help to elucidate the roles of individual proteins in the function of mast cells where gene manipulation can induce embryonic lethality in the mid to late stages of pregnancy.PLoS ONE 01/2013; 8(4):e60837. · 3.73 Impact Factor