Cells In Allergy Research Articles

Increased IgE-dependent mast cell activation and anaphylactic responses in mice lacking the calcium-activated nonselective cation channel TRPM4

Mast cells are key effector cells in allergic reactions. Aggregation of the receptor FcepsilonRI in mast cells triggers the influx of calcium (Ca(2+)) and the release of inflammatory mediators. Here we show that transient receptor potential TRPM4 proteins acted as calcium-activated nonselective cation channels and critically determined the driving force for Ca(2+) influx in mast cells. Trpm4(-/-) bone marrow-derived mast cells had more Ca(2+) entry than did TRPM4(+/+) cells after FcepsilonRI stimulation. Consequently, Trpm4(-/-) bone marrow-derived mast cells had augmented degranulation and released more histamine, leukotrienes and tumor necrosis factor. Trpm4(-/-) mice had a more severe IgE-mediated acute passive cutaneous anaphylactic response, whereas late-phase passive cutaneous anaphylaxis was not affected. Our results establish the physiological function of TRPM4 channels as critical regulators of Ca(2+) entry in mast cells.

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

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 Regulatory T Cells in Allergy: Implications for Therapeutic Strategy

The interest in regulatory T cells (Tregs) has been revived following the discovery of developing multiorgan autoimmune diseases as a result of depleting CD4+CD25+ T cells from mice. The importance of Tregs is being recognized in various clinical fields such as tumor and microbial immunities, transplantation and allergy. Prevalence of allergic diseases such as asthma, atopic dermatitis and rhinitis is significantly increasing worldwide. A better understanding of the mechanisms of T-cell regulation in allergic diseases may help in developing more effective therapeutic strategies. The well-known role of Tregs in preventing autoimmune diseases indicates that these important cells might be involved in prevention of allergy, and allergic diseases are associated with a low frequency and/or an impaired function of Tregs. Recent data show that natural CD4+CD25+ Tregs and interleukin (IL)-10-producing Tregs are normally able to suppress Th2 responses to allergens, while such suppression is diminished in allergic conditions. In this review, I summarize the role of Tregs in allergic diseases and discuss the possibility of manipulating these cells for treating allergic diseases.

Green Tea Extract and (−)-Epigallocatechin-3-Gallate Inhibit Mast Cell-Stimulated Type I Collagen Expression in Keloid Fibroblasts via Blocking PI-3K/Akt Signaling Pathways

Keloid, a chronic fibro-proliferative disease, exhibits distinctive histological features characterized by an abundant extracellular matrix stroma, a local infiltration of inflammatory cells including mast cells (MCs), and a milieu of enriched cytokines. Previous studies have demonstrated that co-culture with MCs stimulate type I collagen synthesis in fibroblasts, but the signaling mechanisms remain largely unknown. In this study, we investigated the signaling pathways involved in MC-stimulated type I collagen synthesis and the effects of green tea extract (GTE) and its major catechin, (-)-epigallocatechin-3-gallate (EGCG), on collagen homeostasis in keloid fibroblasts. Our results showed that MCs significantly stimulated type I collagen expression in keloid fibroblasts, and the upregulation of type I collagen was significantly attenuated by blockade of phosphatidylinositol-3-kinase (PI-3K), mammalian target of rapamycin (mTOR), and p38 MAPK signaling pathways, but not by blockade of ERK1/2 pathway. Furthermore, GTE and EGCG dramatically inhibited type I collagen production possibly by interfering with the PI-3K/Akt/mTOR signaling pathway. Our findings suggest that interaction between MCs and keloid fibroblasts may contribute to excessive collagen accumulation in keloids and imply a therapeutic potential of green tea for the intervention and prevention of keloids and other fibrotic diseases.

Intracellular signaling pathways in IgE-dependent mast cell activation

Mast cells (MCs) are both central effectors and signaling cells in allergic reactions. Their key role in the immunopathology of asthma and other allergic diseases has been well documented. Molecular events leading to MC activation have not been yet fully established, however. Recent studies emphasize the key role of the protein tyrosine kinases Lyn and Fyn in MC signal transduction. The finding that Lyn kinase negatively regulates MC degranulation and that Fyn kinase enhances this effector response is of great importance. This creates new possibilities for therapeutic intervention in asthma and other allergic diseases. This review summarizes current knowledge on MC intracellular signaling and discusses the most recent strategies for the treatment of allergic diseases based on MC signaling pathway inhibition.

The Critical Role of Mast Cells in Allergy and Inflammation

Mast cells are well known for their involvement in allergic and anaphylactic reactions, but recent findings implicate them in a variety of inflammatory diseases affecting different organs, including the heart, joints, lungs, and skin. In these cases, mast cells appear to be activated by triggers other than aggregation of their IgE receptors (FcepsilonRI), such as anaphylatoxins, immunoglobulin-free light chains, superantigens, neuropeptides, and cytokines leading to selective release of mediators without degranulation. These findings could explain inflammatory diseases, such as asthma, atopic dermatitis, coronary inflammation, and inflammatory arthritis, all of which worsen by stress. It is proposed that the pathogenesis of these diseases involve mast cell activation by local release of corticotropin-releasing hormone (CRH) or related peptides. Combination of CRH receptor antagonists and mast cell inhibitors may present novel therapeutic interventions.

Molecular Mechanisms for Transcriptional Regulation of Human High-Affinity IgE Receptor β-Chain Gene Induced by GM-CSF

The beta-chain of the high-affinity receptor for IgE (FcepsilonRI) plays an important role in regulating activation of FcepsilonRI-expressing cells such as mast cells in allergic reactions. We already reported that the transcription factor myeloid zinc finger (MZF) 1 which formed a high m.w. complex including four and a half LIM-only protein (FHL)3 in the nucleus repressed human beta-chain gene expression through an element in the fourth intron. We also found that GM-CSF induced expression of MZF-1 and nuclear translocation of FHL3. We screened a human cDNA library and identified NFY which was reported to bind histone deacetylases (HDACs) as a constituent of the complex. The C-subunit of NFY was demonstrated to form a ternary complex with MZF-1/FHL3 and interact with a beta-chain gene region including the element in the fourth intron. HDAC1 and HDAC2 were also shown to interact with the fourth intron region of the beta-chain gene. In a human mast cell line HMC-1 cultured with GM-CSF, both beta-chain expression and acetylation of histones interacting with the fourth intron region of the beta-chain gene were decreased. Collectively, these results indicated that HDACs, which were recruited to the beta-chain gene through the element in the fourth intron by MZF-1/FHL3/NFY, repressed beta-chain gene transcription by deacetylation of histones in the presence of GM-CSF. These mechanisms will be involved in not only the cell type-specific repression of beta-chain gene expression in differentiating hemopoietic cells but also the repression of beta-chain gene expression in the peripheral cells under specific circumstances.

Interleukin-10-Secreting regulatory T cells in allergy and asthma

Allergic diseases, including asthma, are chronic inflammatory disorders originating from an aberrant immune response to innocuous antigens in our environment (allergens). In susceptible individuals, sensitization to allergen leads to the induction of allergen-specific T-helper type 2 (Th2) responses and immunoglobulin E (IgE) production. Subsequent challenge with allergen results in IgE-mediated mast cell activation and the recruitment and activation of effector cells, leading to clinical symptoms of disease. In this review, we discuss evidence that the anti-inflammatory cytokine interleukin-10 (IL-10) offers therapeutic promise for the control of asthma and allergy. We highlight the potential role of IL-10 secretion by a specialized T-cell subset, T regulatory cells, to prevent allergic inflammation in healthy individuals and to provide long-term relief from disease symptoms in allergic patients.

Detection of novel leukocyte differentiation antigens on basophils and mast cells by HLDA8 antibodies

Basophils (BA) and mast cells (MC) are important effector cells in allergic reactions. Development, growth and effector cell functions are regulated by a network of cytokines, other ligands, and respective cell surface antigens. We examined the expression of novel CD antigens on human BA, lung MC, the BA cell line KU-812, and the MC line HMC-1. Expression of surface antigens was analyzed by monoclonal antibodies (mAb) of the HLDA8 workshop and flow cytometry. Basophils were found to stain positive for CXCR1 (CD181), CCR1 (CD191), CCR2 (CD192), CCR7 (CD197), IL-18Ralpha (CDw218a), IL-18Rbeta (CDw218b), TRAIL-R1 (CD261), TRAIL-R2 (CD262), TACI (CD267), TLR-4 (CD284), LAIR1 (CD305), EMR-2 (CD312), JAM1 (CD321), and JAM2 (CD322). Lung MC were found to react with mAb against EMR-2 (CD312) and JAM1 (CD321). KU-812 cells were found to stain positive for CXCR1 (CD181), TRAIL-R2 (CD262), B7H2 (CD275), TLR-4 (CD284), JAM1 (CD321), and E-Cadherin (CD324). HMC-1 cells were recognized by mAb against TRAIL-R2 (CD262), B7H2 (CD275), LAIR1 (CD305), EMR-2 (CD312), JAM1 (CD321), and Siglec-6 (CDw327). Extensive phenotyping with antibodies against novel CD antigens provides further evidence that BA and MC represent two separate hematopoietic cell lineages with unique phenotypic properties observed in mature cells as well as malignant immature cells. Further studies are required to define the functional role of these CD antigens expressed in BA and MC.

Continuing Medical Education examination: T regulatory cells in allergy: Novel concepts in the pathogenesis, prevention, and treatment of allergic diseases

Continuing Medical Education examination: T regulatory cells in allergy: Novel concepts in the pathogenesis, prevention, and treatment of allergic diseases

T regulatory cells in allergy: Novel concepts in the pathogenesis, prevention, and treatment of allergic diseases

The identification of T regulatory (T(Reg)) cells as key regulators of immunologic processes in peripheral tolerance to allergens has opened an important era in the prevention and treatment of allergic diseases. Both naturally occurring CD4(+)CD25(+) T(Reg) cells and inducible populations of allergen-specific IL-10-secreting T(R)1 cells inhibit allergen-specific effector cells in experimental models. Allergen-specific T(Reg) cell responses contribute to the control of allergic inflammation in several ways. Skewing of allergen-specific effector T cells to a T(Reg) phenotype appears to be a crucial event in the development of a healthy immune response to allergens and successful outcome in allergen-specific immunotherapy. The increased levels of IL-10 and TGF-beta produced by T(Reg) cells can potently suppress IgE production while simultaneously increasing the production of the noninflammatory antibody isotypes IgG4 and IgA, respectively. T(Reg) cells directly or indirectly suppress effector cells of allergic inflammation, such as mast cells, basophils, and eosinophils, and contribute to remodeling in asthma and atopic dermatitis. In addition, mediators of allergic inflammation that trigger cyclic AMP-associated G protein-coupled receptors, such as histamine receptor 2, might play a role in peripheral tolerance mechanisms against allergens. Current strategies for drug development and allergen-specific immunotherapy exploit these observations with the potential to provide cure for allergic diseases.

Suppression of eosinophilic airway inflammation by treatment with α‐galactosylceramide

To clarify the essential role of NKT cells in allergy, we investigated the contribution of NKT cells to the pathogenesis of eosinophilic airway inflammation using alpha-galactosylceramide (alpha-GalCer), a selective ligand for NKT cells. Although continuous administration of alpha-GalCer during ovalbumin (OVA) sensitization increased OVA-specific IgE levels and worsened eosinophil inflammation, a single administration of alpha-GalCer at the time of OVA challenge completely prevented eosinophilic infiltration in wild-type mice. This inhibitory effect of alpha-GalCer was associated with a decrease in airway hyperresponsiveness, an increase in IFN-gamma, and decreases in IL-4, IL-5 and IL-13 levels in the bronchoalveolar lavage fluids. Analysis of lung lymphocytes revealed that production of IFN-gamma increased in NK cells, but not in T or NKT cells, following alpha-GalCer administration. Induction of vascular cell adhesion molecule-1 in the lungs of wild-type mice was also significantly attenuated by treatment with alpha-GalCer. These effects of alpha-GalCer were abrogated in J alpha281-/- mice, which lack NKT cells, and in wild-type mice treated with anti-IFN-gamma Ab. Hence, our data indicate that alpha-GalCer suppresses allergen-induced eosinophilic airway inflammation, possibly by inducing a Th1 bias that results in inhibition of eosinophil adhesion to the lung vessels.

Mast Cell Survival and Activation by IgE in the Absence of Antigen: A Consideration of the Biologic Mechanisms and Relevance

Mast cells are not only major effector cells in allergy and host defense against parasites and bacteria but also important cellular components in other immune responses. Recent studies on the effects of monomeric IgE on mast cell survival and activation have made an impact on our view of the IgE binding to its high-affinity receptors, Fc epsilonRI. Traditionally, IgE binding to Fc epsilonRI has been considered as a passive action of "sensitization" before receptor aggregation by Ag. However, recent studies indicate that at high concentrations some monoclonal IgEs have effects on mast cells similar to or identical to those induced by IgE+Ag stimulation. These effects may be due to induction of Fc epsilonRI aggregation by these IgEs in the absence of Ag. This review will synthesize recent findings of the heterogeneity of IgEs in their ability to induce survival and activation events, their mechanisms, the potential in vivo significance of IgE-Fc epsilonRI interactions, and the implications of the mouse studies to human diseases.

Mast cells and eosinophils: A novel link between inflammation and angiogenesis in allergic diseases

Mast cells and eosinophils are the key cells in the early and late stages of allergic inflammation. There is increasing evidence that angiogenesis plays an important role both in the development of inflammation and in the pathophysiology of tissue remodeling during allergic disorders. In this review we provide recent data showing a link between allergy and angiogenesis and some possible mechanisms through which vascular endothelial growth factor and the immune system can interact. We discuss the multifaceted roles of mast cells and eosinophils in tissue remodeling and angiogenesis during allergic diseases and whether these cells can be both source and target cells for pro-angiogenic mediators.

Bronchial Epithelial Cells in Allergic Reactions

Bronchial epithelial cells (BEC) are known to play an integral role in the airway defense mechanism via mucociliary system as well as mechanical barriers. Recent studies further indicate that BEC produce and release biologically active compounds including lipid mediators, growth factors, endothelin and a variety of cytokines/chemokines important in the pathogenesis of airway disorders. Cytokines and chemokines produced by BEC include IL-6, IL-8, G-CSF, GM-CSF, RANTES, eotaxin and TARC. Pro-inflammatory cytokines IL-1 and TNF-alpha, generally upregulate expression and release these cytokines/chemokines. BEC from patients with bronchial asthma showed increased levels of mRNA for these potent inflammatory peptides. BEC also interact with immune and inflammatory cells by direct adhesion as well as by humoral factors including cytokines. For example, eosinophil adhesion to BEC may be an important signal for the activation and degranulation of eosinophils. BEC is also believed to take part in the airway mucosal immunity via Toll-like receptors. Finally, BEC may play a crucial role in the processes of airway remodeling by cross-talk with mesenchymal cells. These findings strongly suggest that BEC are actively involved as regulators of allergic inflammatory responses, and become a target for therapeutic intervention.

Does allo‐immune reactivity play a role in the prenatal programming of childhood allergy?

Does allo‐immune reactivity play a role in the prenatal programming of childhood allergy?

Potential role of interleukin-10-secreting regulatory T cells in allergy and asthma

Allergic diseases are caused by aberrant T-helper-2 immune responses in susceptible individuals. Both naturally occurring CD4(+)CD25(+) regulatory T cells and inducible populations of antigen-specific interleukin-10-secreting regulatory T cells inhibit these inappropriate immune responses in experimental models. This article discusses the evidence that regulatory T-cell function might be impaired in allergic and asthmatic disease and that certain therapeutic regimens might function, at least in part, to promote regulatory T-cell generation. Current research strategies seek to exploit these observations to improve the generation of allergen-specific regulatory T-cell populations with the potential to provide the safe and long-term alleviation of disease symptoms.

Role of regulatory dendritic cells in allergy and asthma

Dendritic cells (DCs) are the most efficient inducers of all immune responses, and are capable of either inducing productive immunity or maintaining the state of tolerance to self antigens and allergens. In this review, we summarize the emerging literature on DCs, with emphasis on the regulatory function of DCs in allergy and asthma. In particular, we summarize recent data regarding the relationship between DC subsets and TH1, TH2, and regulatory T (TReg) cells. The diverse functions of DCs have been attributed to distinct lineages of DCs, which arise from common immature precursor cells that differentiate in response to specific maturation-inducing or local microenvironment conditions. These subsets of DCs induce different lineages of T cells, such as TH1, TH2, and TReg cells, including Th1Reg and Th2Reg cells, which regulate allergic diseases and asthma. Subsets of DCs regulate the induction of a variety of T-cell subtypes, which suppress the development of allergy and asthma, thus providing anti-inflammatory responses and protective immunity.

Role of regulatory dendritic cells in allergy and asthma

Dendritic cells are the most efficient inducers of all immune responses, and are capable of inducing either productive immunity or maintaining the state of tolerance to self-antigens and allergens. The present review summarizes the emerging literature on dendritic cells, with the emphasis on regulatory function of dendritic cells in allergy and asthma. In particular we summarize recent data regarding the relationship between dendritic cell subsets and Th1, Th2 and regulatory T (TReg) cells. The diverse functions of dendritic cells have been attributed to distinct lineages of dendritic cells, which arise from common immature precursor cells that differentiate in response to specific maturation-inducing or local microenvironment conditions. These subsets induce different lineages of T cells such as Th1, Th2 and TReg cells, including Th1Reg and Th2Reg cells, which regulate allergic diseases and asthma. Subsets of dendritic cells regulate the induction of a variety of T-cell subtypes, which suppress the development of allergy and asthma, thus providing antiinflammatory responses and protective immunity.

Rodent and Human Mast Cells Produce Functionally Significant Intracellular Reactive Oxygen Species but Not Nitric Oxide

In immunity, reactive oxygen species (ROS) and nitric oxide (NO) are important antimicrobial agents and regulators of cell signaling and activation pathways. However, the cellular sources of ROS and NO are much debated. Particularly, there is contention over whether mast cells, key secretory cells in allergy and immunity, can generate these chemical species, and if so, whether they are of functional significance. We therefore examined directly by flow cytometry the capacity of mast cells to generate intracellular ROS and NO using the respective cell-permeable fluorescent probes dichlorodihydrofluorescein and diaminofluorescein and evaluated the effects of inhibitors of ROS and NO synthesis on cell degranulation. For each of three mast cell types (rat peritoneal mast cells, mouse bone marrow-derived mast cells, and human blood-derived mast cells), degranulation stimulated by IgE/antigen was accompanied by production of intracellular ROS but not NO. Inhibition of ROS production led to reduced degranulation, indicating a facilitatory role for ROS, whereas NO synthase inhibitors were without effect. Likewise, bacterial lipopolysaccharide and interferon-gamma over a wide range of conditions failed to generate intracellular NO in mast cells, whereas these agents readily induced intracellular NO in macrophages. NO synthase protein, as assessed by Western blotting, was readily induced in macrophages but not mast cells. We conclude that rodent and human mast cells generate intracellular ROS but not NO and that intracellular ROS but not intracellular NO are functionally linked to mast cell degranulation.