The mast cell IgG receptors and their roles in tissue inflammation

Summary:  Mast cells are effector cells of the innate immune system, but because they express Fc receptors (FcRs), they can be engaged in adaptive immunity by antibodies. Mast cell FcRs include immunoglobulin E (IgE) and IgG receptors and, among these, activating and inhibitory receptors. The engagement of mast cell IgG receptors by immune complexes may or may not trigger cell activation, depending on the type of mast cell. The coengagement of IgG and IgE receptors results in inhibition of mast cell activation. The Src homology-2 domain-containing inositol 5-phosphatase-1 is a major effector of negative regulation. Biological responses of mast cells depend on the balance between positive and negative signals that are generated in FcR complexes. The contribution of human mast cell IgG receptors in allergies remains to be clarified. Increasing evidence indicates that mast cells play critical roles in IgG-dependent tissue-specific autoimmune diseases. Convincing evidence was obtained in murine models of multiple sclerosis, rheumatoid arthritis, bullous pemphigoid, and glomerulonephritis. In these models, the intensity of lesions depended on the relative engagement of activating and inhibitory IgG receptors. In vitro models of mature tissue-specific murine mast cells are needed to investigate the roles of mast cells in these diseases. One such model unraveled unique differentiation/maturation-dependent biological responses of serosal-type mast cells.     

Proximal signaling events in Fc epsilon RI-mediated mast cell activation

Mast cells are central mediators of allergic diseases. Their involvement in allergic reactions is largely dependent on activation through the specific receptor for IgE (Fc epsilon RI). Cross-linking of Fc epsilon RI on mast cells initiates a cascade of signaling events that eventually results in degranulation, cytokine/chemokine production, and leukotriene release, contributing to allergic symptomology. Because of the importance of IgE in allergy, much focus has been placed on deciphering the signaling events that take place downstream of Fc epsilon RI. Studies have identified spleen tyrosine kinase as a key proximal regulator of Fc epsilon RI-mediated signaling. In this review, we discuss the multiple pathways that diverge from spleen tyrosine kinase with emphasis on the role of adapter molecules to orchestrate these signaling events. Understanding the molecular mechanisms underlying mast cell activation ideally will provide insights into the development of novel therapeutics to control allergic disease.     

Human mast cell proteases and mast cell heterogeneity

Mast cell neutral proteases are distinctive markers of the MC(T) and MC(TC) cells in humans. Measurements of tryptase levels in vivo serve as an overall indicator of mast cell activity. Further research is needed to evaluate the functional role of these proteases as well as each mast cell type in situations related to both health and disease.     

Biomarkers for evaluation of mast cell and basophil activation

Mast cells and basophils play a pathogenetic role in allergic, inflammatory, and autoimmune disorders. These cells have different development, anatomical location and life span but share many similarities in mechanisms of activation and type of mediators. Mediators secreted by mast cells and basophils correlate with clinical severity in asthma, chronic urticaria, anaphylaxis, and other diseases. Therefore, effective biomarkers to measure mast cell and basophil activation in vivo could potentially have high diagnostic and prognostic values. An ideal biomarker should be specific for mast cells or basophils, easily and reproducibly detectable in blood or biological fluids and should be metabolically stable. Markers of mast cell and basophil include molecules secreted by stimulated cells and surface molecules expressed upon activation. Some markers, such as histamine and lipid mediators are common to mast cells and basophils whereas others, such as tryptase and other proteases, are relatively specific for mast cells. The best surface markers of activation expressed on mast cells and basophils are CD63 and CD203. While these mediators and surface molecules have been associated to a variety of diseases, none of them fulfills requirements for an optimal biomarker and search for better indicators of mast cell/basophil activation in vivo is ongoing.     

Development, migration, and survival of mast cells

Mast cells play a pivotal role in immediate hypersensitivity and chronic allergic reactions that can contribute to asthma, atopic dermatitis, and other allergic diseases. Because mast cell numbers are increased at sites of inflammation in allergic diseases, pharmacologic intervention into the proliferation, migration, and survival (or apoptosis) of mast cells could be a promising strategy for the management of allergic diseases. Mast cells differentiate from multipotent hematopoietic progenitors in the bone marrow. Stem cell factor (SCF) is a major chemotactic factor for mast cells and their progenitors. SCF also elicits cell-cell and cell-substratum adhesion, facilitates the proliferation, and sustains the survival, differentiation, and maturation, of mast cells. Therefore, many aspects of mast cell biology can be understood as interactions of mast cells and their precursors with SCF and factors that modulate their responses to SCF and its signaling pathways. Numerous factors known to have such a capacity include cytokines that are secreted from activated T cells and other immune cells including mast cells themselves. Recent studies also demonstrated that monomeric IgE binding to FcωRI can enhance mast-cell survival. In this review we discuss the factors that regulate mast cell development, migration, and survival.     

Transcriptional regulation of mast cell and basophil lineage commitment

Basophils and mast cells have long been known to play critical roles in allergic disease and in immunity against parasitic infection. Accumulated evidence also supports that basophils and mast cells have important roles in immune regulations, host defense against bacteria and viruses, and autoimmune diseases. However, origin and molecular regulation of basophil and mast cell differentiation remain incompletely understood. In this review, we focus on recent advances in the understanding of origin and molecular regulation of mouse and human basophil and mast cell development. A more complete understanding of how basophils and mast cells develop at the molecular level will lead to development of interventions that are more effective in achieving long-term success.     

Stereological quantification of mast cells in human synovium

Mast cells participate in both the acute allergic reaction as well as in chronic inflammatory diseases. Earlier studies have revealed divergent results regarding the quantification of mast cells in the human synovium. The aim of the present study was therefore to quantify these cells in the human synovium, using stereological techniques. Different methods of staining and quantification have previously been used for mast cell quantification in human synovium. Stereological techniques provide precise and unbiased information on the number of cell profiles in two-dimensional tissue sections of, in this case, human synovium. In 10 patients suffering from osteoarthritis a median of 3.6 mast cells/mm2 synovial membrane was found. The total number of cells (synoviocytes, fibroblasts, lymphocytes, leukocytes) present was 395.9 cells/mm2 (median). The mast cells constituted 0.8% of all the cell profiles present in the synovium. A significantly positive correlation was demonstrated between the number of mast cells and the total number of cells. Thus, the present study reports stereological quantification of the mast cells and the total number of cells in synovium from patients with osteoarthritis. A possible link between the mast cell and osteoarthritis is discussed upon obtaining a precise estimate of cell profiles in human synovium.     

Allergy therapy: the therapeutic potential of targeting sphingosine kinase signalling in mast cells

Mast cell activation is a central event in allergic diseases, and investigating the signalling pathways triggered during mast cell activation may lead to the discovery of novel therapeutic targets. Mast cells can be activated by a multitude of stimuli including antibodies/antigen, cytokines/chemokines and neuropeptides, resulting in a variety of responses including the immediate release of potent inflammatory mediators. Moreover, recent data suggest that mast cell-mediated responses are also influenced by the differential sphingolipids/sphingosine to sphingosine-1-phosphate ratio. The importance of sphingolipids as potent biological mediators of both intracellular and extracellular responses is being increasingly recognized and accepted; it is now appreciated that activation of mast cells, via the high-affinity IgE-receptor (FcepsilonRI) leads to the activation of sphingosine kinases (SphK), resulting in increased formation of sphingosine-1-phosphate. Furthermore, FcepsilonRI activates SphK-dependent calcium mobilization in mast cells, leading to degranulation, cytokine, and eicosanoid production, and chemotaxis. In the past two years a critical role for SphK in allergic responses in vivo has emerged. In this review, I focus on the current understanding of the role of sphingosine kinases during mast cell signalling in vitro and their role during hypersensitivity responses in vivo, and discuss the potential of these enzymes as novel therapeutic targets to treat allergic diseases.     

Listeria monocytogenes induces mast cell extracellular traps

Mast cells play an essential role in different immunological phenomena including allergy and infectious diseases. Several bacteria induce mast cell activation leading to degranulation and the production of several cytokines and chemokines. However, mast cells also have different microbicidal activities such as phagocytosis and the release of DNA with embedded granular proteins known as Mast Cell Extracellular Traps (MCETs). Although previous reports indicate that extracellular bacteria are able to induce MCETs little is known if intracellular bacteria can induce these structures. In this work, we evaluated MCETs induction by the intracellular bacteria Listeria monocytogenes. We found that mast cells released DNA after stimulation with L. monocytogenes, and this DNA was complexed to histone and tryptase. Before extracellular DNA release, L. monocytogenes induced modifications to the mast cell nuclear envelope and DNA was detected outside the nucleus. L. monocytogenes stimulated mast cells to produce significant amounts of reactive oxygen species (ROS) and blocking NADPH oxidase diminished DNA release by mast cells. Finally, MCETs showed antimicrobial activity against L. monocytogenes that was partially blocked when β-hexosaminidase activity was inhibited. These results show that L. monocytogenes induces mast cells to produce microbicidal MCETs, suggesting a role for mast cells in containing infection beyond the induction of inflammation.     

Increased numbers of activated mast cells in endometriosis lesions positive for corticotropin-releasing hormone and urocortin

PROBLEM: Mast cells are critical in allergic and inflammatory diseases such as interstitial cystitis, which is often clinically associated with or mistaken as endometriosis. Mast cells had previously been reported to be increased at sites of endometriosis, and tryptase may contribute to the fibrosis and inflammation characterizing endometriosis. METHOD OF STUDY: This is a pilot study of mast cell numbers and its activation in endometriosis biopsies (n = 10) by immunostaining for mast cell tryptase, corticotropin-releasing hormone (CRH) and urocortin (Ucn). RESULTS: This is the first report that tryptase positive mast cells were not only increased (64-157 mast cells/mm(2)) in human endometriosis, but also highly activated (89%) in areas strongly stained positive for CRH/Ucn. Normal endometrium was weakly positive for both CRH/Ucn. CONCLUSION: High numbers of activated mast cells are present in endometriosis sites that were strongly positive for CRH/Ucn. CRH and Ucn may activate mast cells and contribute to the fibrosis and inflammation in endometriosis.     

Mast cell infiltrates in vulvodynia represent secondary and idiopathic mast cell hyperplasias

Mast cell infiltrates in tissues of vulvodynia are common, but they have not been characterized for criteria of neoplastic mast cell disease or correlated with patient's concomitant diseases associated with increased mast cells. Formalin‐fixed specimens of 35 patients with vulvodynia were evaluated immunohistochemically with antibodies to CD 3,4,8,20,117c and human mast cell tryptase, and for WHO‐criteria of neoplastic mastocytosis (>25% spindled mast cell, CD25 expression, point mutations of the c‐kit gene (D816V), and chronically elevated serum tryptase levels). Only 20/35 specimens showed a T‐lymphocyte dominant inflammatory infiltrate on HE‐stained sections, but all showed mast cells. 4/35 biopsies showed <10 mast cells/mm², 15/35 specimens 40–60 mast cells/mm² and 16/35 specimens >60 mast cells/mm² (average 80/mm²). Control tissue contained typically <10 mast cells/mm². Spindling, CD25‐expression, c‐kit gene mutations, or increased serum tryptase levels were not detected. 26/35 (74%) patients had concomitant autoimmune diseases, psoriasis, atopy, various allergies, preceding infections. Independent of the subtype of vulvodynia, the majority of mast cell rich biopsies with >40 mast cells/mm² were classified as a secondary mast cell disorder reflecting an activated immune system in 75% of vulvodynia patients. Patients with increased mast cells may benefit from medical therapy targeting mast cells.     

Differential release of mast cell mediators and the pathogenesis of inflammation

Summary:  Mast cells are well known for their involvement in allergic and anaphylactic reactions, during which immunoglobulin E (IgE) receptor (FcɛRI) aggregation leads to exocytosis of the content of secretory granules (1000 nm), commonly known as degranulation, and secretion of multiple mediators. Recent findings implicate mast cells also in inflammatory diseases, such as multiple sclerosis, where mast cells appear to be intact by light microscopy. Mast cells can be activated by bacterial or viral antigens, cytokines, growth factors, and hormones, leading to differential release of distinct mediators without degranulation. This process appears to involve de novo synthesis of mediators, such as interleukin-6 and vascular endothelial growth factor, with release through secretory vesicles (50 nm), similar to those in synaptic transmission. Moreover, the signal transduction steps necessary for this process appear to be largely distinct from those known in FcɛRI-dependent degranulation. How these differential mast cell responses are controlled is still unresolved. No clinically available pharmacological agents can inhibit either degranulation or mast cell mediator release. Understanding this process could help develop mast cell inhibitors of selective mediator release with novel therapeutic applications.     

The role of the mast cell in the pathophysiology of asthma

There is compelling evidence that human mast cells contribute to the pathophysiology of asthma. Mast cells, but not T cells or eosinophils, localize within the bronchial smooth muscle bundles in patients with asthma but not in normal subjects or those with eosinophilic bronchitis, a factor likely to be important in determining the asthmatic phenotype. The mechanism of mast cell recruitment by asthmatic airway smooth muscle involves the CXCL10/CXCR3 axis, and several mast cell mediators have profound effects on airway smooth muscle function. The autacoids are established as potent bronchoconstrictors, whereas the proteases tryptase and chymase are being demonstrated to have a range of actions consistent with key roles in inflammation, tissue remodeling, and bronchial hyperresponsiveness. IL-4 and IL-13, known mast cell products, also induce bronchial hyperresponsiveness in the mouse independent of the inflammatory response and enhance the magnitude of agonist-induced intracellular Ca2+ responses in cultured human airway smooth muscle. There are therefore many pathways by which the close approximation of mast cells with airway smooth muscle cells might lead to disordered airway smooth muscle function. Mast cells also infiltrate the airway mucous glands in subjects with asthma, showing features of degranulation, and a positive correlation with the degree of mucus obstructing the airway lumen, suggesting that mast cells play an important role in regulating mucous gland secretion. The development of potent and specific inhibitors of mast cell secretion, which remain active when administered long-term to asthmatic airways, should offer a novel approach to the treatment of asthma.     

Roles and relevance of mast cells in infection and vaccination

In addition to their well-established role in allergy mast cells have been described as contributing to functional regulation of both innate and adaptive immune responses in host defense.Mast cells are of hematopoietic origin but typically complete their differentiation in tissues where they express immune regulatory functions by releasing diverse mediators and cytokines.Mast cells are abundant at mucosal tissues which are portals of entry for common infectious agents in addition to allergens.Here,we review the current understanding of the participation of mast cells in defense against infection.We also discuss possibilities of exploiting mast cell activation to provide adequate adjuvant activity that is needed in high-quality vaccination against infectious diseases.     

Effects of eosinophils on mast cells: a new pathway for the perpetuation of allergic inflammation

Mast cells have a clear-cut pathologic role in allergy, participating in a number of chronic inflammatory conditions, in helmintic parasitosis, and in some solid tumor reactions, but also in physiological situations, such as wound healing and innate immunity. Mast cells release a large number of proinflammatory, immunoregulatory, and tissue regulatory mediators after activation induced by either IgE-dependent or IgE-independent mechanisms. While much information has been gathered on the immunological mast cell activation both in rodent and human systems, only minimal knowledge exists on the non-immunological activation especially in human mast cells. Mast cell IgE-independent activation occurs through G(i3alpha) which has been identified as the pertussis toxin (Ptx)-sensitive heterotrimeric G protein that interacts with cationic secretagogues inducing PLC-independent mast cell exocytosis. Mast cell IgE-independent activation in allergy probably occurs when mast cells encounter eosinophils, the main inflammatory cells of the allergic reactions that persist throughout the late phase and when the inflammatory condition becomes chronic. This review summarizes regarding the influence of eosinophils on mast cell activation, thus demonstrating that IgE-independent activation has a relevant role in pathophysiological processes as well as in mast cell IgE-dependent activation.     

肥大细胞的存活和凋亡

肥大细胞不仅参与过敏性炎症反应,而且在许多慢性炎症性疾病和天然免疫中也起着相当的作用.在正常情况下肥大细胞在组织中保持恒定的数量,在哮喘及慢性炎症的损伤修复阶段可以观察到肥大细胞数量增加.本文就肥大细胞存活和凋亡的因素调节机制作一综述.     

Suppression of mast cell activation by glucocorticoid

Mast cells play a critical role in allergic diseases. When mast cells are activated by cross-linking of their high affinity IgE receptors by the antigen and IgE antibodies, release of chemical mediators is followed by secretion of multiple cytokines. We report that IL-3-dependent mucosal-type mast cells undergo apoptosis when IL-3 is withdrawn. In addition, cross-linking of high affinity IgE receptors prevents apoptosis of mast cells by paracrine mechanisms, producing IL-3, IL-4 and granulocyte/macrophage colony-stimulating factor (GM-CSF). However, the secretion of endogenous growth factors are not enough for cell survival, whereas IL-4 induces cell aggregation by expressing adhesion molecules such as leukocyte function-associated antigen 1 (LFA-1), and makes it reactive to endogenous growth factors by contact cell to cell interaction. On the other hand, dexamethazone down-regulates the expression of intracelluar adhesion molecule 1 (ICAM-1) and IL-4 in activated mast cells, by which the self-aggregation of mast cells is inhibited and apoptosis is induced. Thus, glucocorticoids suppress mast cell survival by inhibiting IL-4 production and expression of adhesion molecules.