Mast Cells In Disease Research Articles

Mast Cells as a Double Edged Sword in Immunity: Disorders of Mast Cell Activation and Therapeutic Management. Second of Two Parts.

Mast cells (MCs) bear many receptors that allow them to respond to a variety of exogenous and endogenous stimuli. However, MC function is dual since they can initiate pathological events or protect the host against infectious challenges. The role of MCs in disease will be analyzed in a broad sense, describing cellular and molecular mechanisms related to their involvement in auto-inflammatory diseases, asthma, autoimmune diseases and cancer. On the other hand, their protective role in the course of bacterial, fungal and parasitic infections will also be illustrated. As far as treatment of MC-derived diseases is concerned, allergen immunotherapy as well as other attempts to reduce MC-activation will be outlined according to the recent data. Finally, in agreement with current literature and our own data polyphenols have been demonstrated to attenuate type I allergic reactions and contact dermatitis in response to nickel. The use of polyphenols in these diseases will be discussed also in view of MC involvement.

The emerging role of mast cells in liver disease.

The depth of our knowledge regarding mast cells has widened exponentially in the last 20 years. Once thought to be only important for allergy-mediated events, mast cells are now recognized to be important regulators of a number of pathological processes. The revelation that mast cells can influence organs, tissues, and cells has increased interest in mast cell research during liver disease. The purpose of this review is to refresh the reader's knowledge of the development, type, and location of mast cells and to review recent work that demonstrates the role of hepatic mast cells during diseased states. This review focuses primarily on liver diseases and mast cells during autoimmune disease, hepatitis, fatty liver disease, liver cancer, and aging in the liver. Overall, these studies demonstrate the potential role of mast cells in disease progression.

Proteome analysis of mast cell releasates reveals a role for chymase in the regulation of coagulation factor XIIIA levels via proteolytic degradation

Mast cells are significantly involved in IgE-mediated allergic reactions; however, their roles in health and disease are incompletely understood. We aimed to define the proteome contained in mast cell releasates on activation to better understand the factors secreted by mast cells that are relevant to the contribution of mast cells in diseases. Bone marrow-derived cultured mast cells (BMCMCs) and peritoneal cell-derived mast cells were used as "surrogates" for mucosal and connective tissue mast cells, respectively, and their releasate proteomes were analyzed by mass spectrometry. Our studies showed that BMCMCs and peritoneal cell-derived mast cells produced substantially different releasates following IgE-mediated activation. Moreover, we observed that the transglutaminase coagulation factor XIIIA (FXIIIA) was one of the most abundant proteins contained in the BMCMC releasates. Mast cell-deficient mice exhibited increased FXIIIA plasma and activity levels as well as reduced bleeding times, indicating that mast cells are more efficient in their ability to downregulate FXIIIA than in contributing to its amounts and functions in homeostatic conditions. We found that human chymase and mouse mast cell protease-4 (the mouse homologue of human chymase) had the ability to reduce FXIIIA levels and function via proteolytic degradation. Moreover, we found that chymase deficiency led to increased FXIIIA amounts and activity, as well as reduced bleeding times in homeostatic conditions and during sepsis. Our study indicates that the mast cell protease content can shape its releasate proteome. Moreover, we found that chymase plays an important role in the regulation of FXIIIA via proteolytic degradation.

Induction of mast cell apoptosis by a novel secretory granule-mediated pathway.

Mast cells (MCs) have detrimental functions in the context of numerous pathologies, and regimens aimed at neutralizing MCs or individual MC products can thus be of therapeutic value. One way to target MCs in disease is to selectively induce MC apoptosis, but there is so far no agent available that selectively induces apoptosis in MCs. Mast cells are heavily loaded with secretory granules containing large amounts of fully active proteases bound to serglycin proteoglycan. Damage to the secretory granules will thus lead to the release of serglycin-protease complexes into the cytosol. A potential consequence of this would be that the unleashed granular proteases cause apoptosis by proteolytic activation of proapoptotic compounds located in the cytosol. Indeed, we have recently found that MCs are highly sensitive to apoptosis induced by permeabilization of the secretory granules. In this chapter, we describe the methods used to study MC apoptosis induced by this novel, secretory granule-mediated pathway.

The essential role of mast cells in orchestrating inflammation

The essential role of mast cells in orchestrating inflammation

Mast cell CD30 ligand is upregulated in cutaneous inflammation and mediates degranulation-independent chemokine secretion

Mast cells are involved in many disorders where the triggering mechanism that leads to degranulation and/or cytokine secretion has not been defined. Several chronic inflammatory diseases are associated with increased mast cell numbers and upregulation of the TNF receptor family member CD30, but the role of elevated CD30 expression is poorly understood. Here we report what we believe to be a novel way to activate mast cells with CD30 that leads to degranulation-independent secretion of chemokines. CD30 induced a de novo synthesis and secretion of the chemokines IL-8, macrophage inflammatory protein-1alpha (MIP-1alpha), and MIP-1beta, a process involving the MAPK/ERK pathway. Mast cells were found to be the predominant CD30 ligand-positive (CD30L-positive) cell in the chronic inflammatory skin diseases psoriasis and atopic dermatitis, and both CD30 and CD30L expression were upregulated in lesional skin in these conditions. Furthermore, the number of IL-8-positive mast cells was elevated both in psoriatic and atopic dermatitis lesional skin as well as in ex vivo CD30-treated healthy skin organ cultures. In summary, characterization of CD30 activation of mast cells has uncovered an IgE-independent pathway that is of importance in understanding the entirety of the role of mast cells in diseases associated with mast cells and CD30 expression. These diseases include Hodgkin lymphoma, atopic dermatitis, and psoriasis.

Specific differences in the cytokine/receptor expression pattern of Crohn's disease mast cells and mast cells from normal mucosa

Specific differences in the cytokine/receptor expression pattern of Crohn's disease mast cells and mast cells from normal mucosa

Resting and activation-dependent ion channels in human mast cells.

The mechanism of mediator secretion from mast cells in disease is likely to include modulation of ion channel activity. Several distinct Ca(2+), K(+), and Cl(-) conductances have been identified in rodent mast cells, but there are no data on human mast cells. We have used the whole-cell variant of the patch clamp technique to characterize for the first time macroscopic ion currents in purified human lung mast cells and human peripheral blood-derived mast cells at rest and following IgE-dependent activation. The majority of both mast cell types were electrically silent at rest with a resting membrane potential of around 0 mV. Following IgE-dependent activation, >90% of human peripheral blood-derived mast cells responded within 2 min with the development of a Ca(2+)-activated K(+) current exhibiting weak inward rectification, which polarized the cells to around -40 mV and a smaller outwardly rectifying Ca(2+)-independent Cl(-) conductance. Human lung mast cells showed more heterogeneity in their response to anti-IgE, with Ca(2+)-activated K(+) currents and Ca(2+)-independent Cl(-) currents developing in approximately 50% of cells. In both cell types, the K(+) current was blocked reversibly by charybdotoxin, which along with its electrophysiological properties suggests it is carried by a channel similar to the intermediate conductance Ca(2+)-activated K(+) channel. Charybdotoxin did not consistently attenuate histamine or leukotriene C(4) release, indicating that the Ca(2+)-activated K(+) current may enhance, but is not essential for, the release of these mediators.

Voltage-dependent and calcium-activated ion channels in the human mast cell line HMC-1

The mechanisms underlying the recruitment, differentiation, and sustained activation of mast cells in disease are likely to include modulation of ion channels. Specific Ca(2+), K(+), and Cl(-) conductances have been identified in rodent mast cells, but there are no equivalent data on human mast cells. We have used the whole-cell patch-clamp technique to characterize macroscopic ion currents in both the human mast cell line HMC-1 and human skin mast cells (HSMCs) at rest and in HMC-1 after activation with calcium ionophore. HSMCs were electrically silent at rest. In contrast, HMC-1 expressed a strong outwardly rectifying voltage-dependent Cl(-) conductance characteristic of ClC-4 or ClC-5 and a small inwardly rectifying K(+) current not carried by the classical Kir family of K(+) channels. Calcium ionophore induced the appearance of outwardly rectifying Ca(2+)-activated Cl(-) and K(+) currents, while hypotonicity induced another outwardly rectifying conductance typical of ClC-3. Reverse transcription-PCRs confirmed that mRNAs for the voltage-dependent Cl(-) channels ClC-3 and -5 were expressed. This is the first definitive description of a ClC-4/5-like current in a native leukocyte. We suggest that this current may contribute to the malignant phenotype while the Ca(2+)-activated K(+) and Cl(-) currents may be involved in cell activation.

Human mast cells transmigrate through human umbilical vein endothelial monolayers and selectively produce IL-8 in response to stromal cell-derived factor-1 alpha.

Mature mast cells are generally considered to be less mobile cells residing within tissue sites. However, mast cell numbers are known to increase in the context of inflammation, and mast cells are recognized to be important in regulating local neutrophil infiltration. CXC chemokines may play a critical role in this process. In this study two human mast cell-like lines, HMC-1 and KU812, and human cord blood-derived primary cultured mast cells were employed to examine role of stromal cell-derived factor-1 (SDF-1) in regulating mast cell migration and mediator production. It was demonstrated that human mast cells constitutively express mRNA and protein for CXCR4. Stimulation of human mast cells with SDF-1, the only known ligand for CXCR4, induced a significant increase in intracellular calcium levels. In vitro, SDF-1 alpha mediated dose-dependent migration of human cord blood-derived mast cells and HMC-1 cells across HUVEC monolayers. Although SDF-1 alpha did not induce mast cell degranulation, it selectively stimulated production of the neutrophil chemoattractant IL-8 without affecting TNF-alpha, IL-1beta, IL-6, GM-CSF, IFN-gamma, or RANTES production, providing further evidence of the selective modulation of mast cell function by this chemokine. These findings provide a novel, SDF-1-dependent mechanism for mast cell transendothelial migration and functional regulation, which may have important implications for the local regulation of mast cells in disease.

Mast cells in granulomatous liver disease

Mast cells are known to be present in normal liver tissue but the data on their association with diseases of the liver are limited. In this study we used a long toluidine blue technique to investigate the mast cell numbers in 20 normal and 45 diseased liver biopsies containing granulomas (20 tuberculosis, 14 sarcoidosis, 4 schistosomiasis, 4 neoplasia-associated, 3 drug idiosyncrasy). Our results show that the mast cells are regular constituents of normal portal tracts and the amount of mast cells in the diseased samples corresponds to the area occupied by non-parenchymal tissues. As compared to normal controls, significantly less mast cells were present in biopsies from tuberculosis patients (p less than 0.025). Highest numbers were found in the schistosomiasis group. No link between the mast cell numbers and the cause of the granulomas could be demonstrated.

Mast Cell in Disease and its Pharmacologic Regulation

The factors regulating the magnitude of histamine-mediated reactions in the skin need to be elucidated if we are to devise a rational therapy for urticaria. Attempts to prevent biosynthesis of histamine in vivo have proved unrewarding. Depletion of histamine stores in skin by repeated provocation of release until a state of tolerance has been reached has proved a useful procedure in patients with cold urticaria, but because of its inconvenience it requires a high degree of motivation. Attempts to moderate histamine secretion by mast cells, for example, by drugs that increase cyclic AMP, including isoproterenol and theophylline, have not met with success. Doxantrazole, a systemically administered compound with actions resembling the better known disodium cromoglycate, has been effective in suppressing histamine release evoked by cold in patients with cold urticaria, but there has been a puzzling discrepancy between clinical response and reduction in histamine release. Rate of enzymic histamine degradation may be an important factor in determining the magnitude of histamine-mediated reactions in skin. Degradation of histamine in human skin takes place by N-methylation, catalyzed by N-methyl transferase. Blockade of histamine degradation in the guinea pig leads to amplification of the histamine-mediated passive cutaneous anaphylaxis reaction in this species. Histamine-mediated skin reactions can be modulated by blockade of vascular histamine receptors. Recently the presence of 2 sub-classes of histamine receptors, H 1 and H 2 , on human skin blood vessels, has been established. Combined treatment by classical H 1 antihistamines and H 2 antihistamines offers a possibility of more effective antihistamine treatment.

Mast cells in diseases of the skin; their relation to tissue eosinophilia.

Mast cells in diseases of the skin; their relation to tissue eosinophilia.