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Bidirectional interactions between eosinophils and mast cells (MCs) have been reported in various allergic diseases. Bone marrow (BM) eosinophilia, and to a lesser extent blood eosinophilia, is common in systemic mastocytosis (SM), but its significance remains unknown. We described blood and BM eosinophil characteristics in SM. A large collection of BM biopsy samples was analyzed using immunohistochemical staining and whole-slide imaging. Eosinophil and extracellular granules were detected by eosinophil peroxidase (EPX) staining and MCs by KIT staining. Complementary analyses were conducted using flow cytometry and immunofluorescence. Eosinophil infiltrates and large areas of eosinophil degranulation were observed within or around BM MC infiltrates in SM. EPX staining surface, highlighting intact eosinophils and eosinophil degranulation, was higher in nonadvanced SM (n = 37 BM biopsy samples) compared with both controls (n = 8, P =.0003) and advanced SM (n = 24, P =.014). In nonadvanced SM, positive correlations were observed between serum tryptase levels and percentages of eosinophil counts in BM aspirations (Spearman r coefficient r = 0.38, P =.038), eosinophils count in BM biopsy samples (r = 0.45, P =.007), EPX staining (r = 0.37, P =.035), and eosinophil degranulation (r = 0.39, P =.023). Eosinophil counts in BM biopsy samples also correlated with MC counts (r = 0.47, P =.006) and KIT staining surface (r = 0.49, P =.003). BM MCs expressed IL-5 receptor and other usual eosinophil cytokine/chemokine receptors, and blood eosinophils displayed several increased surface markers compared with controls, suggesting an activated state. Our data suggest possible cross talk between MCs and eosinophils, supporting MC tryptase release and MC activation-related symptoms. This suggests a rationale for targeting eosinophils in nonadvanced SM not fully controlled by other therapies. [ABSTRACT FROM AUTHOR]

Background: The relationship between the alarming cytokine interleukin-33 (IL-33) and lung autophagy in systemic anaphylaxis mouse models is not yet fully elucidated, hence, the current study attempts to explain the regulation of lung autophagy in systemic anaphylactic mouse models. IL-33 plays a critical role in endoplasmic reticulum (ER) stress and autophagy regulation via insulin-like growth factor-binding protein-3 (IGFBP-3). Results: The results of the present study confirmed the induction of systemic anaphylaxis in mice through the elevated mast cell mediators in the peritoneal lavage. Consequently, lung stress triggered IL-33 secretion that influenced autophagy markers; IGFBP-3, activating transcription factor-6 (ATF-6), autophagy related gene 4B (ATG4B), p62, microtubule-associated protein light chain3-II (LC3-II) as well as DNA damage-regulated autophagy modulator 1 (DRAM1). Conclusion: This research is a trial to investigate lung autophagy in compound 48/80 or ovalbumin-induced systemic anaphylaxis mouse models and pay a particular attention to the role of IL-33 in lung autophagy in such models. [ABSTRACT FROM AUTHOR]

Mast cell activation syndrome (MCAS) is a term applied to several clinical entities that have gained increased attention from patients and medical providers. Although several descriptive publications about MCAS exist, there are many gaps in knowledge, resulting in confusion about this clinical syndrome. Whether MCAS is a primary syndrome or exists as a constellation of symptoms in the context of known inflammatory, allergic, or clonal disorders associated with systemic mast cell activation is not well understood. More importantly, the underlying mechanisms and pathways that lead to mast cell activation in MCAS patients remain to be elucidated. Here we summarize the known literature, identify gaps in knowledge, and highlight research needs. Covered topics include contextualization of MCAS and MCAS-like endotypes and related diagnostic evaluations; mechanistic research; management of typical and refractory symptoms; and MCAS-specific education for patients and health care providers. [ABSTRACT FROM AUTHOR]

Mast cell degranulation plays a pivotal role in urticaria and is also an early histologic characteristic of psoriasis. However, whether the activation of mast cells contributes to psoriasis recurrence after discontinuation of interleukin (IL)-17A blockers remains unclear. To investigate the role of mast cells in ixekizumab treatment-associated urticaria (ITAUR) and assess the effect of urticaria eruption on psoriasis relapse. A retrospective analysis was performed on biopsies of patients who experienced psoriasis relapse after discontinuation of ixekizumab. Transcriptomic and histopathologic features were assessed. Patterns were compared between patients with ITAUR and nonurticaria (NUR) as well as psoriasis-like mice with mast cell activation or inactivation. Patients with ITAUR experienced early relapse compared with NUR group after treatment withdrawal. Transcriptomic and histopathologic analyses revealed that patients with ITAUR had an elevated proportion of mast cells in resolved skin. Especially, the proportion of IL-17A+ mast cells was inversely correlated with the duration of remission. The mechanism of mast cell activation in ITAUR has not been precisely elucidated. Ixekizumab treatment increases IL-17A+ mast cells in lesions of ITAUR, which is associated with early psoriasis relapse after ixekizumab withdrawal. [ABSTRACT FROM AUTHOR]

Mast cells (MCs) are tissue-resident immune cells, well-positioned at the host-environment interface for detecting external antigens and playing a critical role in mobilizing innate and adaptive immune responses. Sensory neurons are afferent neurons innervating most areas of the body but especially in the periphery, where they sense external and internal signals and relay information to the brain. The significance of MC–sensory neuron communication is now increasingly becoming recognized, especially because both cell types are in close physical proximity at the host-environment interface and around major organs of the body and produce specific mediators that can activate each other. In this review, we explore the roles of MC–sensory neuron crosstalk in allergic diseases, shedding light on how activated MCs trigger sensory neurons to initiate signaling in pruritus, shock, and potentially abdominal pain in allergy, and how activated sensory neurons regulate MCs in homeostasis and atopic dermatitis associated with contact hypersensitivity and type 2 inflammation. Throughout the review, we also discuss how these 2 sentinel cell types signal each other, potentially resulting in a positive feedback loop that can sustain inflammation. Unraveling the mysteries of MC–sensory neuron crosstalk is likely to unveil their critical roles in various disease conditions and enable the development of new therapeutic approaches to combat these maladies. [ABSTRACT FROM AUTHOR]

Background: Acupuncture, practiced for millennia, lacks a clear anatomical definition for acupoints. A prevailing theory suggests that acupoints overlap with skin areas with higher mast cell density. Skin spots stained with intravenously infused Evans blue (EB), indicative of neurogenic inflammation, have recently been posited as acupoints in rats. Objectives: To demonstrate the concordance between EB-reactive skin spots and mast cell-enriched acupoints. Methods: We employed staining and RNA-seq analysis to delineate the morphological characteristics and gene expression profiles of EB-reactive skin spots in rats. Results: EB infusion revealed a novel nodal structure on the rat skin surface, visible to the naked eye, with dimensions of approximately 1 mm in both diameter and height. Around 30 such nodes were identified on one side of the abdominal area, spaced roughly 3 mm apart, excluding the linea alba. RNA-seq analysis indicated that the gene expression patterns within these nodes markedly differed from both non-nodal skin areas and lymph nodes. Histological examination using toluidine blue revealed a significantly greater mast cell count in the nodes than in non-nodal skin regions. Additionally, the nodes stained positively with Alcian blue and Hemacolor, reagents known to mark primo vascular tissues. Conclusion: Our findings suggest that EB-reactive nodes are indeed rich in mast cells. Further research is warranted to establish these skin nodes as surface primo nodes. [ABSTRACT FROM AUTHOR]

Type I hypersensitivity is triggered by mast cell degranulation, a stimulus-induced exocytosis of preformed secretory granules (SGs) containing various inflammatory mediators. The degree of degranulation is generally expressed as a percentage of secretory granule markers (such as β-hexosaminidase and histamine) released into the external solution, and considerable time and labor are required for the quantification of markers in both the supernatants and cell lysates. In this study, we developed a simple fluorimetry-based degranulation assay using rat basophilic leukemia (RBL-2H3) mast cells. During degranulation, the styryl dye FM1-43 in the external solution fluorescently labeled the newly exocytosed SGs, whose increase in intensity was successively measured using a fluorescence microplate reader. In addition to the rate of β-hexosaminidase secretion, the cellular FM1-43 intensity successfully represented the degree and kinetics of degranulation under various conditions, suggesting that this method facilitates multi-sample and/or multi-time-point analyses required for screening substances regulating mast cell degranulation. [ABSTRACT FROM AUTHOR]

Systemic mastocytosis is characterized by expansion of clonal mast cells in various tissues. Several biomarkers with diagnostic and therapeutic potential have recently been characterized in mastocytosis, such as the serum marker tryptase and the immune checkpoint molecule PD-L1. We aimed to investigate whether serum levels of other checkpoint molecules are altered in systemic mastocytosis and whether these proteins are expressed in mastocytosis infiltrates in the bone marrow. Levels of different checkpoint molecules were analyzed in serum of patients with different categories of systemic mastocytosis and healthy controls and correlated to disease severity. Bone marrow biopsies from patients with systemic mastocytosis were stained to confirm expression. Serum levels of TIM-3 and galectin-9 were increased in systemic mastocytosis, particularly in advanced subtypes, compared with healthy controls. TIM-3 and galectin-9 levels were also found to correlate with other biomarkers of systemic mastocytosis, such as serum tryptase and KIT D816V variant allele frequency in the peripheral blood. Moreover, we observed expression of TIM-3 and galectin-9 in mastocytosis infiltrates in bone marrow. Together, our results demonstrate for the first time that serum levels of TIM-3 and galectin-9 are increased in advanced systemic mastocytosis. Moreover, TIM-3 and galectin-9 are expressed in bone marrow infiltrates in mastocytosis. These findings provide a rationale for exploring TIM-3 and galectin-9 as diagnostic markers and eventually therapeutic targets in systemic mastocytosis, particularly in advanced forms. [ABSTRACT FROM AUTHOR]

Physical urticaria is a type of urticaria in which recurrent wheals and/or angioedema occur following exposure of the skin to a physical stimulus. It is classified according to its triggers, which may be mechanical (friction, pressure, and vibration), thermal (cold and heat), or solar electromagnetic radiation. Symptoms of different physical urticarias can develop following specific activities that expose patients to an eliciting stimulus and may be variably accompanied by mucosal involvement and systemic symptoms, including nausea, headache, or even anaphylaxis. Differentiation of physical urticaria from other chronic urticarias requires careful clinical assessment and confirmatory provocation testing, which in turn can inform appropriate management. This clinical review provides an evidence-based summary of the epidemiology, clinical features, pathogenesis, diagnostic work-up, and management of physical urticaria. [ABSTRACT FROM AUTHOR]

Aspirin-exacerbated respiratory disease (AERD) is a unique and often clinically severe disease affecting a subgroup of adults with asthma and chronic rhinosinusitis with nasal polyposis. Works published in 2021-2022 confirmed the critical role of lipid mediator dysregulation and mast cell activation and expanded our understanding of basophils, macrophages, fibrin dysregulation, and the 15-lipoxygenase pathway in disease pathogenesis. Translational studies established inflammatory heterogeneity in the upper and lower airway at baseline and during aspirin-induced respiratory reactions. Clinical cohorts provided insights into the mechanistic actions of frequently utilized biologic therapies in AERD. These advances are already changing clinical care delivery and affecting patient outcomes. Despite this, further work is needed to improve clinical tools to reliably diagnose AERD and identify factors that could prevent development of the disease altogether. Additionally, the impact of inflammatory heterogeneity on clinical trajectories and the utility and safety of combination biologic and daily aspirin therapies remains unanswered. [ABSTRACT FROM AUTHOR]

Mast cells (MCs) within the airway epithelium in asthma are closely related to airway dysfunction, but cross talk between airway epithelial cells (AECs) and MCs in asthma remains incompletely understood. Human rhinovirus (RV) infections are key triggers for asthma progression, and AECs from individuals with asthma may have dysregulated antiviral responses. We utilized primary AECs in an ex vivo coculture model system to examine cross talk between AECs and MCs after epithelial rhinovirus infection. Primary AECs were obtained from 11 children with asthma and 10 healthy children, differentiated at air–liquid interface, and cultured in the presence of laboratory of allergic diseases 2 (LAD2) MCs. AECs were infected with rhinovirus serogroup A 16 (RV16) for 48 hours. RNA isolated from both AECs and MCs underwent RNA sequencing. Direct effects of epithelial-derived interferons on LAD2 MCs were examined by real-time quantitative PCR. MCs increased expression of proinflammatory and antiviral genes in AECs. AECs demonstrated a robust antiviral response after RV16 infection that resulted in significant changes in MC gene expression, including upregulation of genes involved in antiviral responses, leukocyte activation, and type 2 inflammation. Subsequent ex vivo modeling demonstrated that IFN-β induces MC type 2 gene expression. The effects of AEC donor phenotype were small relative to the effects of viral infection and the presence of MCs. There is significant cross talk between AECs and MCs, which are present in the epithelium in asthma. Epithelial-derived interferons not only play a role in viral suppression but also further alter MC immune responses including specific type 2 genes. [Display omitted] [ABSTRACT FROM AUTHOR]

Mast cells are distributed throughout the gastrointestinal tract and function as the main effector cells of IgE-mediated allergic reactions to foods. Allergen-induced cross-linking of IgE antibodies bound to high-affinity IgE receptors, FcεRI, on the surface of mast cells triggers their activation, resulting in the release of mediators of immediate hypersensitivity. These mediators rapidly induce both local gastrointestinal and systemic physiological responses including anaphylaxis. Emerging evidence has revealed that, in addition to inciting immediate reactions, mast cells are key regulators of adaptive immunity to foods. In the gastrointestinal mucosa they provide the priming cytokines that initiate and, over time, consolidate adaptive T H 2 responses to ingested allergens as well as TNF and chemokines that orchestrate the recruitment of tissue-infiltrating leukocytes that drive type 2 tissue inflammation. Patients with atopic dermatitis have increased intestinal mast cell numbers and are at a greater risk for food allergy. Recent studies have uncovered a skin-gut axis in which epicutaneous allergen exposure drives intestinal mast cell expansion. The activating effects of IgE antibodies in mast cells are countered by food-specific IgG antibodies that signal via the inhibitory IgG receptor, FcγR2b, suppressing both immediate allergic reactions to foods and the type 2 immune adjuvant activity of mast cells. [ABSTRACT FROM AUTHOR]

Thymic stromal lymphopoietin (TSLP) has been shown to play a central role in the initiation and persistence of allergic responses. We evaluated whether tezepelumab, a human monoclonal anti-TSLP antibody, improved the efficacy of subcutaneous allergen immunotherapy (SCIT) and promoted the development of tolerance in patients with allergic rhinitis. We conducted a double-blind parallel design trial in patients with cat allergy. A total of 121 patients were randomized to receive either intravenous tezepelumab plus subcutaneous cat SCIT, cat SCIT alone, tezepelumab alone, or placebo for 52 weeks, followed by 52 weeks of observation. Nasal allergen challenge (NAC), skin testing, and blood and nasal samples were obtained throughout the study. At week 52, the NAC-induced total nasal symptom scores (TNSS) (calculated as area under the curve [AUC 0-1h ] and as peak score [Peak 0-1h ] during the first hour after NAC) were significantly reduced in patients receiving tezepelumab/SCIT compared to SCIT alone. At week 104, one year after stopping treatment, the primary end point TNSS AUC 0-1h was not significantly different in the tezepelumab/SCIT group compared to SCIT alone, while TNSS Peak 0-1h was significantly lower in those receiving combination treatment versus SCIT. Transcriptomic analysis of nasal epithelial samples demonstrated that treatment with the combination of SCIT/tezepelumab, but neither monotherapy, caused persistent downregulation of a gene network related to type 2 inflammation that was associated with improvement in NAC responses. Inhibition of TSLP augments the efficacy of SCIT during therapy and may promote tolerance after a 1-year course of treatment. (ClinicalTrials.gov NCT02237196). [Display omitted] [ABSTRACT FROM AUTHOR]

Urticaria is a heterogeneous inflammatory disorder that can be acute or chronic and is defined by the appearance of wheals, angioedema, or both. Very recently, the newest update and revision of the international European Academy of Allergy and Clinical Immunology/Global Allergy and Asthma European Network/European Dermatology Forum/Asia Pacific Association of Allergy Asthma Clinical Immunology guideline for the definition, classification, diagnosis, and management of urticaria was published. It aims to help primary care physicians and specialists in the management of their patients with urticaria. The guideline applied the Grading of Recommendations Assessment Development and Evaluations approach to developing consensus recommendations. These recommendations were then discussed in a Delphi conference that included more than 250 specialists in the field, and they are endorsed by more than 50 international societies. Here, we highlight changes from previous versions of the international urticaria guideline and their impact on clinical practice. [ABSTRACT FROM AUTHOR]

Propofol has been shown to against intestinal reperfusion injury when treated either before or after ischemia, during which mast cell could be activated. The aim of this study was to evaluate the role of propofol in restoring the intestinal epithelial cells integrity disrupted by mast cell activation or the released tryptase after activation in vitro. We investigated the effect of: (1) tryptase on Caco-2 monolayers in the presence of PAR-2 inhibitor or propofol, (2) mast cell degranulation in a Caco-2/LAD-2 co-culture model in the presence of propofol, and (3) propofol on mast cell degranulation. Epithelial integrity was detected using transepithelial resistance (TER) and permeability to fluorescein isothiocyanate (FITC)-dextran (the apparent permeability coefficient, Papp). The expression of junctional proteins zonula occludens-1 (ZO-1/TJP1) and occludin were determined using western blot analysis and immunofluorescence microscopy. The intracellular levels of reactive oxidative species (ROS) and Ca2+ were measured using flow cytometry. Tryptase directly enhanced intestinal barrier permeability as demonstrated by significant reductions in TER, ZO-1, and occludin protein expression and concomitant increases in Papp. The intestinal barrier integrity was restored by PAR-2 inhibitor but not by propofol. Meanwhile, mast cell degranulation resulted in epithelial integrity disruption in the Caco-2/LAD-2 co-culture model, which was dramatically attenuated by propofol. Mast cell degranulation caused significant increases in intracellular ROS and Ca2+ levels, which were blocked by propofol and NAC. Propofol pretreatment can inhibit mast cell activation via ROS/Ca2+ and restore the intestinal barrier integrity induced by mast cell activation, instead of by tryptase. [ABSTRACT FROM AUTHOR]

Introduction: Placental pathology and pregnancy complications are associated with unfavorable regulation of the maternal immune system. Although much research has been performed towards the role of immune cells like macrophages and T cells in this context, little is known about the presence and function of mast cells (MC). MC can be sub classified in tryptase-positive (MCT) and tryptase- and chymase-positive (MCTC). This study investigates the presence of MC in the decidua of pregnancies complicated by fetal growth restriction (FGR) and stillbirth (SB).Methods: Placental tissue from FGR (n = 250), SB (n = 64) and healthy pregnancies (n = 42) was included. Histopathological lesions were classified according to the Amsterdam Placental Workshop Group criteria. Tissue sections were stained for tryptase and chymase. Decidual MC were counted manually, and the results were expressed as number of cells/mm2 decidual tissue.Results: A significant lower median number of MCTC was found in the decidua of FGR (0.40 per mm2; p < 0.001) and SB (0.51 per mm2; p < 0.05) compared to healthy controls (1.04 per mm2). No difference in MCT number (1.19 per mm2, 1.88 per mm2 and 1.37 per mm2 respectively) was seen between the groups. There was no difference in number of MCT and MCTC between placental pathological lesions.Discussion: Our findings suggest a shift in decidual MC balance towards MCT in pregnancy complications. No difference in numbers of MC subtypes was found to be related to histopathologic lesions. [ABSTRACT FROM AUTHOR]

Copyright of Revue Francaise d'Allergologie is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Parmi les cellules immunitaires participant à la réaction allergique, les mastocytes et les éosinophiles occupent une place majeure. Cependant, ces cellules jouent aussi un rôle de premier plan dans l'immunité innée. Ici, nous proposons une courte revue des connaissances actuelles sur l'ontogénie, la physiologie et la physiopathologie de ces deux types cellulaires. Mast cells and eosinophils are prominent players of allergic reactions. However, these cells also make significant contributions to the innate immune defense. Here, we provide a concise update on the ontogeny, physiology and pathophysiology of mast cells and eosinophils. [ABSTRACT FROM AUTHOR]

Mast cells (MCs) are key effectors of the allergic response. Following the cross-linking of IgE receptors (FcεRIs), they release crucial inflammatory mediators through degranulation. Although degranulation depends critically on secretory granule (SG) trafficking toward the plasma membrane, the molecular machinery underlying this transport has not been fully characterized. This study analyzed the function of Rab44, a large, atypical Rab guanosine triphosphatase highly expressed in MC, in the MC degranulation process. Murine knockout (KO) mouse models (KORab44 and DKOKif5b/Rab44) were used to perform passive cutaneous anaphylaxis experiments and analyze granule translocation in bone marrow-derived MCs during degranulation. This study demonstrate that mice lacking Rab44 (KORab44) in their bone marrow-derived MCs are impaired in their ability to translocate and degranulate SGs at the plasma membrane on FcεRI stimulation. Accordingly, KORab44 mice were less sensitive to IgE-mediated passive cutaneous anaphylaxis in vivo. A lack of Rab44 did not impair early FcεRI-stimulated signaling pathways, microtubule reorganization, lipid mediator release, or cytokine secretion. Mechanistically, Rab44 appears to interact with and function as part of the previously described kinesin-1–dependent transport pathway. These results highlight a novel role of Rab44 as a regulator of SG transport during degranulation and anaphylaxis acting through the kinesin-1–dependent microtubule transport machinery. Rab44 can thus be considered a potential target for modulating MC degranulation and inhibiting IgE-mediated allergic reactions. [Display omitted] [ABSTRACT FROM AUTHOR]

Les mastocytes peuvent être activés dans de nombreuses conditions physiologiques et pathologiques. Les troubles d'activation mastocytaire sont classés comme primaires – associés à une population monoclonale mastocytaire –, ou secondaires (avec un nombre normal de mastocytes dits hyperréactifs), ou encore idiopathiques. Le syndrome d'activation mastocytaire (MCAS, Mast Cell Activation Syndrome) est caractérisé par une libération inappropriée et excessive par les mastocytes de médiateurs engendrant divers symptômes pouvant concerner plusieurs apparats, voire provoquer des réactions à type d'anaphylaxie à répétition. Nous avons voulu apporter des réponses claires aux questions suivantes pour aider la prise en charge globale des patients atteints de MACS : quelles sont la définition et la classification actuelles du MCAS ? Quels sont les critères diagnostiques, cliniques et biologiques à utiliser ? Quelles sont les stratégies thérapeutiques à mettre en œuvre ? Le but de ce travail est de présenter les connaissances actuelles concernant les MCAS, pour apporter une aide au processus diagnostique et thérapeutique de ces pathologies. Mast cells may be activated secondary to different physiological and pathological conditions. Mast cell activation disorders are classified as primary – associated with a monoclonal mast cell population – or secondary (with a normal number of so-called hyperreactive mast cells), or even idiopathic. Mast Cell Activation Syndrome (MCAS) is characterized by an inappropriate and excessive release of mast cells mediators, leading to clinical symptoms that may affect several body systems, or even cause repeated anaphylaxis. We wanted to provide clear answers to the following questions to help the overall management of patients presenting with MACS: what is the current definition and classification of MCAS? Which diagnostic, clinical and laboratory criteria should be used? What are the most comment therapeutic strategies? The aim of the present work is to present current knowledge on MCAS, to aid clinicians in the diagnostic and therapeutic process of these conditions. [ABSTRACT FROM AUTHOR]

Allergic inflammation is closely related to the activation of mast cells (MCs), which is regulated by its intracellular Ca2+ level, but the intake and effects of the intracellular Ca2+ remain unclear. The Ca2+ influx is controlled by members of Ca2+ channels, among which calcium voltage-gated channel subunit alpha1 C (Ca V 1.2) is the most robust. This study aimed to reveal the role and underlying mechanism of MC Ca V 1.2 in allergic inflammation. We found that Ca V 1.2 participated in MC activation and allergic inflammation. Nimodipine (Nim), as a strong Ca V 1.2-specific antagonist, ameliorated allergic inflammation in mice. Further, Ca V 1.2 activation in MC was triggered by phosphatizing at its Ser1928 through protein kinase C (PKC), which calcium/calmodulin-dependent protein kinase II (CaMKII) catalyzed. Overexpression or knockdown of MC Ca V 1.2 influenced MC activation. Importantly, Ca V 1.2 expression in MC had detrimental effects, while its deficiency ameliorated allergic pulmonary inflammation. Results provide novel insights into Ca V 1.2 function and a potential drug target for controlling allergic inflammation. [Display omitted] • MC Ca V 1.2 deficiency or inhibition ameliorates degranulation and allergic inflammation. • The opening of MC Ca V 1.2 does not require depolarization of membrane potential. • MC Ca V 1.2 activation is triggered by CaMKII/PKC/Ser1928 phosphorylation. [ABSTRACT FROM AUTHOR]

Peptide based therapeutics are desirable owing to their high biological specificity. However, a number of these fail in clinical testing due to an adverse inflammatory response. Mast cells play a key role in directing the host response to drugs and related products. Although the role of FcεRI receptor is well known, Mas-related G-protein coupled receptor X2 (MRGPRX2) binding of endogenous peptides, and drugs will activate mast cells independent of FcεRI. Identifying peptides that activate mast cells through MRGPRX2, and their respective activation potency, can be used to reduce the failure rate of peptide therapeutics at clinical trial. Moreover, it will allow for peptide design where mast cell activation is actually desired. It was found that FRKKW and WNKWAL are two motifs that activate human LAD2 cells similar to PAMP-12 controls. Peptide activators of MRGPRX2 could be reduced to X a -(Y) (n ≥ 3) -X b where: X a is an aromatic residue; X b is a hydrophobic residue; and Y is a minimum 3 residue long sequence, containing a minimum of one positively charged residue with the remainder being uncharged residues. Artificial peptides WKKKW and FKKKF were constructed to test this structural functionality and were similar to PAMP-12 controls. Peptides with different activation potentials were found where FRKKW = WKKKW = FKKKF > PAMP-12 = WNKWAL > YKKKY > FRKKANKWALSR = FRKKWNKAALSR > KWKWK > FRKK = WNKWA > KYKYK > NKWALSR = YKKY = WNK. These sequences should be considered when designing peptide-based therapeutics. Mast cells release immune regulating molecules upon activation that direct host's immune response. MRGPRX2 receptor provides an alternate pathway for mast cell activation that is independent of FcεRI receptor. It is thought that mast cell activation through MRGPRX2 plays a critical role in high failure rates of drugs in clinical trials. Identifying peptide sequences that activate mast cells through MRGPRX2 can serve two important purposes, namely, sequences to avoid when designing peptide therapeutics, and artificial peptides with different activation potentials for mast cells. Herein, we have identified a general amino acid sequence that induces mast cell activation through MRGPRX2. Furthermore, by modulating the identified sequence, artificial peptides have been designed which activate mast cells by varying degrees for therapeutic applications. [Display omitted] [ABSTRACT FROM AUTHOR]

OBJECTIVE: Mast cells (MCs) are known to be involved in several physiological and pathological processes in humans and animals. Recently, their potential role in tumor development and angiogenesis has been investigated, arising interesting results to be potentially applied in clinics. Mast cells' granules contain a huge quantity of protease enzymes that, through different mechanisms, induce the formation of new microvessels, feeding tumor burden. Among them, tryptase and chymase are the most abundant enzymes: tryptase is well known for its multiple activities, on the contrary, the role of chymase in pancreatic cancer angiogenesis has not been investigated yet. PATIENTS AND METHODS: Our research aims to correlate to each other and to angiogenesis four different tissue parameters (MCs density positive to chymase, MCs area positive to chymase, microvascular density and endothelial area) together with the main clinical-pathological characteristics in 52 patients surgically resected for pancreatiCDuctal adenocarcinoma, employing immunohistochemistry and image analysis system. RESULTS: All reported tissue parameters match to confirm the correlation between chymase enzyme and angiogenesis in pancreatic cancer. CONCLUSIONS: This evidence could become a starting point for a new potential therapeutic route exploiting chymase inhibitors as a novel anti-angiogenetic strategy in pancreatic cancer patients. [ABSTRACT FROM AUTHOR]

Mastocytosis encompasses a heterogeneous group of disorders characterized by accumulation of clonal mast cells (MCs) in the skin and/or internal organs. Patients typically present with a broad variety of recurrent mediator-related clinical symptoms, including severe anaphylaxis. However, not all patients with mastocytosis experience anaphylactic reactions. We sought to identify disease-specific biomarkers in plasma that could be used to predict patients with mastocytosis with increased risk of anaphylaxis. Nineteen patients (≥18 years) and 2 control groups (11 subjects with allergic asthma and 13 healthy volunteers without history of atopy) were recruited. In total, 248 plasma proteins were analyzed by Proximity Extension Assay using Olink Proseek Multiplex panels. We identified 4 novel proteins, in addition to tryptase, E-selectin, adrenomedullin, T-cell immunoglobulin, and mucin domain 1, and CUB domain–containing protein 1/CD138 to be significantly increased in patients with mastocytosis compared with both patients with asthma and healthy controls. Furthermore, we investigated whether we could discriminate between patients with mastocytosis with or without anaphylaxis. In addition to tryptase, we identified 3 novel proteins, that is, allergin-1, pregnancy-associated plasma protein-A, and galectin-3, with significantly different levels in patients with mastocytosis with anaphylaxis compared with those without anaphylaxis. Newly identified proteomic biomarkers may be used to predict patients with mastocytosis with increased risk of anaphylaxis. [ABSTRACT FROM AUTHOR]

Copyright of China Journal of Oral & Maxillofacial Surgery is the property of Shanghai Jiao Tong University, College of Stomatology and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Histamine and leukotrienes (LTs), the chemical mediators released from mast cells, play an important role in type-I allergies such as hay fever. Echinacea purpurea (EP) has traditionally been used for herbal tea and has been reported to show biological functions. We evaluated the inhibitory activity of water extracts of EP petals, leaves, and stems against the chemical mediators released from mast cell lines. Petal and leaf extracts exhibited a significant inhibitory effect on histamine release from the stimulated cells, while the stem extract did not exert any effect. Activity of the petal extract was much stronger than that of the leaf extract. All the extracts significantly suppressed LTB4 production in the stimulated cells and displayed similar activities. The petal extract decreased Syk phosphorylation and Ca2+ influx associated with signal transduction in the stimulated cells. These results suggest that EP petal extract may have a relieving effect on allergic symptoms. [ABSTRACT FROM AUTHOR]

The major challenge of allergy diagnosis lies in the development of accessible and reliable diagnostics allowing correct prediction of the clinical outcome following exposure to the offending allergen(s) and cross-reactive structures. Since the late nineties, evidence has accumulated that flow-assisted analysis and quantification of ex vivo –activated basophils (according to the basophil activation test [BAT]) might meet this requirement for different IgE-dependent allergies and particular forms of autoimmune urticaria. Other so-called nondiagnostic applications of the BAT involve therapeutic monitoring, follow-up of natural histories, and identification of allergenic recognition sites. However, it has also become clear that appropriate use of the BAT necessitates knowledge about degranulation metrics and guidance to guarantee correct execution and interpretation of the results. Here, we have reviewed the most relevant applications and limitations of the BAT. Some personal statements and views about its perspectives are made. [ABSTRACT FROM AUTHOR]

This study group has previously identified IL-9–producing mucosal mast cell (MMC9) as the primary source of IL-9 to drive intestinal mastocytosis and experimental IgE-mediated food allergy. However, the molecular mechanisms that regulate the expansion of MMC9s remain unknown. This study hypothesized that IL-4 regulates MMC9 development and MMC9-dependent experimental IgE-mediated food allergy. An epicutaneous sensitization model was used and bone marrow reconstitution experiments were performed to test the requirement of IL-4 receptor α (IL-4Rα) signaling on MMC9s in experimental IgE-mediated food allergy. Flow cytometric, bulk, and single-cell RNA-sequencing analyses on small intestine (SI) MMC9s were performed to illuminate MMC9 transcriptional signature and the effect of IL-4Rα signaling on MMC9 function. A bone marrow–derived MMC9 culture system was used to define IL-4–BATF signaling in MMC9 development. Epicutaneous sensitization– and bone marrow reconstitution–based models of IgE-mediated food allergy revealed an IL-4 signaling-dependent cell-intrinsic effect on SI MMC9 accumulation and food allergy severity. RNA-sequencing analysis of SI-MMC9s identified 410 gene transcripts reciprocally regulated by IL-4 signaling, including Il9 and Batf. In silico analyses identified a 3491-gene MMC9 transcriptional signature and identified 2 transcriptionally distinct SI MMC9 populations enriched for metabolic or inflammatory programs. Employing an in vitro MMC9-culture model system showed that generation of MMC9-like cells was induced by IL-4 and this was in part dependent on BATF. IL-4Rα signaling directly modulates MMC9 function and exacerbation of experimental IgE-mediated food allergic reactions. IL-4Rα regulation of MMC9s is in part BATF-dependent and occurs via modulation of metabolic transcriptional programs. [ABSTRACT FROM AUTHOR]

The author reports two cases of Bullous pemphigoid (BP) with neurofibroma (NF)-like histopathological change. The two patients without neurofibromatosis type 1 (NF1) presented with several bullae on their trunk. Based on the results of positivity for anti-BP180 antibody, direct immunofluorescence, and histopathological findings, they were diagnosed with BP. Histologically, another lesion in the dermis, which was composed of spindle cells with wavy nuclei, collagen fibers, and mast cells, was located close to the bulla. Immunohistochemically, the spindle cells were diffusely positive for S-100 protein and CD34, and weakly positive for epithelial membrane antigen in certain foci. These findings were considered to be "NF-like" histopathological change. This is the first two cases of BP with NF-like histopathological change in patients without NF1. [ABSTRACT FROM AUTHOR]

Mast cells and IgE are most familiar as the effectors of type I hypersensitivity reactions including anaphylaxis. It is becoming clear however that this pair has important immunomodulatory effects on innate and adaptive cells of the immune system. In this purview, they act as endogenous adjuvants to ignite evolving immune responses, promote the transition of allergic disease into chronic illness and disrupt the development of active mechanisms of tolerance to ingested foods. Suppression of IgE-mediated mast cell activation can be exerted by molecules targeting IgE, FcɛRI or signaling kinases including Syk, or by IgG antibodies acting via inhibitory Fcγ receptors. In 2015 we reviewed the evidence for the adjuvant functions of mast cells. This update includes the original text, incorporates some important developments in the field over the past five years and discusses how interventions targeting these pathways might have promise in the development of strategies to treat allergic disease. [ABSTRACT FROM AUTHOR]

This study was designed to investigate mast cell activation and related TLR4-NF-κB/TNF-a pathway variation in 3 and 7 days' rats intestinal I/R injury, and TXL's intervention effect. Rat intestine I/R injury was carried out using superior mesenteric artery occlusion model with 30 min ischemia followed 3 or 7 days' reperfusion. Rats were administered TXL ultrafine power of 0.4, 0.8 and 1.6g/kg/d respectively for 3 or 7 days after modeling. Mast cell activation was determined by immunofluorescent double staining. TLR4, ANGPTL4 and microRNA126 were determined by RT-PCR. PECAM-1, NF-κB p65, TNF-a and VE-Cadherin were determined by immunohistochemical staining. Intestine I/R induced massively mast cell activation and overexpressed TLR4, NF-κB, TNF-a, PECAM-1, miR126 in 3 and 7 days. VE-cadherin and ANGPTL4 expression was reduced. TXL treatment attenuated mast cell activation and inhibited TLR4, NF-κB, TNF-a, PECAM-1 over-expression in 3 and 7 days, protected VE-cadherin and ANGPTL4 protein. Inflammation boomed in rats' intestine I/R injury for 3 and 7 days, characterized by mast cell and related TLR4-NF-κB/TNF-a pathway activation, accompanied with endothelial barrier dysfunction and enhanced vascular permeability. TXL treatment attenuated inflammation, protected endothelial barrier function. TXL treat intestine I/R injury, according with "Treat different diseases with the same method" in TCM theory. [ABSTRACT FROM AUTHOR]

IgE-mediated activation of Nhe1 (Na+-H+ exchanger-1) induces aortic cell extracellular acidification and promotes cell apoptosis. A pH-sensitive probe pHrodo identified acidic regions at positions of macrophage accumulation, IgE expression, and cell apoptosis in human and mouse abdominal aortic aneurysm (AAA) lesions. Ang II (angiotensin II)-induced AAA in Nhe1-insufficient Apoe-/-Nhe1+/- mice and Apoe-/-Nhe1+/+ littermates tested Nhe1 activity in experimental AAA, because Nhe1-/- mice develop ataxia and epileptic-like seizures and die early. Nhe1 insufficiency reduced AAA incidence and size, lesion macrophage and T-cell accumulation, collagen deposition, elastin fragmentation, cell apoptosis, smooth muscle cell loss, and MMP (matrix metalloproteinase) activity. Nhe1 insufficiency also reduced blood pressure and the plasma apoptosis marker TCTP (translationally controlled tumor protein) but did not affect plasma IgE. While pHrodo localized the acidic regions to macrophage clusters, IgE expression, and cell apoptosis in AAA lesions from Apoe-/-Nhe1+/+ mice, such acidic areas were much smaller in lesions from Apoe-/-Nhe1+/- mice. Nhe1-FcεR1 colocalization in macrophages from AAA lesions support a role of IgE-mediated Nhe1 activation. Gelatin zymography, immunoblot, and real-time polymerase chain reaction analyses demonstrated that Nhe1 insufficiency reduced the MMP activity, cysteinyl cathepsin expression, IgE-induced apoptosis, and NF-κB activation in macrophages and blocked IgE-induced adhesion molecule expression in endothelial cells. A near-infrared fluorescent probe (LS662) together with fluorescence reflectance imaging of intact aortas showed reduced acidity in AAA lesions from Nhe-1-insufficient mice. This study revealed extracellular acidity at regions rich in macrophages, IgE expression, and cell apoptosis in human and mouse AAA lesions and established a direct role of Nhe1 in AAA pathogenesis. [ABSTRACT FROM AUTHOR]

Chronic spontaneous urticaria (CSU) is considered to be primarily a mast cell–driven disease. However, recent evidence suggests that eosinophils may also have an axial role in symptomology. Histologic studies have demonstrated the presence of both eosinophils and eosinophil granules, indicative of activation, in CSU lesions. Although many allergic and inflammatory conditions are associated with a peripheral blood eosinophilia, the converse appears to be the case in CSU, with a peripheral blood eosinopenia being observed in many patients. Possible mechanisms include the depletion of blood eosinophils by recruitment into the skin during active disease and immunologic destruction in the blood. We also address in some detail the interactions between eosinophils and mast cells, particularly the cytokine cross-talk of these cells and mediator release possibly leading to clinical symptoms. Also, activation by eosinophil proteins of the coagulation pathway leads to the generation of thrombin and increased mast cell degranulation. Finally, treatments aimed at reducing eosinophil accumulation and activation, such as the anti–IL-5 antibodies mepolizumab, reslizumab, and benralizumab, have been reported to reduce CSU symptoms. Clearly, a new picture of an important role of eosinophils in the pathogenesis of CSU is emerging. [ABSTRACT FROM AUTHOR]

Mast cells are a major component of the immune microenvironment in tumour tissues and modulate tumour progression by releasing pro‐tumorigenic and antitumorigenic molecules. Regarding the impact of mast cells on the outcomes of patients with lung adenocarcinoma (LUAD) patient, several published studies have shown contradictory results. Here, we aimed at elucidating the role of mast cells in early‐stage LUAD. We found that high mast cell abundance was correlated with prolonged survival in early‐stage LUAD patients. The mast cell‐related gene signature and gene mutation data sets were used to stratify early‐stage LUAD patients into two molecular subtypes (subtype 1 and subtype 2). The neural network‐based framework constructed with the mast cell‐related signature showed high accuracy in predicting response to immunotherapy. Importantly, the prognostic mast cell‐related signature predicted the survival probability and the potential relationship between TP53 mutation, c‐MYC activation and mast cell activities. The meta‐analysis confirmed the prognostic value of the mast cell‐related gene signature. In summary, this study might improve our understanding of the role of mast cells in early‐stage LUAD and aid in the development of immunotherapy and personalized treatments for early‐stage LUAD patients. [ABSTRACT FROM AUTHOR]

Les mastocytes et les basophiles sont des cellules apparentees aux pathologies d'ordre allergique notamment par leur expression commune du Fc recepteur de haute affinite pour le IgE, FcεRI. Ces deux types cellulaires presentent egalement des caracteristiques similaires en termes de fonctions et de developpement. En plus de fonctions homeostatiques, ces cellules sont essentielles au cours des pathologies de type allergique ou infectieux. Elles presentent egalement des caracteristiques differentes mises a profit pour leur investigation clinique. Cette revue propose de resumer les diversites et les points communs de ces deux types cellulaires avec une approche ciblee sur leur contribution dans la reponse immune allergique. Mast cells and basophils are immune cells associated to allergic diseases in particular by their common expression of the Fc receptor of high affinity for IgE, FcεRI. These two cell types also exhibit similar developmental and functional characteristics. In addition to homeostatic functions, mast cells and basophils perform essential roles in metabolic, anti-infectious and allergic responses. They exhibit different characteristics that constitute a useful tool for their clinical investigation. This review summarizes the diversities and commonalities of these two cell types with a focused approach to their contribution in allergic immune response. [ABSTRACT FROM AUTHOR]

L'allergie IgE-dépendante, en pleine expansion au niveau mondial, devient un vrai problème de société. En 2050, certaines projections considèrent que 50 % des enfants en seront atteints. Il s'agit d'un exemple typique de maladie multifactorielle dans laquelle un terrain génétique prédisposant, l'atopie, rencontre des modifications multiples de notre environnement liées au mode de vie occidental. Cela induit un déséquilibre du microbiote intestinal, puis du compartiment des lymphocytes T régulateurs et in fine un excès de lymphocytes Th2. Il en résultera la formation de plasmocytes sécrétant des IgE spécifiques de l'allergène, puis la sensibilisation des mastocytes et des polynucléaires basophiles. Dans un second temps, les polynucléaires éosinophiles seront recrutés à leur tour. IgE-dependent allergy, which is expanding rapidly worldwide, is becoming a real social problem. In 2050, some projections consider that 50 % of children will be affected. This is a typical example of multifactorial disease in which a predisposing genetic background, atopy, encounters multiple changes in our environment related to Western lifestyle. This induces an imbalance of the intestinal microbiota and then the compartment of regulatory T cells and ultimately an excess of Th2 lymphocytes. This will result in the formation of allergen-specific IgE-secreting plasma cells, followed by sensitization of mast cells and basophilic polynuclear cells. In a second time, the eosinophilic polynuclear will be recruited in their turn. [ABSTRACT FROM AUTHOR]

[Display omitted] Itch is a common symptom that can greatly diminish quality of life. Histamine is a potent endogenous pruritogen, and while antihistamines are often the first-line treatment for itch, in conditions like chronic spontaneous urticaria (CSU), many patients remain symptomatic while receiving maximal doses. Mechanisms that drive resistance to antihistamines are poorly defined. Signaling of the alarmin cytokine IL-33 in sensory neurons is postulated to drive chronic itch by inducing neuronal sensitization to pruritogens. Thus, we sought to determine if IL-33 can augment histamine-induced (histaminergic) itch. Itch behavior was assessed in response to histamine after IL-33 or saline administration. Various stimuli and conditional and global knockout mice were utilized to dissect cellular mechanisms. Multiple existing transcriptomic data sets were evaluated, including single-cell RNA sequencing of human and mouse skin, microarrays of isolated mouse mast cells at steady state and after stimulation with IL-33, and microarrays of skin biopsy samples from subjects with CSU and healthy controls. IL-33 amplifies histaminergic itch independent of IL-33 signaling in sensory neurons. Mast cells are the top expressors of the IL-33 receptor in both human and mouse skin. When stimulated by IL-33, mouse mast cells significantly increase IL-13 levels. Enhancement of histaminergic itch by IL-33 relies on a mast cell– and IL-13–dependent mechanism. IL-33 receptor expression is increased in lesional skin of subjects with CSU compared to healthy controls. Our findings suggest that IL-33 signaling may be a key driver of histaminergic itch in mast cell–associated pruritic conditions such as CSU. [ABSTRACT FROM AUTHOR]

Tumour histological classification and grade are frequently used to predict the prognosis of canine mammary gland tumours. While these techniques provide some information about tumour behaviour, it is currently difficult to predict which tumours will metastasize. Mast cell density has been shown to predict metastasis in human breast cancer. The present study investigated whether the average mast cell density in 10 high-power (×400) microscopical fields (10 HPFs), evaluated by toluidine blue staining, similarly predicted the behaviour of canine mammary gland tumours. Mast cell density was evaluated in 53 canine mammary neoplasms for which the clinical outcome was known. Stromal mast cell density in malignant tumours that had subsequently developed radiographical evidence of metastasis (n = 21) was significantly lower (P <0.001) than in malignant tumours that did not show evidence of metastases (n = 20) or in benign tumours (n = 12). The density of stromal mast cells that best predicted the disease outcome was ≤10/10 HPFs. Eighty-one percent of malignant tumours with ≤10 stromal mast cells/10 HPFs subsequently metastasized, while only 9.5% of malignant tumours with >10 stromal mast cells/10 HPFs developed metastases. There was a positive correlation between stromal mast cell density and survival time (r s = 0.50, P <0.001). These findings suggest that assessing stromal mast cell density using toluidine blue staining may represent an easy to perform and cost-effective histopathological measure that, in conjunction with classification and grading, could better predict the behaviour of canine mammary neoplasms. [ABSTRACT FROM AUTHOR]

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Mast cells (MCs), which are well known for their effector functions in T H 2-skewed allergic and also autoimmune inflammation, have become increasingly acknowledged for their role in protection of health. It is now clear that they are also key modulators of immune responses at interface organs, such as the skin or gut. MCs can prime tissues for adequate inflammatory responses and cooperate with dendritic cells in T-cell activation. They also regulate harmful immune responses in trauma and help to successfully orchestrate pregnancy. This review focuses on the beneficial effects of MCs on tissue homeostasis and elimination of toxins or venoms. MCs can enhance pathogen clearance in many bacterial, viral, and parasitic infections, such as through Toll-like receptor 2–triggered degranulation, secretion of antimicrobial cathelicidins, neutrophil recruitment, or provision of extracellular DNA traps. The role of MCs in tumors is more ambiguous; however, encouraging new findings show they can change the tumor microenvironment toward antitumor immunity when adequately triggered. Uterine tissue remodeling by α-chymase (mast cell protease [MCP] 5) is crucial for successful embryo implantation. MCP-4 and the tryptase MCP-6 emerge to be protective in central nervous system trauma by reducing inflammatory damage and excessive scar formation, thereby protecting axon growth. Last but not least, proteases, such as carboxypeptidase A, released by FcεRI-activated MCs detoxify an increasing number of venoms and endogenous toxins. A better understanding of the plasticity of MCs will help improve these advantageous effects and hint at ways to cut down detrimental MC actions. [ABSTRACT FROM AUTHOR]

Background: An emerging trend in clinical research has centered on improving the characteristics of chronic rhinosinusitis (CRS) according to phenotypes and endotypes. The objective of this study is to utilize histopathological markers to better characterize CRS phenotypes that are defined by the presence or absence of comorbid bronchial asthma (BA) and allergic rhinitis (AR). Methods: A prospective case-controlled study of CRS patients was conducted. For the CRS cohort, mucosal biopsies were obtained during endoscopic sinus surgery, while samples of ethmoid mucosa were collected in control patients undergoing endoscopic skull base surgery. Histopathological analysis of tissue samples determined the relative frequency of inflammatory cell types, including eosinophils, lymphocytes, neutrophils, mast cells, and plasma cells. The presence and absence of comorbid BA and AR were used to further divide CRS, allowing for further subgroup analysis. Results: Of 82 recruited patients, there were 67 CRS patients and 15 controls. Significantly increased eosinophil ratios were found in CRS patients with AR, BA, or both, when compared with controls (P <.001). Conversely, CRS patients with neither comorbid diagnosis failed to demonstrate statistically significant elevations in eosinophil ratios (P >.05). Lymphocyte ratios showed a significantly inverse correlation with trends demonstrated by eosinophil ratios in all patient subgroups (P <.001). Neutrophil, mast cell, and plasma cell ratios did not show significant differences across the evaluated subgroups. Conclusions: The clinical diagnosis of comorbid BA and AR may aid in better characterizing CRS endotypes without invasive testing and better direct management of the disease. [ABSTRACT FROM AUTHOR]

Background and Objective: We reported neutrophil-associated tissue damage in cedar pollinosis subjects with refractory nasal symptoms prior to pollinosis season. Because the leukotriene receptor antagonist, montelukast, can inhibit neutrophil recruitment and activation, we investigated its effects on symptom relief and nasal neutrophilia in pollinosis subjects in the preseason. Methods: In the pollinosis preseason, symptomatic (PreSyP, n = 149) and asymptomatic subjects (PreAsP, n = 145) were prophylactically treated, and in season symptomatic subjects (InSyP, n = 134) were treated. Individuals were assigned to 1 of 2 treatment protocols: administration of cetirizine and fluticasone nasal spray (Cet-Flu) or montelukast, fexofenadine, and fluticasone nasal spray (Mo-Fex-Flu). Differences in symptom relief and inflammatory cell infiltration in nasal swabs were investigated. Results: In pollen season, 59% of PreSyP subjects given Cet-Flu and 88% of those treated with Mo-Fex-Flu had none or mild symptoms (P <.00001). In PreAsP subjects in season, 71% of Cet-Flu and 98% of Mo-Fex-Flu recipients had none to mild symptoms (P <.0000001). The proportions of subjects in the PreSyP group with nasal swabs with neutrophils 1+ to 3+ before and after treatment by Mo-Fex-Flu were 59% and 18%, respectively (P <.0001), and in PreAsyP, subjects with neutrophils 2+ to 3+ were 17% and 5%, respectively (P =.034). In PreSyP, a significant reduction in the percentage of subjects with mast cells >1+ was seen following both Cet-Flu (P =.027) and Mo-Fex-Flu (P =.0014) treatments. Conclusion: In PreSyP and PreAsP subjects, treatments with Mo-Fex-Flu were more effective than Cet-Flu to reduce nasal symptom scores. These effects were associated with reduction in the number of neutrophils and mast cells in nasal swabs. [ABSTRACT FROM AUTHOR]

The roles of mast cells in allergic diseases and helminth infections are well known. However, the roles of mast cells in T. gondii infection is poorly understood. This study was focused on the production of pro-inflammatory cytokines (TNF-α, IL-4), chemokines (CXCL8, MCP-1) and nitric oxide (NO) by mast cells in response to soluble lysate of T. gondii tachyzoites. Production of CXCL8 (IL-8), MCP-1, TNF-α and IL-4 were measured by RT-PCR and ELISA. Western blot were used for detection of CXCR-1 and CXCR2. Our results showed that T. gondii lysates triggered mast cells to release CXCL8, MCP-1, TNF-α, IL-4 and to produce NO. This suggests that mast cells play an important role in inflammatory responses to T. gondii. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • ORAI-family channels play a dominant role in store-operated calcium signaling in innate immune cells. • CRAC channels are required for IgE-mediated mast cell activation. • Store-operated calcium entry is required for many neutrophil functions; the contribution of ORAI family members remains under investigation. • Store-operated calcium signaling is required for proper antigen processing in dendritic cells. • Store-operated calcium entry has diverse effects in innate immune cells, with implications for host defense, allergy and inflammatory disease. Abstract Calcium is a major intracellular signaling messenger in innate immune cells. Similar to other immune cell subsets, the majority of calcium entry into innate immune cells is induced by cell surface receptors that stimulate store-operated calcium entry through calcium-release activated calcium (CRAC) channels. Since the molecular description of the STIM family of calcium sensors and the ORAI family of CRAC channel proteins, the majority of studies support a dominant role for these proteins in calcium signaling in innate cells. In reviewing the literature on CRAC channel function in innate cells, several general themes emerge. All innate cells express multiple members of the STIM and ORAI family members, however the ratio and relative contribution of individual isoforms changes depending on the cell type and activation state of the cell. It is evident that study of functional roles for STIM molecules is clearly ahead of studies of specific ORAI family members in all innate cell types, and that studies of CRAC channels in innate cells are not nearly as advanced as studies in lymphocytes. However, taken together, evidence from both STIM calcium sensors and ORAI channels in innate cells indicates that deficiency of STIM and ORAI proteins tends not to affect the development of any innate cell lineage, but certainly affects their function, in particular activation of the neutrophil oxidase and mast cell activation via IgE receptors. Furthermore, there are clearly hints that therapeutic targeting of CRAC channels in innate cells offers a new approach to various inflammatory and allergic diseases. [ABSTRACT FROM AUTHOR]