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Lactation anaphylaxis is extremely rare and has been scarcely reported in the literature. Breast feeding and/or milk expression immediately induces life-threatening anaphylactic reactions, including generalized urticaria, angioedema, respiratory symptoms, and hypotension. Six English-language case reports have described the clinical course in detail. The present report describes a case involving a 24-year-old woman with no history of allergic reactions or anaphylaxis who experienced anaphylactic reactions three times immediately after milk expression. Lactation anaphylaxis was suspected when a detailed medical history revealed lactation-related recurrent anaphylactic symptoms. The authors prescribed bromocriptine to stop lactation and switched her to formula feeding, which resulted in no further anaphylactic episodes. Based on a review of the relevant literature, this report describes the characteristics of lactation anaphylaxis and possible management strategies. The pathogenesis of lactation anaphylaxis has been inferred from various experimental results.

Basophils and mast cells (MCs) play an important role in immune responses against allergens and parasitic infection. To elucidate the mechanisms that determine the commitment between basophils and mast cell (MCs), transcription factors and epigenetic modifications regulating the gene expression of basophil‐specific enzymes, Mcpt8 and Mcpt11, were analyzed using bone marrow‐derived (BM) cells containing basophils and MCs. Knockdown (KD) and overexpression experiments revealed that the transcription factor C/EBPα positively regulated the gene expression of Mcpt8 and Prss34 (encoding Mcpt11). Cebpa, Mcpt8, and Prss34 mRNAs levels were upregulated by histone deacetylases and downregulated by DNA methyltransferases. Gata2 KD significantly reduced the mRNA levels of Mcpt8 and Prss34, while TGF‐β treatment increased those of Mcpt8 and Prss34. These results show that basophil‐specific protease genes were transactivated by C/EBPα, GATA2, and TGF‐β signaling and modified with epigenetic regulation. [ABSTRACT FROM AUTHOR]

Kallikrein-related peptidase 7 (KLK7) is one of 15 members of the tissue kallikrein family and is primarily expressed in the skin epidermis. The activity of KLK7 is tightly regulated by multiple stages of maturation and reversible inhibition, similar to several other extracellular proteases. In this work, we used protease-specific inhibitors and active site variants to show that KLK7 undergoes autolysis at two separate sites in the 170 and 99 loops (chymotrypsinogen numbering), resulting in a loss of enzymatic activity. A protein BLAST search using the autolyzed KLK7 loop sequences identified mast cell chymase as a potential KLK7 substrate. Indeed, KLK7 cleaves chymase resulting in a concomitant loss of activity. We further demonstrate that KLK7 can hydrolyze other mast cell proteases as well as several cytokines. These cytokines belong mainly to the interferon and IL-10 families including IFN-α, IFN-β, IFN-γ, IL-28A/IFN-λ2, IL-20, IL-22, and IL-27. This is the first study to identify a possible molecular interaction link between KLK7 and mast cell proteases and cytokines. Although the precise biological implications of these findings are unclear, this study extends our understanding of the delicate balance of proteolytic regulation of enzyme activity that maintains physiological homeostasis, and facilitates further biological investigations. [ABSTRACT FROM AUTHOR]

Mas-related G protein-coupled receptor b2 (Mrgprb2) binding to its cationic endogenous and exogenous ligands induces mast cell degranulation and promotes inflammation in mice. However, the physiological roles of its human homologue MRGPRX2 remain unclear. Here we aimed to elucidate the mechanisms by which MRGPRX2 regulates vascular permeability, and generated MRGPRX2 knock-in (MRGPRX2-KI) and Mrgprb2 knockout (Mrgprb2-KO) mice. Substance P (SP) and ciprofloxacin strongly degranulated MRGPRX2-KI peritoneal mast cells (PMCs) better than WT PMCs, whereas Dermatophagoides pteronyssinus (Der p) extract and phenol-soluble modulin α3 (PSMα3) did not degranulate PMCs. SP-stimulated MRGPRX2-KI PMCs released large amounts of histamine and mast cell protease 4 (MCPT4) chymase. Der p extract, PSMα3, and MCPT4, but not histamine, induced SP release from dorsal root ganglion (DRG) cells. However, this effect of Der p extract/PSMα3 was suppressed by a transient receptor potential vanilloid 1 (TRPV1) antagonist. SP-, ciprofloxacin-, Der p extract-, PSMα3-, and MCPT4-induced vascular permeability was highest in MRGPRX2-KI mice, which depended on SP. In addition, SP-, ciprofloxacin- and PSMα3-induced MRGPRX2-dependent vascular hyperpermeability was suppressed by antihistamine and chymase inhibitor. TRPV1 antagonist also inhibited PSMα3-induced MRGPRX2-dependent vascular hyperpermeability. Both Mrgprb2-KO and MRGPRX2-KI did not influence the histamine-induced murine vascular hyperpermeability. Overall, our results suggest that neuronal SP induces MRGPRX2-dependent mast cell degranulation, releasing histamine and chymase, which promote vascular hyperpermeability directly or indirectly via DRG cell activation. Importantly, the worsening cycle (MRGPRX2 → mast cell degranulation → chymase → DRG activation → SP → MRGPRX2) seems to play an important role in human MRGPRX2-depdendent inflammation. [ABSTRACT FROM AUTHOR]

Purpose: Mast cells, their serine proteinase tryptase, and immunoglobulin E (IgE) can be involved in cutaneous carcinogenesis. Materials and methods: To study the association of tryptase+ and IgE+ cells with photodamage and skin cancers 385 adult patients (201 males, 184 females, 75 with immunosuppression) at risk of any type of skin cancer were examined. Skin biopsies were taken from the sun-protected medial arm and from the photodamaged dorsal forearm skin followed by immunohistochemical staining for tryptase and IgE. Results: The results show that tryptase+ and IgE+ cells are significantly higher in number in the photodamaged than sun-protected skin, both in immunocompetent and -compromised subjects, and there is a strong correlation between tryptase+ and IgE+ cells. The numbers of forearm tryptase+and especially IgE+cells associated significantly with the forearm photodamage severity. In the logistic regression analysis, the forearm to upper arm ratio of IgE+ cells produced a univariate odds ratio of 1.521 (p=.010) and a multivariate one of 3.875 (p=.047) for the history of squamous cell carcinoma. The serum level of total IgE correlated significantly to the IgE to tryptase ratio in both skin sites. Conclusions: Therefore, IgE+ mast cells participate in photodamage and carcinogenesis, though it is unclear whether they are tumor-protective or -causative. [ABSTRACT FROM AUTHOR]

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]

Purpose of Review: Biphasic anaphylaxis is a variant of anaphylaxis characterized by recurrence of symptoms after initial resolution of anaphylaxis. It was first described in the mid 1990s by Popa and Lerner. Our understanding of the pathophysiology and epidemiology of the condition has advanced considerably since then. The purpose of this manuscript is to review the literature surrounding biphasic anaphylaxis while highlighting key works and recent advances. Recent Findings: Prior studies have estimated biphasic anaphylaxis occurs in 0.4–20% of anaphylaxis episodes. The wide range may be related to differences in anaphylaxis diagnostic criteria which was inconsistent across studies. Recently identified risk factors for occurrence of biphasic anaphylaxis include severe initial symptoms including hypotension or hypoxia, delay in epinephrine use, and greater than one dose of epinephrine required to treat symptoms. Summary: Despite our progress to better understand biphasic anaphylaxis, there remain gaps in the literature. This article aims to review the recent literature including, epidemiology, risk factors, and management of biphasic anaphylaxis. [ABSTRACT FROM AUTHOR]

Background: Microbial infections, particularly those caused by rhinovirus (RV) and respiratory syncytial virus (RSV), are major triggers for asthma exacerbations. These viruses activate toll-like receptors (TLRs), initiating an innate immune response. To better understand microbial-induced asthma exacerbations, animal models that closely mimic human lung characteristics are essential. This study aimed to assess airway responses in guinea pigs exposed to TLR agonists, simulating microbial infections. Methods: The agonists poly(I: C) (TLR3), lipopolysaccharide (LPS; TLR4) and imiquimod (TLR7), or the combination of poly(I: C) and imiquimod (P/I) were administered intranasally once a day over four consecutive days. The latter group received daily intraperitoneal injections of dexamethasone starting one day before the TLR agonists challenge. Respiratory functions were measured by whole-body plethysmography and forced oscillatory technique. Bronchoalveolar lavage fluid (BALF) cells and lungs were collected for analysis. Results: The intranasal exposure of LPS and P/I caused an increase in enhanced pause (Penh) after challenge, whereas neither poly(I: C) nor imiquimod alone showed any effect. After the challenges of LPS, poly(I: C) or P/I, but not imiquimod alone, induced an increase of both Rrs (resistance of the respiratory system) and Ers (elastance of the respiratory system). LPS exposure caused an increase of neutrophils in BALF, whereas none of the other exposures affected the composition of cells in BALF. Exposure to LPS, poly (I: C), imiquimod, and P/I all caused a marked infiltration of inflammatory cells and an increase of mast cells around the small airways. For the expression of inflammatory mediators, LPS increased CXCL8, poly(I: C) and imiquimod decreased IL-4 and IL-5, and increased IFNγ. Imiquimod increased CXCL8 and IL-6, whereas P/I decreased IL-5, and increased IL-6 and IFNγ. The increases in Rrs, Ers, and airway inflammation, but not the altered expression of inflammatory cytokines, were attenuated by dexamethasone. Conclusions: TLR agonists promote acute airway inflammation and induce airway obstruction and hyperresponsiveness in guinea pigs. The severity of these effects varies depending on the specific agonists used. Notably, dexamethasone reversed pulmonary functional changes and mitigated bronchial inflammation caused by the combined treatment of P/I. However, it had no impact on the expression of inflammatory mediators. [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]

COVID-19 is an infectious disease caused by SARS-CoV-2; over the course of the disease, a dysregulated immune response leads to excessive inflammation that damages lung parenchyma and compromises its function. One of the cell lineages classically associated with pathological inflammatory processes is mast cells (MCs). MCs and their mediators have been associated with COVID-19; we previously reported the role of carboxypeptidase A3 (CPA3) in severe COVID-19. However, sequelae of SARS-CoV-2 infection have been poorly studied. In patients who successfully resolve the infection, one of the reported sequelae is pulmonary fibrosis (PF). The etiology and exact mechanisms are unknown, and few studies exist. Therefore, the aim of this study was to evaluate whether MCs are associated with PF development after SARS-CoV-2 infection. Our findings demonstrate that during severe cases of SARS-CoV-2 infection, there is an increased amount of CPA3+ MCs in areas with pneumonia, around thrombotic blood vessels, and in fibrotic tissue. Moreover, higher numbers of CPA3-expressing MCs correlate with fibrotic tissue development (r = 0.8323; p = 0.001170). These results suggest that during COVID-19, exacerbated inflammation favors the recruitment or expansion of MCs and CPA3 expression in the lungs, which favors tissue damage and a failure of repair mechanisms, leading to fibrosis. [ABSTRACT FROM AUTHOR]

Although antimicrobial peptides (AMPs) exhibit a range of biological functions, reports on AMPs with therapeutic effects in allergic disorders are limited. In this study, we investigated the anti-allergic effects of Pro10-1D, a 10-meric AMP derived from insect defensin protaetiamycine. Our findings demonstrate that Pro10-1D effectively inhibits antigen-induced degranulation of mast cells (MCs) with IC50 values of approximately 11.6 μM for RBL-2H3 cells and 2.7 μM for bone marrow-derived MCs. Furthermore, Pro10-1D suppressed the secretion of cytokines with IC50 values of approximately 2.8 μM for IL-4 and approximately 8.6 μM for TNF-α. Mechanistically, Pro10-1D inhibited the Syk-LAT-PLCγ1 signaling pathway in MCs and decreased the activation of mitogen-activated protein kinases (MAPKs). Pro10-1D demonstrated a dose-dependent reduction in IgE-mediated passive cutaneous anaphylaxis in mice with an ED50 value of approximately 7.6 mg/kg. Further investigation revealed that Pro10-1D significantly reduced the activity of key kinases Fyn and Lyn, which are critical in the initial phase of the FcεRI-mediated signaling pathway, with IC50 values of approximately 22.6 μM for Fyn and approximately 1.5 μM for Lyn. Collectively, these findings suggest that Pro10-1D represents a novel therapeutic candidate for the treatment of IgE-mediated allergic disorders by targeting the Lyn/Fyn Src family kinases in MCs. [ABSTRACT FROM AUTHOR]

Introduction: Hereditary alpha-tryptasemia (HαT) is associated with postural orthostatic tachycardia syndrome (POTS), hypermobile Ehlers-Danlos syndrome (hEDS), and mast cell activation syndrome (MCAS). While POTS, hEDS, and MCAS have all demonstrated increased prevalence of autoimmunity, this has not been investigated in HαT populations. Our objective was to describe the prevalence of autoantibodies in individuals with HαT. Methods: We retrospectively studied a cohort of patients with positive genotyping for HαT at a tertiary-care allergy clinic. Demographic data including previous autoimmune history and autoantibody serologies were extracted on chart review. A literature search was conducted to determine the prevalence of specific autoimmune and autoantibody prevalences in the general population. We compared the proportions of autoantibody positivity and established autoimmune diseases in our cohort of HαT individuals against those in general populations. Results: We identified 101 patients with HαT. Median age was 43 years (range 15–75), and most were female (87/101; 86.1%). Prevalence of self-reported drug hypersensitivity was 52/101 (52.5%) patients. The proportion of individuals with HαT with positive tTG antibody (3/61, 4.9%) was significantly higher than that reported in the general population (133/16,667, 0.8%) (p < 0.001). The prevalence of systemic lupus erythematosus (SLE) (1/101, 1%) and celiac disease (5/101, 5%) in our cohort were found to be significantly higher than the prevalence in the general population (194/96,996, 0.2% [p = 0.035] and 26/2,845, 0.9% [p < 0.001], respectively). Conclusion: Patients with HαT have increased prevalence of celiac disease, SLE, and positive anti-tTG serology, as well as self-reported drug hypersensitivity, relative to general populations. [ABSTRACT FROM AUTHOR]

The article discusses the assessment of IgE and basophil activity in blood samples from nonhuman primates, specifically cynomolgus monkeys, in the context of developing new drugs to combat allergies. The study compares IgE biology between humans and cynomolgus monkeys, finding similarities in key residues and binding affinities for FcεRI. The research suggests that cynomolgus monkeys could serve as a relevant model for testing novel anti-IgE therapies, with potential applications in drug development and clinical trials. [Extracted from the article]

Chronic wounds significantly burden health care systems worldwide, requiring novel strategies to ease their impact. Many physiological processes underlying wound healing are well studied but the role of mast cells remains controversial. Mast cells are innate immune cells and play an essential role in barrier function by inducing inflammation to defend the host against chemical irritants and infections, among others. Many mast cell–derived mediators have proposed roles in wound healing; however, in vivo evidence using mouse models has produced conflicting results. Recently, studies involving more complex wound models such as infected wounds, diabetic wounds and wounds healing under psychological stress suggest that mast cells play critical roles in these processes. This review briefly summarizes the existing literature regarding mast cells in normal wounds and the potential reasons for the contradictory results. Focus will be placed on examining more recent work emerging in the last 5 years that explores mast cells in more complex systems of wound healing, including infection, psychological stress and diabetes, with a discussion of how these discoveries may inspire future work in the field. [ABSTRACT FROM AUTHOR]

Mast cells are commonly found in pancreatic ductal adenocarcinoma (PDAC), yet their role in the disease remains uncertain. Although mast cells have been associated with depression in several diseases, their connection to PDAC in this context remains unclear. This study explored the correlation between mast cells and psychosocial stress in patients with PDAC. Prior to surgery, 40 patients with PDAC (n = 29 primary resected, n = 11 neoadjuvant treated) completed four questionnaires assessing stress and quality of life. Immunostaining was performed on the resected tumor tissue. Spearman analysis was employed to correlate mast cells with distress and neuropeptides serotonin and beta-endorphin serum and tissue levels. Patients with PDAC exhibited elevated levels of distress and worry. Lower number of mast cells within the tumor correlated with greater psychological burden. Among primary resected patients, mast cell count moderately correlated with joy and inversely with worries. Following neoadjuvant chemotherapy, strong inverse correlation was observed between anxiety, depression, and mast cell quantity. No correlation was found between mast cells and serotonin or beta-endorphin levels. In summary, mast cell presence inversely correlates with psychosocial stress, suggesting a link between immune cells and psychological well-being in pancreatic cancer. Targeting mast cells might offer therapeutic avenues for addressing cancer-induced depression and anxiety. [ABSTRACT FROM AUTHOR]

Background: Histopathologic criteria for diagnosis of cutaneous mastocytosis include 20 mast cells per high‐power field or clusters of 15 mast cells. We aimed to determine the specificity of these criteria for cutaneous mastocytosis in comparison with inflammatory disorders of mast cell activation. Methods: Twenty‐six cases of spongiotic dermatitis or urticaria were identified from 2021 to 2022. Recuts were stained with mast cell tryptase and slides were reviewed for the presence of 20 mast cells per high‐power field and for clusters of 15 mast cells. In addition, seven cases of mastocytosis were reviewed for the same criteria. Results: Twelve of 26 cases (46.1%) of spongiotic dermatitis/urticaria had at least 20 mast cells per high‐power field. Three of 26 cases (11.5%) of spongiotic dermatitis/urticaria had a cluster of 15 mast cells. Six of seven cases (85.7%) of mastocytosis had at least 20 mast cells per high‐power field; four of seven cases (57.1%) of mastocytosis had a cluster of 15 mast cells. Conclusions: In our study, the finding of 20 mast cells per high‐power field was nonspecific as a single criterion for cutaneous mastocytosis. The finding of clusters of 15 mast cells was more specific but not sensitive. [ABSTRACT FROM AUTHOR]

Introduction: Because MRGPRX2 is now recognized as the mast cell receptor for basic secretagogues, there is currently a tremendous interest in whetherMRGRPX2 could play an important role in various pruritic dermatoses such as chronic spontaneous urticaria. Therefore, we sought to identify new potent and selective antagonists to pharmacologically characterize the biological role of MRGPRX2. Methods: Various relevant in vitro, ex vivo, and in vivo model systems were used to investigate the role of MRGPRX2. This included the study of freshly isolated human skin mast cells and human basophils as well as an ex vivo human skin microdialysis preparation. The additivity of MRGPRX2 and FceR1-mediated degranulation was also investigated. Human MRGPRX2 knock-in mice were generated to interrogate pharmacokinetic/pharmacodynamic relationships because both antagonists studied were shown to be human specific. Results: Two novel and structurally distinct MRGPRX2 antagonists were identified with one, Compound B, being orally active and demonstrating high potency in blocking Substance P-mediated degranulation using freshly isolated human skin mast cells with half maximal inhibitory concentration (IC50) at 0.42 nM. Compound B also potently blocked Substance P-stimulated histamine release from resident mast cells in a human skin explant setup as well as blocking itch in an established behavioral scratching model using MRGPRX2 knock-in mice. Unlike human mast cells, Substance P failed to elicit a functional response in human basophils. Conclusion: These data fully support the investigation of MRGPRX2 receptor antagonists in mast cell-driven allergic skin disorders such as chronic spontaneous urticaria. [ABSTRACT FROM AUTHOR]

Interleukin-33 (IL-33) is an alarmin released by epithelial cells in response to tissue damage. It activates resident immune sentinel cells, which then produce signals commonly associated with type 2 immune responses, particularly affecting infiltrating antigen-specific T cells. Given that mast cells (MCs) are a primary target of IL-33 and can shape T helper (Th) cell responses, we investigated the effect of IL-33 priming on the ability of MCs to influence Th cell cytokine production. To examine the Th cell/MC interaction, we developed human primary MC/memory CD4+ T-cell coculture systems involving both cognate and non-cognate interactions. Our results demonstrated that IL-33-primed MCs, whether as bystander cells cocultured with activated effector T cells or functioning as antigen-presenting cells, promoted IL-9 and increased IL-13 production in Th cells via an OX40L-dependent mechanism. This indicates that MCs sense IL-33-associated danger, prompting them to direct Th cells to produce the key type 2 effector cytokines IL-9 and IL-13. [ABSTRACT FROM AUTHOR]

Skin mast cells (MCs) mediate acute allergic reactions in the cutaneous environment and contribute to chronic dermatoses, including urticaria, and atopic or contact dermatitis. The cAMP response element binding protein (CREB), an evolutionarily well conserved transcription factor (TF) with over 4,000 binding sites in the genome, was recently found to form a feedforward loop with KIT, maintaining MC survival. The most selective MC function is degranulation with its acute release of prestored mediators. Herein, we asked whether CREB contributes to the expression and function of the degranulation-competent receptors FcεRI and MRGPRX2. Interference with CREB by pharmacological inhibition (CREBi, 666-15) or RNA interference only slightly affected the expression of these receptors, while KIT was strongly attenuated. Interestingly, MRGPRX2 surface expression moderately increased following CREB-knockdown, whereas MRGPRX2-dependent exocytosis simultaneously decreased. FcεRI expression and function were regulated consistently, although the effect was stronger at the functional level. Preformed MC mediators (tryptase, histamine, β-hexosaminidase) remained comparable following CREB attenuation, suggesting that granule synthesis did not rely on CREB function. Collectively, in contrast to KIT, FcεRI and MRGPRX2 moderately depend on unperturbed CREB function. Nevertheless, CREB is required to maintain MC releasability irrespective of stimulus, insinuating that CREB may operate by safeguarding the degranulation machinery. To our knowledge, CREB is the first factor identified to regulate MRGPRX2 expression and function in opposite direction. Overall, the ancient TF is an indispensable component of skin MCs, orchestrating not only survival and proliferation but also their secretory competence. [ABSTRACT FROM AUTHOR]

Interleukin-33 (IL-33) is an alarmin released by epithelial cells in response to tissue damage. It activates resident immune sentinel cells, which then produce signals commonly associated with type 2 immune responses, particularly affecting infiltrating antigen-specific T cells. Given that mast cells (MCs) are a primary target of IL-33 and can shape T helper (Th) cell responses, we investigated the effect of IL-33 priming on the ability of MCs to influence Th cell cytokine production. To examine the Th cell/MC interaction, we developed human primary MC/memory CD4+ T-cell coculture systems involving both cognate and non-cognate interactions. Our results demonstrated that IL-33-primed MCs, whether as bystander cells cocultured with activated effector T cells or functioning as antigen-presenting cells, promoted IL-9 and increased IL-13 production in Th cells via an OX40L-dependent mechanism. This indicates that MCs sense IL-33-associated danger, prompting them to direct Th cells to produce the key type 2 effector cytokines IL-9 and IL-13. [ABSTRACT FROM AUTHOR]

Cationic liposomes composed of cholesteryl‐3β‐carboxyamidoethylene‐N‐hydroxyethylamine (OH‐chol) and 1,2‐dioleoyl‐sn‐glycero‐3‐phosphatidylethanolamine (DOPE) inhibit mast cell degranulation mediated via crosslinking of high‐affinity IgE receptors (FcεRI). Although the inhibitory efficiency of mast cell degranulation is altered by modifying the ratio of OH‐chol and DOPE in cationic liposomes, the manner in which physicochemical properties, such as surface charge and size, influence suppression is not clear. We observed that positive surface charge, but not the size, of liposomes plays a role in suppressing rat basophilic leukemia (RBL‐2H3) cell activation. Pretreatment with middle‐ratio OH‐chol liposomes (zeta potential, 62.2 ± 0.5 mV; diameter, 325.4 ± 7.3 nm) exhibited a larger suppression of RBL‐2H3 cell degranulation evoked by FcεRI crosslinking compared with that by low‐ratio OH‐chol liposomes (zeta potential, 48.6 ± 1.9 mV; diameter, 344.4 ± 25.0 nm), although both liposomes were similarly attached to RBL‐2H3 cells. Preparation of middle‐ratio OH‐chol liposomes, classified roughly by size using an extrusion method, revealed that the liposomal size did not affect the inhibitory efficiency of RBL‐2H3 cell activation. Mechanistically, we found that middle‐ratio OH‐chol liposomes increased the inhibition of antigen‐induced Akt phosphorylation compared to low‐ratio OH‐chol liposomes. We measured the phosphorylation of linker for activation of T cells (LAT) and paxillin, which are important proteins in FcεRI‐ and focal adhesions (FAs)‐mediated signaling, respectively. Middle ratio OH‐chol liposomes significantly suppressed antigen‐induced paxillin phosphorylation, but did not affect LAT phosphorylation, suggesting that middle‐ratio OH‐chol liposomes attached to RBL‐2H3 cells suppress the degranulation by impairing FA‐mediated Akt phosphorylation evoked by FcεRI crosslinking. [ABSTRACT FROM AUTHOR]

BACKGROUND: Stress‐related diseases are on the rise and stress is one of the common factors that lead to ulcer. Stress‐induced mucosal bleeding is a serious complication observed in many critically ill patients. Due to the harmful side effects of proton pump inhibitors, natural and active alternative treatment methods for peptic ulcer treatment that are safe in terms of side effects are an urgent need for human health. We aimed to investigate the dose‐dependent protective effects of Lactobacillus rhamnosus GG (LGG) against stress ulcer induced by cold restraint stress in rats. This study was performed in a total of 42 rats, in control group (C), stress group (S), pantoprazole (20 mg kg−1 day−1) group (P), LGG (3 × 108 cfu mL−1 day−1) + stress group (M1), LGG (15 × 108 mL−1 day−1) + stress group (M5) and LGG (30 × 108 mL−1 day−1) + stress group (M10) (each n = 7). Ulceration areas (mm2) were determined quantitatively with ImageJ software. Glucocorticoid, catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels were determined by ELISA and malondialdehyde levels were determined by spectrophotometric measurement. Histopathological examinations were performed in gastric tissue. RESULTS: Therapeutic dose of LGG increased CAT, SOD and GPx levels; prevented excessive activation of the hypothalamic–pituitary–adrenal axis; reduced ulceration and bleeding in the gastric mucosal layer; and provided stabilization of mast cells. CONCLUSIONS: We can suggest that LGG may be beneficial for reducing the negative effects of stress on the body, for protecting against ulcer disease and for reducing or preventing the risk of stress‐induced gastrointestinal bleeding in patients staying in intensive care units. © 2024 The Author(s). Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

As one of the key components of the immune system, mast cells are well known for their role in allergic reactions. However, they are also involved in inflammatory and fibrotic processes. Mast cells participate in all the stages of acute inflammatory responses, playing an immunomodulatory role in both innate and adaptive immunity. Mast cell-derived histamine, TNF-α, and IL-6 contribute to the inflammatory processes, while IL-10 mediates the suppression of inflammation. Crosstalk between mast cells and other immune cells is also involved in the development of inflammation. The cell-cell adhesion of mast cells and fibroblasts is crucial for fibrosis. Mast cell mediators, including cytokines and proteases, play contradictory roles in the fibrotic process. Here, we review the double-edged role of mast cells in inflammation and fibrosis. [ABSTRACT FROM AUTHOR]

Contagious caprine pleuropneumonia (CCPP) in goats is defined as a highly contagious and rapidly spreading mycoplasmal disease that is now among the leading causes of major economic losses on many continents (Asia, Africa and the Middle East). In this study, we aimed to evaluate immunohistochemically mast cells (MCs) profile and local interleukin (IL)-17 and IL-1β protein expressions in naturally infected CCPP according to the course of the inflammation (peracute-acute, subacute-chronic). The material of the study consisted of 40 naturally infected CCPP and 6 healthy control goat lung tissues. Appropriate samples were taken from the necropsied goats and subjected to histopathological and immunohistochemical examination. In the histopathological examination of the samples, it was determined that 29 samples had a peracute-acute course and 11 had a subacute-chronic course. In immunohistochemical examination, MC profile and local IL-17 and IL-1β protein expressions were evaluated in the peracute-acute and subacute-chronic course. Immunohistochemically, significant increases in MC number, local IL-17 and IL-1β scores were detected in the peracuteacute course compared to the control group. There were significant decreases in the relevant scores in the subacute-chronic course compared to the peracute-acute course. Current findings indicated that MC, IL-17, and IL-1β expressions played important roles in the pathogenesis of infection in naturally infected CCPP, especially in the peracute-acute course. Additionally, MC profile was evaluated for the first time in naturally infected CCPP. [ABSTRACT FROM AUTHOR]

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Chronic wasting disease (CWD) is a transmissible and fatal prion disease that affects cervids. While both oral and nasal routes of exposure to prions cause disease, the spatial and temporal details of how prions enter the central nervous system (CNS) are unknown. Carotid bodies (CBs) are structures that are exposed to blood-borne prions and are densely innervated by nerves that are directly connected to brainstem nuclei, known to be early sites of prion neuroinvasion. All CBs examined contained mast cells expressing the prion protein which is consistent with these cells playing a role in neuroinvasion following prionemia.

Abstract 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. Graphical abstract

Abstract Background Microbial infections, particularly those caused by rhinovirus (RV) and respiratory syncytial virus (RSV), are major triggers for asthma exacerbations. These viruses activate toll-like receptors (TLRs), initiating an innate immune response. To better understand microbial-induced asthma exacerbations, animal models that closely mimic human lung characteristics are essential. This study aimed to assess airway responses in guinea pigs exposed to TLR agonists, simulating microbial infections. Methods The agonists poly(I: C) (TLR3), lipopolysaccharide (LPS; TLR4) and imiquimod (TLR7), or the combination of poly(I: C) and imiquimod (P/I) were administered intranasally once a day over four consecutive days. The latter group received daily intraperitoneal injections of dexamethasone starting one day before the TLR agonists challenge. Respiratory functions were measured by whole-body plethysmography and forced oscillatory technique. Bronchoalveolar lavage fluid (BALF) cells and lungs were collected for analysis. Results The intranasal exposure of LPS and P/I caused an increase in enhanced pause (Penh) after challenge, whereas neither poly(I: C) nor imiquimod alone showed any effect. After the challenges of LPS, poly(I: C) or P/I, but not imiquimod alone, induced an increase of both Rrs (resistance of the respiratory system) and Ers (elastance of the respiratory system). LPS exposure caused an increase of neutrophils in BALF, whereas none of the other exposures affected the composition of cells in BALF. Exposure to LPS, poly (I: C), imiquimod, and P/I all caused a marked infiltration of inflammatory cells and an increase of mast cells around the small airways. For the expression of inflammatory mediators, LPS increased CXCL8, poly(I: C) and imiquimod decreased IL-4 and IL-5, and increased IFNγ. Imiquimod increased CXCL8 and IL-6, whereas P/I decreased IL-5, and increased IL-6 and IFNγ. The increases in Rrs, Ers, and airway inflammation, but not the altered expression of inflammatory cytokines, were attenuated by dexamethasone. Conclusions TLR agonists promote acute airway inflammation and induce airway obstruction and hyperresponsiveness in guinea pigs. The severity of these effects varies depending on the specific agonists used. Notably, dexamethasone reversed pulmonary functional changes and mitigated bronchial inflammation caused by the combined treatment of P/I. However, it had no impact on the expression of inflammatory mediators.

Abstract Mast cells are commonly found in pancreatic ductal adenocarcinoma (PDAC), yet their role in the disease remains uncertain. Although mast cells have been associated with depression in several diseases, their connection to PDAC in this context remains unclear. This study explored the correlation between mast cells and psychosocial stress in patients with PDAC. Prior to surgery, 40 patients with PDAC (n = 29 primary resected, n = 11 neoadjuvant treated) completed four questionnaires assessing stress and quality of life. Immunostaining was performed on the resected tumor tissue. Spearman analysis was employed to correlate mast cells with distress and neuropeptides serotonin and beta-endorphin serum and tissue levels. Patients with PDAC exhibited elevated levels of distress and worry. Lower number of mast cells within the tumor correlated with greater psychological burden. Among primary resected patients, mast cell count moderately correlated with joy and inversely with worries. Following neoadjuvant chemotherapy, strong inverse correlation was observed between anxiety, depression, and mast cell quantity. No correlation was found between mast cells and serotonin or beta-endorphin levels. In summary, mast cell presence inversely correlates with psychosocial stress, suggesting a link between immune cells and psychological well-being in pancreatic cancer. Targeting mast cells might offer therapeutic avenues for addressing cancer-induced depression and anxiety.

Abstract Although the cellular prion protein (PrPC) has been evolutionarily conserved, the role of this protein remains elusive. Recent evidence indicates that PrPC may be involved in neuroinflammation and the immune response in the brain, and its expression may be modified via various mechanisms. Histamine is a proinflammatory mediator and neurotransmitter that stimulates numerous cells via interactions with histamine receptors 1-4 (HRH1-4). Since microglia are the innate immune cells of the central nervous system, we hypothesized that histamine-induced stimulation regulates the expression of PrPC in human-derived microglia. The human microglial clone 3 (HMC3) cell line was treated with histamine, and intracellular calcium levels were measured via a calcium flux assay. Cytokine production was monitored by enzyme-linked immunosorbent assay (ELISA). Western blotting and quantitative reverse transcription-polymerase chain reaction were used to determine protein and gene expression of HRH1-4. Flow cytometry and western blotting were used to measure PrPC expression levels. Fluorescence microscopy was used to examine Iba-1 and PrPC localization. HMC3 cells stimulated by histamine exhibited increased intracellular calcium levels and increased release of IL-6 and IL-8, while also modifying PrPC localization. HMC3 stimulated with histamine for 6 and 24 hours exhibited increased surface PrPC expression. Specifically, we found that stimulation of the HRH2 receptor was responsible for changes in surface PrPC. Histamine-induced increases in surface PrPC were attenuated following inhibition of the HRH2 receptor via the HRH2 antagonist ranitidine. These changes were unique to HRH2 activation, as stimulation of HRH1, HRH3, or HRH4 did not alter surface PrPC. Prolonged stimulation of HMC3 decreased PrPC expression following 48 and 72 hours of histamine stimulation. HMC3 cells can be stimulated by histamine to undergo intracellular calcium influx. Surface expression levels of PrPC on HMC3 cells are altered by histamine exposure, primarily mediated by HRH2. While histamine exposure also increases release of IL-6 and IL-8 in these cells, this cytokine release is not fully dependent on PrPC levels, as IL-6 release is only partially reduced and IL-8 release is unchanged under the conditions of HRH2 blockade that prevent PrPC changes. Overall, this suggests that PrPC may play a role in modulating microglial responses.

Background: Mast cells play an important role in allergic reactions by releasing potent mediators, including histamine and platelet-activating factor (PAF), upon activation. We recently reported that a biotinylated heptapeptide (peptide 2), D-Lys(Biotinyl)-Trp-Tyr-Lys-Asp-Gly-Asp, which is highly stable in the plasma, inhibits PAF bioactivity and anaphylactic hypothermia in vivo. However, the effects of this peptide on allergy induction by mast cells have not been investigated. Methods and Results: Several biotinylated heptapeptides, including peptide 2, inhibited IgE/antigen-stimulated degranulation in RBL-2H3 cells. Peptide 2 also markedly inhibited the degranulation induced by calcium ionophore A23187. All peptides (peptide 1, 2 and 3) inhibited activating stimuli-induced increase in intracellular Ca2+ levels. The transforming growth factor-alpha shedding assay indicated that peptide 2 antagonized against the histamine H1 receptor. Furthermore, peptide 2 inhibited histamine-induced rat paw edema. Conclusion: These results highlight the potential of peptide 2 in the prevention and treatment of various allergic diseases mediated by mast cell activation. [ABSTRACT FROM AUTHOR]

Abstract Morbihan's disease is a rare condition characterized by chronic facial edema. While its exact cause is unknown, it is thought to involve local cutaneous vascularization and lymphatic drainage imbalance. Traditional treatment options are often ineffective, and no established efficient treatment exists. We present a case study of a 17‐year‐old male with Morbihan's syndrome who showed resistance to traditional treatments but responded well to a combination of cromolyn sodium nasal spray and oral montelukast after histopathology revealed hyperplasia of plasma cells and mast cells. This combination has not been used before for Morbihan's syndrome. Our review of the literature also provides insight for clinicians seeking to manage this condition.

Mast cells serve as crucial effector cells within the innate immune system and are predominantly localized in the skin, airways, gastrointestinal tract, urinary and reproductive tracts, as well as in the brain. Under physiological conditions, brainresident mast cells secrete a diverse array of neuro-regulatory mediators to actively participate in neuroprotection. Meanwhile, as the primary source of molecules causing brain inflammation, mast cells also function as the "first responders" in brain injury. They interact with neuroglial cells and neurons to facilitate the release of numerous inflammatory mediators, proteases, and reactive oxygen species. This process initiates and amplifies immuneinflammatory responses in the brain, thereby contributing to the regulation of neuroinflammation and blood-brain barrier permeability. This article provides a comprehensive overview of the potential mechanisms through which mast cells in the brain may modulate neuroprotection and their pathological implications in various neurological disorders. It is our contention that the inhibition of mast cell activation in brain disorders could represent a novel avenue for therapeutic breakthroughs. [ABSTRACT FROM AUTHOR]

Background: In patients who require venom immunotherapy (VIT), there is a need to identify underlying mast cell (MC) disorders since these may affect the risk and severity of future sting reactions and the long‐term effectiveness of VIT. Methods: 1319 individuals with Hymenoptera venom allergy (HVA) who needed VIT from referral centers in Slovenia, Austria, Croatia, and Poland underwent examination for KIT p.D816V in peripheral blood leukocytes (PBL) using a highly sensitive PCR test and tryptase genotyping by digital droplet PCR. We also included 183 control individuals with large local reactions (LLRs) to Hymenoptera stings and with asymptomatic sensitization to Hymenoptera venoms. Results: 285 of 1319 individuals recommended for VIT (21.6%) were positive for KIT p.D816V in PBL, preferably those who present with severe reaction (33.9% [n = 207 of 610] with Ring‐Messmer grade 3–4 vs. 11% [n = 78 of 709] with Grade 1–2; p <.0001), whereas only 1.3% (n = 2 of 152) of controls with LLR and none with asymptomatic sensitization (n = 31) had KIT p.D816V. KIT p.D816V allelic burden was higher in those with severe reaction (median 0.018% [n = 207] in Grade 3–4 vs. 0.001% [n = 78] in Grade 1–2; p <.0001), and the majority had normal baseline serum tryptase levels (69% [n = 196 of 285]). All KIT p.D816V‐positive individuals (n = 41) who underwent bone marrow (BM) biopsy were found to have underlying clonal diseases, principally BM mastocytosis. HαT was also associated with severe HVA and symptoms (p <.01), and remarkably, 31.0% (n = 31 of 100) were found to have concomitant KIT p.D816V. Concomitant HαT and KIT p.D816V showed an additive effect, and having both was associated with the highest risk for severe HVA, even higher than having either HαT or KIT p.D816V alone (OR = 3.8; p <.01). Conclusions: By employing prospective universal tryptase genotyping and examination for KIT p.D816V in PBL in large HVA populations, we have demonstrated a high burden of clonal MC disorders and HαT in patients who require VIT. [ABSTRACT FROM AUTHOR]

The gut–skin axis has recently been widely recognized, and both the gut and skin have been found to affect each other through a bidirectional connection; however, the precise mechanisms remain to be elucidated. Therefore, we aimed to investigate the effects of chronic skin damage (CSD) on mouse intestines. Following the CSD model, 4% sodium dodecyl sulfate was applied to the back-shaved murine skin six times for 2 weeks after tape stripping. The small and large intestines were analyzed histologically and immunologically, respectively. Intestinal permeability was measured using fluorescein isothiocyanate-conjugated-dextran. The role of interleukin-13 (IL-13) in the ileum was investigated using an anti-IL-13 antibody. Apoptotic intestinal cells were analyzed using TUNEL staining. Villus atrophy was observed in the small intestine in the CSD model, along with increased permeability. Mast cells, but not T cells, eosinophils, or innate lymph cell-2, were increased in the intestinal mucosa. However, no significant changes were observed in the large intestine. mRNA expression of IL-13 was increased only in the ileum of the CSD model. Apoptotic intestinal epithelial cells were significantly increased in the ileum of the CSD model. Administration of an anti-IL-13 antibody ameliorated the intestinal damage caused by CSD, along with decreased apoptotic cells and mast cell infiltration. Skin damage causes morphological changes in the small intestine, accompanied by increased intestinal permeability, possibly through the IL-13-induced apoptosis of mast cells in the epithelium. Surfactant-mediated mechanical skin damage can cause a leaky gut. Gut and skin have been found to affect each other through a bidirectional connection (gut–skin axis), though the precise mechanisms remain to be elucidated. In this study, surfactant-mediated mechanical chronic skin damage caused morphological changes in the small intestine of mice, accompanied by increased intestinal permeability, possibly through the interleukin-13-induced apoptosis of mast cells in the epithelium. Graphical Abstract [ABSTRACT FROM AUTHOR]

Introduction: Tryptase is an important biomarker widely used in the laboratory confirmation of severe hypersensitivity reactions, especially anaphylaxis. It also plays a crucial role in the diagnosis, risk stratification, management and prognostic evaluation of many other mast cell-related conditions. Aim: This paper aims to highlight the role of serum tryptase, both in allergic disorders and other mast cell-related conditions. Two clinical cases regarding timely serum tryptase acquisition (in drug hypersensitivity reactions during the imaging procedure and perioperative anaphylaxis) are meant to emphasize the clinical potential of this protease. Method: We performed a comprehensive literature search of the PubMed/Medline and Scopus databases. From a total of 640 subject related publications, dating from 1940 to 2024, 45 articles written in English were selected. Literature search results: Total serum tryptase is a simple, cost-effective analysis with a normal baseline tryptase (sBT) level below 8.4 µg/L. Elevated sBT can indicate hereditary alpha-tryptasemia (HαT), mastocytosis and other non-allergic disorders. Patients with higher sBT levels, especially with insect venom allergy, have an increased risk of severe reactions and thereby require a prolonged treatment. All immediate systemic hypersensitivity reactions require a correlation between serum acute tryptase (sAT) and sBT. According to the guidelines, measuring sAT 30 min to 2 h after the symptom onset and sBT 24 h after the resolution, using the 20 + 2 rule and an sAT/sBT ratio of 1.685, improves the diagnostic accuracy in anaphylaxis. Conclusions: Tryptase levels should be acquired in all cases with clinical suspicion of MC degranulation. Given the increasing clinical relevance, elevated baseline serum tryptase levels require a multidisciplinary approach and further investigation. [ABSTRACT FROM AUTHOR]

Lactation anaphylaxis is extremely rare and has been scarcely reported in the literature. Breast feeding and/or milk expression immediately induces lifethreatening anaphylactic reactions, including generalized urticaria, angioedema, respiratory symptoms, and hypotension. Six English-language case reports have described the clinical course in detail. The present report describes a case involving a 24-year-old woman with no history of allergic reactions or anaphylaxis who experienced anaphylactic reactions three times immediately after milk expression. Lactation anaphylaxis was suspected when a detailed medical history revealed lactation-related recurrent anaphylactic symptoms. The authors prescribed bromocriptine to stop lactation and switched her to formula feeding, which resulted in no further anaphylactic episodes. Based on a review of the relevant literature, this report describes the characteristics of lactation anaphylaxis and possible management strategies. The pathogenesis of lactation anaphylaxis has been inferred from various experimental results. [ABSTRACT FROM AUTHOR]

Neurology and connective tissue are intimately interdependent systems and are critical in regulating many of the body’s systems. Unlocking their multifaceted relationship can transform clinical understanding of the mechanisms involved in multisystemic regulation and dysregulation. The fascial system is highly innervated and rich with blood vessels, lymphatics, and hormonal and neurotransmitter receptors. Given its ubiquity, fascia may serve as a “watchman,” receiving and processing information on whole body health. This paper reviews what constitutes fascia, why it is clinically important, and its contiguous and interdependent relationship with the nervous system. Unquestionably, fascial integrity is paramount to human locomotion, interaction with our environment, bodily sense, and general physical and emotional wellbeing, so an understanding of the fascial dysregulation that defines a range of pathological states, including hypermobility syndromes, autonomic dysregulation, mast cell activation, and acquired connective tissue disorders is critical in ensuring recognition, research, and appropriate management of these conditions, to the satisfaction of the patient as well as the treating practitioner. [ABSTRACT FROM AUTHOR]

Introduction: Mast cells are the principal cells involved in acute and chronic colitis due to radiation, known as radiation-induced colitis (RIC). In this study, we investigated whether pretreatment with tranilast, a mast cell inhibitor, could alleviate chronic RIC. Methods: A total of 23 Sprague-Dawley rats were randomly divided into three groups: control group (n = 5), radiation group (RG, n = 9), and tranilast-pretreated radiation group (TG, n = 9). The rats in the RG and the TG were irradiated in the pelvic area (1.5 cm from the anus) with a single dose of 20 Gy under general anesthesia. Tranilast (100 mg/kg) was administered intraperitoneally to the rats of the TG for 10 days, starting from the day of pelvic radiation. Ten weeks after radiation, the rats were euthanized. Rectal tissue samples were histologically evaluated for the total inflammation score (TIS) and mast cell count. The expression of MUC2, MUC5AC, and matrix metalloproteinase-9 (MMP-9) was also assessed immunohistochemically. Results: Both the TIS and specific components of TIS such as epithelial atypia, vascular sclerosis, and colitis cystica profunda (CCP) were significantly higher in the RG than in the TG (p = 0.02, 0.038, 0.025, and 0.01, respectively). Thein number of infiltrating mast cells was significantly higher in the RG than in the TG (median [range]: 20 [3−54] versus 6 [3−25], respectively; p = 0.034). Quantitatively, the number of MMP-9-positive cells was significantly higher in the RG (23.67 ± 19.00) than in the TG (10.25 ± 8.45) (mean ± standard deviation; p < 0.05). TIS and MMP-9 exhibited a strong association (correlation coefficient r = 0.56, p < 0.05). Immunohistochemically, the mucin-lake of CCP showed no staining for MUC5AC but was stained positive for MUC2. Conclusion: Tranilast pretreatment of chronic RIC showed an anti-inflammatory effect associated with the reduction of mast cell infiltration and MMP-9 expression. [ABSTRACT FROM AUTHOR]

The high-affinity IgE receptor, FcεRI, is typically associated with type 2 effectors such as mast cells (MC). The relatively unique expression profile of FcεRI and accumulating evidence from pre-clinical and clinical settings, such as MC interactions with tumors, have led us to study MCs as a potential therapeutic target in breast cancer. Our work identified MCs interacting with tumor cells at primary sites using the 4T1 (BALB/c) adenocarcinoma model in vivo. However, this analysis was complicated by a surprising finding that the tumor cells intrinsically and strongly expressed FcεRI. We further studied the expression and function of FcεRI in breast cancer cells in vitro. The 4T1 cells expressed FcεRI to a level similar to mouse bone marrow-derived MC (BMMC). Additionally, two established breast cancer cultures derived from human T-47D cells, one estrogen-dependent (E3) and the other estrogen-withdrawn (EWD8), also expressed FcεRI with EWD8 cells showing the greatest abundance. Functional analyses indicated that IgE-mediated antigen stimulation did not elicit classic Ca2+ flux in breast cancer cells as seen in the respective species' MCs; however, FcεRI crosslinking could stimulate IL-6 production from the T-47D derivatives. Preliminary analysis of primary breast cancer biopsy datasets using R2: Genomics Analysis and Visualization Platform was discordant with our in vivo model and in vitro observations. Indeed, FcεRI mRNA abundance declined in metastatic breast cancers compared to non-cancerous breast tissue. Altogether, we report a previously unidentified and immunologically substantive difference between breast cancer models and human primary tumors. Investigators pursuing FcεRI-relevant therapeutics in this context should be aware of this translational barrier. [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]

Age-related macular degeneration (AMD) is a common retinal neurodegenerative disease among the elderly. Neovascular AMD (nAMD), a leading cause of AMD-related blindness, involves choroidal neovascularization (CNV), which can be suppressed by anti-angiogenic treatments. However, current CNV treatments do not work in all nAMD patients. Here we investigate a novel target for AMD. Granzyme B (GzmB) is a serine protease that promotes aging, chronic inflammation and vascular permeability through the degradation of the extracellular matrix (ECM) and tight junctions. Extracellular GzmB is increased in retina pigment epithelium (RPE) and mast cells in the choroid of the healthy aging outer retina. It is further increased in donor eyes exhibiting features of nAMD and CNV. Here, we show in RPE-choroidal explant cultures that exogenous GzmB degrades the RPE-choroid ECM, promotes retinal/choroidal inflammation and angiogenesis while diminishing anti-angiogenic factor, thrombospondin-1 (TSP-1). The pharmacological inhibition of either GzmB or mast-cell degranulation significantly reduces choroidal angiogenesis. In line with our in vitro data, GzmB-deficiency reduces the extent of laser-induced CNV lesions and the age-related deterioration of electroretinogram (ERG) responses in mice. These findings suggest that targeting GzmB, a serine protease with no known endogenous inhibitors, may be a potential novel therapeutic approach to suppress CNV in nAMD. [ABSTRACT FROM AUTHOR]

Purpose of Review: Chronic inducible urticaria (CIndU) is a group of long-persisting and challenging to manage diseases, characterized by recurrent wheals and angioedema induced by definite triggers. In this review, we address recent findings on CIndU pathogenesis, diagnosis as well as its treatment, and we discuss novel potential targets that may lead to the development of more effective therapies for CIndU patients. Recent Advances: Meaningful advances in the understanding of its pathogenesis have been reported in the last decades. Novel CIndU-specific patient-reported outcome measures enable a closer and better evaluation of patients. Summary: CIndU is a hard-to-treat disease that highly impairs quality of life (QoL) of affected patients. Provocation tests allow to diagnose CIndU subtypes. The only licensed and recommended treatment for CIndU are second generation non-sedating H1-antihistamines, which lack efficacy in many cases. Omalizumab off-label use has been assessed in all types of CIndU with overall good outcomes. Promising emerging therapies currently assessed in chronic spontaneous urticaria are paving the path for novel treatments for CIndU [ABSTRACT FROM AUTHOR]

Purpose of the review: With increased access and decriminalization of cannabis use, cases of IgE-dependent cannabis allergy (CA) and cross-reactivity syndromes have been increasingly reported. However, the exact prevalence of cannabis allergy and associated cross-reactive food syndromes (CAFS) remains unknown and is likely to be underestimated due to a lack of awareness and insufficient knowledge of the subject among health care professionals. Therefore, this practical roadmap aims to familiarize the reader with the early recognition and correct management of IgE-dependent cannabis-related allergies. In order to understand the mechanisms underlying these cross-reactivity syndromes and to enable personalized diagnosis and management, special attention is given to the molecular diagnosis of cannabis-related allergies. Recent findings: The predominant signs and symptoms of CA are rhinoconjunctivitis and contact urticaria/angioedema. However, CA can also present as a life-threatening condition. In addition, many patients with CA also have distinct cross-reactivity syndromes, mainly involving fruits, vegetables, nuts and cereals. At present, five allergenic components of Cannabis sativa (Can s); Can s 2 (profilin), Can s 3 (a non-specific lipid protein), Can s 4 (oxygen-evolving enhancer protein 2 oxygen), Can s 5 (the Bet v 1 homologue) and Can s 7 (thaumatin-like protein) have been characterized and indexed in the WHO International Union of Immunological Sciences (IUIS) allergen database. However, neither of them is currently readily available for diagnosis, which generally starts by testing crude extracts of native allergens. Summary: The road to a clear understanding of CA and the associated cross-reactive food syndromes (CAFS) is still long and winding, but well worth further exploration. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD), a prevalent and progressive degenerative disease of the macula, is the leading cause of blindness in elderly individuals in developed countries. The advanced stages include neovascular AMD (nAMD), characterized by choroidal neovascularization (CNV), leading to subretinal fibrosis and permanent vision loss. Despite the efficacy of anti-vascular endothelial growth factor (VEGF) therapy in stabilizing or improving vision in nAMD, the development of subretinal fibrosis following CNV remains a significant concern. In this review, we explore multifaceted aspects of subretinal fibrosis in nAMD, focusing on its clinical manifestations, risk factors, and underlying pathophysiology. We also outline the potential sources of myofibroblast precursors and inflammatory mechanisms underlying their recruitment and transdifferentiation. Special attention is given to the potential role of mast cells in CNV and subretinal fibrosis, with a focus on putative mast cell mediators, tryptase and granzyme B. We summarize our findings on the role of GzmB in CNV and speculate how GzmB may be involved in the pathological transition from CNV to subretinal fibrosis in nAMD. Finally, we discuss the advantages and drawbacks of animal models of subretinal fibrosis and pinpoint potential therapeutic targets for subretinal fibrosis. [ABSTRACT FROM AUTHOR]

The high‐affinity IgE receptor FcεRI is the mast cell (MC) receptor responsible for the involvement of MCs in IgE‐associated allergic disorders. Activation of the FcεRI is achieved via crosslinking by multivalent antigen (Ag) recognized by IgE resulting in degranulation and proinflammatory cytokine production. In comparison to the T‐ and B‐cell receptor complexes, for which several co‐receptors orchestrating the initial signaling events have been described, information is scarce about FcεRI‐associated proteins. Additionally, it is unclear how FcεRI signaling synergizes with input from other receptors and how regulators affect this synergistic response. We found that the HDL receptor SR‐BI (gene name: Scarb1/SCARB1) is expressed in MCs, functionally associates with FcεRI, and regulates the plasma membrane cholesterol content in cholesterol‐rich plasma membrane nanodomains. This impacted the activation of MCs upon co‐stimulation of the FcεRI with receptors known to synergize with FcεRI signaling. Amongst them, we investigated the co‐activation of the FcεRI with the receptor tyrosine kinase KIT, the IL‐33 receptor, and GPCRs activated by adenosine or PGE2. Scarb1‐deficient bone marrow‐derived MCs showed reduced cytokine secretion upon co‐stimulation conditions suggesting a role for plasma membrane‐associated cholesterol regulating respective MC activation. Mimicking Scarb1 deficiency by cholesterol depletion employing MβCD, we identified PKB and PLCγ1 as cholesterol‐sensitive proteins downstream of FcεRI activation in bone marrow‐derived MCs. When MCs were co‐stimulated with stem cell factor (SCF) and Ag, PLCγ1 activation was boosted, which could be mitigated by cholesterol depletion and SR‐BI inhibition. Similarly, SR‐BI inhibition attenuated the synergistic response to PGE2 and anti‐IgE in the human ROSAKIT WT MC line, suggesting that SR‐BI is a crucial regulator of synergistic MC activation. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) is a chronic debilitating condition, hallmarked by persistent inflammation of the gastrointestinal tract. Despite recent advances in clinical treatments, the aetiology of IBD is unknown, and a large proportion of patients are refractory to pharmacotherapy. Understanding IBD immunopathogenesis is crucial to discern the cause of IBD and optimise treatments. Mas‐related G protein‐coupled receptors (Mrgprs) are a family of approximately 50 G protein‐coupled receptors that were first identified over 20 years ago. Originally known for their expression in skin nociceptors and their role in transmitting the sensation of itch in the periphery, new reports have described the presence of Mrgprs in the gastrointestinal tract. In this review, we consider the impact of these findings and assess the evidence that suggests that Mrgprs may be involved in the disrupted homeostatic processes that contribute to gastrointestinal disorders and IBD. LINKED ARTICLES: This article is part of a themed issue Therapeutic Targeting of G Protein‐Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc [ABSTRACT FROM AUTHOR]

This is the first study to describe the subtypes, number and distribution of mast cells (MC) in cat tongue by histochemical and immunohistochemical methods. Six male adult felines' tongue tissue samples consist of the study's material. Samples were fixed in 10% formaldehyde. MC number and distribution in the feline tongue were assessed using toluidine blue. Also, sections taken from blocks were stained in alcian blue/safranin O (AB/SO) combined dyes to determine the MC subtypes. The Streptavidin biotin complex method using anti‐chymase and anti‐tryptase primary antibodies was used for immunohistochemistry. Metachromatic MCs were mainly observed in the lamina propria close to the multilayered keratinized stratified squamous epithelium. The high number of MCs in this region may be because the dorsal surface of the tongue plays an essential role in the defence system of tongue tissue and, thus, of the body as a whole. Additionally, the number of MCs stained with AB (+) (1.7 ± 0.08) in the feline tongue was statistically higher than those with SO (+) (0.18 ± 0.02). This might be interpreted as an indication that MC heterogeneity may be due not only to their staining properties but also to their localization. It is also conceivable that the high histamine content may be a factor in this. Tryptase‐positive MCs were found in the loose connective tissue around blood vessels, between the glands, as solitary cells, or in groups of several cells. Chymase‐positive MCs were observed more individually rather than in groups. Moreover, chymase‐positive MCs were detected to be located in the filiform papillae subepithelial and in the blood vessels' immediate vicinity. Animals often lick themselves to clean themselves and promote healing. For this reason, it is very important to protect the tongue, which is in direct contact with the external environment, against foreign agents. Considering both the functional and protective properties of the tongue, we concluded that MCs may play a role in oral cavity immunity and protective effect. [ABSTRACT FROM AUTHOR]

Morbihan's disease is a rare condition characterized by chronic facial edema. While its exact cause is unknown, it is thought to involve local cutaneous vascularization and lymphatic drainage imbalance. Traditional treatment options are often ineffective, and no established efficient treatment exists. We present a case study of a 17‐year‐old male with Morbihan's syndrome who showed resistance to traditional treatments but responded well to a combination of cromolyn sodium nasal spray and oral montelukast after histopathology revealed hyperplasia of plasma cells and mast cells. This combination has not been used before for Morbihan's syndrome. Our review of the literature also provides insight for clinicians seeking to manage this condition. [ABSTRACT FROM AUTHOR]

Objectives: Mast cell (MC) degranulation is a key process in allergic reactions and inflammatory responses. Aspartate aminotransferase 1 (AAT1)-derived endogenous sulfur dioxide (SO2) is an important regulator of MC function. However, the mechanism underlying its role in MC degranulation remains unclear. This study aimed to investigate the mechanism by which endogenous SO2 controlled MC degranulation. Methods: HMC-1 and Rat basophilic leukemia cell MC line (RBL-2H3) were used in the cell experiments. SO2 content was detected by in situ fluorescent probe. MC degranulation represented by the release rate of MC β-hexosaminidase was determined using a colorimetric assay. Sulfenylation of galectin-9 (Gal-9) in MCs and purified protein was detected using a biotin switch assay. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to determine the exact sulfenylation sites of Gal-9 by SO2. Animal models of passive cutaneous anaphylaxis (PCA) and hypoxia-driven pulmonary vascular remodeling were used to investigate the effect of SO2 on mast cell activation in vivo. Site-directed mutation of Gal-9 was conducted to confirm the exact site of SO2 and support the significance of SO2/Gal-9 signal axis in the regulation of MC degranulation. Results: Degranulation was increased in AAT1-knockdowned MCs, and SO2 supplementation reversed the increase in MC degranulation. Furthermore, deficiency of endogenous SO2 contributed to IgE-mediated degranulation in vitro. Besides, SO2 inhibited IgE-mediated and hypoxia-driven MC degranulation in vivo. Mechanistically, LC-MS/MS analysis and site-directed mutation results showed that SO2 sulfenylated Gal-9 at cysteine 74. Sulfenylation of the 74th cysteine of Gal-9 protein was required in the SO2-inhibited MC degranulation under both physiological and pathophysiological conditions. Conclusion: These findings elucidated that SO2 inhibited MC degranulation via sulfenylating Gal-9 under both physiological and pathophysiological conditions, which might provide a novel treatment approach for MC activation-related diseases. [ABSTRACT FROM AUTHOR]