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Background Methods Results Conclusions Alteration of airway neuronal function and density and bidirectional interaction between immune cells and sensory peripheral nerves have been proposed to trigger and perpetuate inflammation that contribute to asthma severity. To date, few studies analysed neuroplasticity and neuroinflammation in tissue of asthmatic individuals. We hypothesized that the presence of these phenomena would be a pathological feature in fatal asthma.We have quantified the expression of the pan‐neuronal marker PGP9.5 and the neuronal sensory‐derived neuropeptide calcitonin gene‐related peptide (CGRP) in the large airways of 12 individuals deceased due to an asthma attack and compared to 10 control lung samples. The proximity between nerve bundles to eosinophils, mast cells and CADM1+ cells was also quantified. We have additionally developed a hPSC‐derived sensory neuron/mast cell co‐culture model, from where mast cells were purified and differences in gene expression profile assessed.Fatal asthma patients presented a higher PGP9.5 and CGRP positive area in the airways, indicating sensory neuroplasticity. Eosinophils, mast cells and CADM1+ cells were observed in close contact or touching the airway nerve bundles, and this was found to be statistically higher in fatal asthma samples. In vitro co‐culture model showed that human mast cells adhere to sensory neurons and develop a distinct gene expression profile characterized by upregulated expression of genes related to heterophilic adhesion, activation and differentiation markers, such as CADM4, PTGS2, C‐KIT, GATA2, HDC, CPA3, ATXN1 and VCAM1.Our results support a significant role for neuroplasticity and neuroimmune interactions in fatal asthma, that could be implicated in the severity of the fatal attack. Accordingly, the presence of physical neuron and mast cell interaction leads to differential gene expression profile in the later cell type. [ABSTRACT FROM AUTHOR]

Long‐COVID caused by SARS‐CoV‐2 infection has significant and increasing effects on human health worldwide. Although a unifying molecular or biological explanation is lacking, several pathophysiological mechanisms have been proposed. Involvement of mast cells—evolutionary old "multipurpose" innate immune cells—was reported recently in studies of acute infection and post‐acute‐COVID‐19 syndrome. Mast cell activity has been suggested in long‐COVID. In this case–control study, we compared data from 24 individuals with long‐COVID (according to the NICE criteria) and 24 age‐ and sex‐matched healthy individuals with a history of SARS‐CoV‐2 infection without developing sequelae. Serum levels of the proteases beta‐tryptase (TPSB2) and carboxypeptidase (CPA3), which are mast cell specific, were measured using immunoassays. The values were compared between the two groups and correlated to measures of physical exertional intolerance. TPSB2 and CPA3 levels were median (range) 26.9 (2.0–1000) and 5.8 (1.5–14.0) ng/mL, respectively, in the long‐COVID group. The corresponding values in the control group were 10.9 (2.0–1000) (p = 0.93) and 5.3 (3.5–12.9) ng/mL (p = 0.82). No significant correlations between TPSB2 or CPA3 levels and scores on the ten physical subscales of SF‐36, 3.1–3.10 were revealed. We found no significant differences in the levels of mast cell activation markers TPSB2 and CPA3 between the long‐COVID and control groups and no correlations with proxy markers of exercise intolerance. Mast cell activation does not appear to be part of long‐term pathogenesis of long‐COVID, at least in the majority of patients. [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]

Background: The subcellular distribution of CD30 on mast cells and the presence of eosinophils in cutaneous mastocytosis require further investigation, especially as the cell surface expression of CD30 is critical for the therapeutic response of systemic mastocytosis to brentuximab vedotin. Objective: Investigation of 147 biopsy specimens from 143 patients with cutaneous mastocytosis for mast cell density and distribution, frequency of CD30 expression, CD30 staining patterns, and presence and distribution of eosinophils. Correlation with clinical patterns. Methods: Retrospective multicenter immunohistochemical study of CD30 expression, eosinophils and basic clinical data in cutaneous mastocytosis. Results: CD30 expression was found in all samples (cut‐off: ≥1%), whereby the staining was predominantly cytoplasmic in 99% of the samples. Additional membrane staining was detected in 62% of the samples. Surface expression of CD30 was more common in biopsy specimens with a high mast cell burden and in biopsy specimens with a higher CD30 expression rate. Eosinophils were admixed in 58% of the samples. Females and older patients showed a trend of a lower mast cell burden. Limitations: Retrospective study on formalin‐fixed and paraffin‐embedded tissue without functional analysis. Conclusion: Most cases of cutaneous mastocytosis show cell surface expression of CD30 expression and is, therefore, in principle, accessible for therapy with antibodies against CD30, provided the overall situation of the patient warrants. [ABSTRACT FROM AUTHOR]

Interleukin (IL)‐33 released from airway epithelial cells plays a vital role in shaping type 2 immune responses by binding to the ST2 receptor present in many immune cells, including mast cells (MCs). Intranasal administration of IL‐33 in mice induces type 2 lung inflammation, an increase in lung MC progenitors, and transepithelial migration of leukocytes to the bronchoalveolar space. The aim of this study was to determine the contribution of MCs in IL‐33‐induced lung pathology. Four daily intranasal administrations of IL‐33 reduced spirometry‐like lung function parameters, induced airway hyperresponsiveness, and increased leukocytes in bronchoalveolar lavage fluid (BAL) in an ST2‐dependent manner. MC‐deficient (Cpa3cre/+) mice, which lack MCs, had intact spirometry‐like lung function but slightly reduced airway hyperresponsiveness, possibly related to reduced IL‐33 or serotonin. Strikingly, Cpa3cre/+ mice exposed to IL‐33 had 50% reduction in BAL T‐cells, and CXCL1 and IL‐33 were reduced in the lung. Intranasal IL‐33 induced CXCR2 expression in T‐cells in a MC‐independent fashion. Furthermore, IL‐33‐induced lung MCs were immunopositive for CXCL1 and localized in the epithelium of wild‐type mice. These results suggest that MCs are required to sustain intact lung IL‐33 and CXCL1 levels in mice with IL‐33‐induced airway inflammation, thereby facilitating T‐cell accumulation in the bronchoalveolar space. [ABSTRACT FROM AUTHOR]

Objectives: To date, few studies have considered the influence of psychological factors on chronic prostatitis (PRO) models. Here, we aimed to refine a murine PRO model combining chemically induced prostatitis with psychological stress. Methods: A total of 40 mice were randomly divided into four groups: normal control (NC) group, PRO group, water avoidance stress (WAS) group, and PRO + WAS group. Ten mice were assigned to each group: five for cystometrograms (CMGs) and five for von Frey testing and histological analysis. PRO was induced through a prostatic injection of 10% paraformaldehyde. The WAS mice were placed on the middle platform for 1 h per day for 10 consecutive days. Results: The results of the von Frey test demonstrated that both WAS and PRO induced bladder hyperalgesia in mice, and the WAS + PRO group showed significant pelvic pain symptoms either. The CMG results suggested that the PRO group, the WAS group, and the PRO + WAS group all exhibited bladder overactivity, presented as a shortened micturition interval and decreased threshold pressure evoking bladder contraction. The symptoms of the PRO group and the PRO + WAS group were more severe than those of the WAS group. The tissue staining results indicated that WAS itself caused only mild prostatic inflammation but could significantly aggravate chemical‐induced prostatic inflammation, as well as the total number of mast cells and proportion of activated mast cells. Conclusions: Our refined murine PRO model could manifest persistent bladder overactivity, pelvic hyperalgesia and prostatic inflammation. WAS could induce mild prostatic inflammation and aggravate primary prostatic inflammation. [ABSTRACT FROM AUTHOR]

Immunoglobulin E (IgE)‐mediated food allergies are reported to affect around 3.5% of children and 2.4% of adults, with symptoms varying in range and severity. While being the gold standard for diagnosis, oral food challenges are burdensome, and diagnostic tools based on specific IgE can be flawed. Furthering our understanding of the mechanisms behind food allergy onset, severity and persistence could help reveal immune profiles associated with the disease, to ultimately aid in diagnosis. Alterations to cytokine levels and immune cell ratios have been identified, though further research is needed to fully capture the heterogenous nature of food allergy. Moreover, the existence of such immune alterations also raises the question of potential wider systemic effects. For example, recent research has emphasised the existence and impact of neuro‐immune interactions and implicated behavioural and neurological changes associated with food allergy. This review will provide an overview of such food allergy‐driven neuro‐immune interactions, with the aim of emphasising the importance of furthering our understanding of the immune mechanisms underlying IgE‐mediated food allergy. [ABSTRACT FROM AUTHOR]

The article "Thoughts on mastocytosis in COVID-19: an author's response" published in Histopathology discusses the potential role of mast cells in thrombosis and pulmonary fibrosis in COVID-19 patients. While the increase in mast cells may not establish a causal relationship, it could play a significant role in these conditions. The authors suggest that further studies are needed to determine the extent to which an increase in mast cells is a normal physiological response to viral infection in the lungs. Additionally, the influence of obesity on tryptase levels in COVID-19 patients is considered, although limited control samples were available for comparison. [Extracted from the article]

The article "Redefining tryptase norms in the pediatric population reveals sex-based differences: Clinical implications" discusses the measurement of serum basal tryptase (sBT) levels in children to diagnose mast cell activation disorders. The study included 398 children, with a median sBT level of 3.2 ng/mL, and found that sBT levels were significantly higher in infants under 1 year old. There were sex-based differences in sBT levels, with males having higher levels than females, particularly in the oldest age group. The study suggests that the 8.0 ng/mL threshold used in adults may also be suitable for screening boys for hereditary alpha-tryptasemia, while a lower threshold of 7.0 ng/mL may be more appropriate for girls aged 5 and above. [Extracted from the article]

ABSTRACT Nodal metastasis is a negative prognostic factor in dogs with mast cell tumours (MCTs), thus early detection enables more informed decision‐making and provides valuable prognostic information. The aim of this study is to assess the concordance between histopathologic findings of LNs and cytology and flow cytometry (FC), respectively, and to evaluate the ability of FC to differentiate between metastatic (HN2–HN3) and non‐metastatic (HN0–HN1) LNs. Overall, 117 LNs from 64 dogs with first occurring MCTs were submitted for cytology, histology and FC. LNs were cytologically and histologically classified according to Krick and Weishaar systems, respectively. Using FC, mast cells (MCs) were identified as IgE+ CD117+ CD5− CD21− cells and quantified as a percentage. When compared with histologic classification, cytology showed an accuracy of 88.2% in distinguishing between metastatic and non‐metastatic LNs but did not detect 25.3% of metastatic cases. FC revealed an increase in the median percentages of MCs across histologic classes, progressing from HN0 to HN3. ROC curves pinpointed 0.3% as the optimal cut‐off for distinguishing between metastatic and non‐metastatic LNs, with an accuracy of 84.3%. A 1.1% cut‐off proved valuable in identifying HN3 LNs. The combined interpretation of cytology and FC increased accuracy to 92.2%. An algorithm for guiding the combined interpretation of cytology and FC is suggested based on these findings. In conclusion, FC proves beneficial in enhancing the early detection of metastatic LNs, particularly when utilised alongside cytology. Histopathology remains essential for confirmation, enabling the discrimination of HN classes or, in doubtful cases, for the detection or exclusion of nodal metastases. [ABSTRACT FROM AUTHOR]

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]

Background Results Conclusion Maintaining low concentrations of plasma low‐density lipoprotein cholesterol (LDLc) over time decreases the number of LDL particles trapped within the artery wall, slows the progression of atherosclerosis and delays the age at which mature atherosclerotic plaques develop. This substantially reduces the lifetime risk of atherosclerotic cardiovascular disease (ASCVD) events. In this context, plaque development and vulnerability result not only from lipid accumulation but also from inflammation.Changes in the composition of immune cells, including macrophages, dendritic cells, T cells, B cells, mast cells and neutrophils, along with altered cytokine and chemokine release, disrupt the equilibrium between inflammation and anti‐inflammatory mechanisms at plaque sites. Considering that it is not a competition between LDLc and inflammation, but instead that they are partners in crime, the present narrative review aims to give an overview of the main inflammatory molecular pathways linked to raised LDLc concentrations and to describe the impact of lipid‐lowering approaches on the inflammatory and lipid burden. Although remarkable changes in LDLc are driven by the most recent lipid lowering combinations, the relative reduction in plasma C‐reactive protein appears to be independent of the magnitude of LDLc lowering.Identifying clinical biomarkers of inflammation (e.g. interleukin‐6) and possible targets for therapy holds promise for monitoring and reducing the ASCVD burden in suitable patients. [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]

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic lung disease. While recent studies have suggested the potential efficacy of tyrosine kinase inhibitors in managing IPF, masitinib, a clinically used tyrosine kinase inhibitor, has not yet been investigated for its efficacy in fibrotic lung diseases. In a previous study on an in vitro neurodegenerative model, we demonstrated the synergistic antitoxic and antioxidant effects of masitinib combined with cromolyn sodium, an FDA‐approved mast cell stabilizer. This study aims to investigate the anti‐fibrotic and antioxidant effects of the masitinib‐cromolyn sodium combination in an in vitro model of pulmonary fibrosis. Fibroblast cell cultures treated with bleomycin and/or hydrogen peroxide (H2O2) were subjected to masitinib and/or cromolyn sodium, followed by assessments of cell viability, morphological and apoptotic nuclear changes, triple‐immunofluorescence labeling, and total oxidant/antioxidant capacities, besides ratio of Bax and Bcl‐2 mRNA expressions as an indication of apoptosis. The combined treatment of masitinib and cromolyn sodium effectively prevented the fibroblast myofibroblast transition, a hallmark of fibrosis, and significantly reduced bleomycin / H2O2‐induced apoptosis and oxidative stress. This study is the first to demonstrate the additive anti‐fibrotic, cell‐protective, and antioxidant effects of the masitinib‐cromolyn sodium combination in an in vitro fibrosis model, suggesting its potential as an innovative therapeutic approach for pulmonary fibrosis. Combination therapy may be more advantageous in that both drugs could be administered in lower doses, exerting less side effects, and at the same time providing diverse mechanisms of action simultaneously. [ABSTRACT FROM AUTHOR]

Background: Various biomarkers are used to define peanut allergy (PA). We aimed to observe changes in PA resolution and persistence over time comparing biomarkers in PA and peanut sensitised but tolerant (PS) children in a population‐based cohort. Methods: Participants were recruited from the EAT and EAT‐On studies, conducted across England and Wales, and were exclusively breastfeed babies recruited at 3 months old and followed up until 7–12 years old. Clinical characteristics, skin prick test (SPT), sIgE to peanut and peanut components and mast cell activation tests (MAT) were assessed at 12 months, 36 months and 7–12 years. PA status was determined at the 7–12 year time point. Results: The prevalence of PA was 2.1% at 7–12 years. Between 3 and 7–12 year, two children developed PA and one outgrew PA. PA children had larger SPT, higher peanut‐sIgE, Ara h 2‐sIgE and MAT (all p <.001) compared to PS children from 12 months onwards. SPT, peanut‐sIgE, Ara h 2‐sIgE and MAT between children with persistent PA, new PA, outgrown PA and PS were statistically significant from 12 months onwards (p <.001). Those with persistent PA had SPT, peanut‐sIgE and Ara h 2‐sIgE that increased over time and MAT which was highest at 36 months. New PA children had increased SPT and peanut‐sIgE from 36 months to 7–12 years, but MAT remained low. PS children had low biomarkers across time. Conclusions: In this cohort, few children outgrow or develop new PA between 36 months and 7–12 years. Children with persistent PA have raised SPT, peanut‐sIgE, Ara h 2‐sIgE and MAT evident from infancy that consistently increase over time. [ABSTRACT FROM AUTHOR]

Adipokines play essential roles in regulating a range of biological processes, but growing evidence indicates that they are also fundamental in immunological mechanisms and, primarily, inflammatory responses. Adipokines mediate their actions through specific receptors. However, although adipokine receptors are widely distributed in many cell and tissue types, limited data are available on their expression in mast cells (MCs) and, consequently, adipokine's significance in the modulation of MC activity within the tissues. In this study, we demonstrate that rat peritoneal MCs constitutively express the leptin receptor (i.e. LEPR), adiponectin receptors (i.e. ADIPOR1 and ADIPOR2) and the chemerin receptor (i.e. CMKLR1). We also found that LEPR, ADIPOR1, ADIPOR2 and CMKLR1 expression in MCs changes in response to stimulation by their specific ligands and some cytokines with potent proinflammatory properties. Furthermore, the involvement of intracellular signaling molecules in leptin‐, adiponectin‐ and chemerin‐induced MC response was analyzed. Overall, our findings suggest that adipokines leptin, adiponectin and chemerin can significantly affect the activity of MCs in various processes, especially during inflammation. These observations may contribute significantly to understanding the relationship between adipokines, immune mechanisms and diseases or conditions with an inflammatory component. [ABSTRACT FROM AUTHOR]

Objective: Dandruff is characterised by the presence of perivascular leukocytes and mild inflammation; however, the immune microenvironment of dandruff‐affected scalp skin and the potential changes to the hair follicle's (HF) physiological immune privilege (HF IP) remain unknown. Here, we characterised the HF immune microenvironment and immune privilege status in dandruff‐affected scalp skin. Methods: We assessed relevant key parameters in healthy versus dandruff‐affected human scalp biopsies using quantitative immunohistomorphometry, laser capture microdissection, and RNA sequencing. Results: The number of epidermal CD4+ and CD8+ T cells was increased in lesional dandruff scalp skin, while the number of MHC class II+/CD1a+ Langerhans cells was decreased in the infundibulum. The number of intrafollicular and perifollicular CD4+ T cells and CD8+ T cells, perifollicular CD68+ macrophages, and tryptase+ mast cells remained unchanged. Interestingly, MHC class Ia and ß2‐microglobulin protein expression were significantly increased specifically in the suprabulbar outer root sheath (ORS) compartment of dandruff‐associated HFs. RNAseq analysis of laser capture micro‐dissected suprabulbar ORS compartment revealed antigen presentation pathway as the top regulated canonical pathway, along with the upregulation of HF‐IP genes such as HLA‐C, HLA‐DP, and TAP1, which are normally down‐regulated in healthy HFs. Intrafollicular protein expression of known HF IP guardians (CD200 and α‐MSH) and 'danger signals' (MICA and CXCL10) remained unaltered at the IP sites of dandruff lesional HFs compared to non‐lesional and healthy HFs. Instead, the expression of macrophage migration inhibiting factor (MIF), another HF IP guardian, was reduced. Conclusion: Together, this work shows that dandruff is associated with epidermal T‐cell infiltration and a weakened HF IP in the suprabulbar ORS of HFs in dandruff lesional scalp. [ABSTRACT FROM AUTHOR]

The antiallergic effects of gut microbiota have been attracting attention in recent years, but the underlying cellular and molecular mechanisms have not yet been fully understood. In this study, we aimed to investigate these mechanisms specifically focusing on mast cells. Mast cells retain intracellular granules containing various inflammatory mediators such as histamine, which are released outside the cells upon IgE and allergen stimulation. We previously reported that increased expression of the transcription factor, CCAAT/enhancer‐binding protein α (C/EBPα), suppresses granule formation in mast cells and that Lacticaseibacillus casei JCM1134T (LC) upregulates C/EBPα levels. Here, granule formation in mouse bone marrow‐derived mast cells was suppressed in a MyD88‐dependent manner after LC treatment due to C/EBPα‐dependent downregulation of the genes encoding serglycin (SRGN) and mast cell protease 4 (Mcpt4). Furthermore, C/EBPα expression was regulated by DNA methylation in the 5′ region far upstream of the transcription start site. LC suppressed DNA methylation of specific CpG motifs in the 5′ region of the C/EBPα gene. These results conclude that specific gut microbial components, such as those from LC, suppress granule formation in mast cells by inhibiting SRGN and Mcpt4 expression via reduced C/EBPα gene methylation. [ABSTRACT FROM AUTHOR]

This study assessed the effects of red and green LEDs on mast cells (MCs) in third‐degree burns in 75 Wistar rats, divided into control, red LED (RED), and green LED (GREEN) groups. Animals were irradiated daily with RED (630 nm, 300 mW, 0.779 W/cm2, 9 J/cm2, 30 s) and GREEN (520 nm, 180 mW, 0.467 W/cm2, 60 J/cm2, 30 s). Histological sections stained with toluidine blue were analyzed for total and subtype MCs. Standardized MC counting was performed across the viable lesion area, considering lesion margins, through intact connective tissue and the integrity of skin appendages. No statistically significant differences in MCs 2 (with released granules and intact cell border) were found between groups. Irradiated groups showed increased total MCs at 7, 14, and 21 days (p < 0.05), with a decrease in MCs 1 (intact MCs) at all time points compared to control (p < 0.05). Significant changes in MCs 3 (with massive degranulation and partial or complete disintegration of the cell border) degranulation were noted in RED at 7, 14, and 21 days (p < 0.009) and in GREEN at 14 (p < 0.009) and 32 days (p < 0.028). Results suggest red and green LEDs modulate MC recruitment and degranulation in third‐degree burns. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Tryptase, a mast cell protease, has been identified as a potential therapeutic target in managing patients with refractory asthma. We assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of MTPS9579A, an anti‐tryptase antibody, in a phase 2a randomized trial for patients with uncontrolled asthma and a phase 1c trial to understand activity within the lower respiratory tract.Phase 2a patients (n = 134) received 1800 mg MTPS9579A or placebo intravenously every 4 weeks for 48 weeks. The primary endpoint was time to the first composite exacerbation event. Phase 1c patients (n = 27) received one intravenous dose of 300 or 1800 mg MTPS9579A or placebo. Both trials measured MTPS9579A concentrations and effects on tryptase in serum and nasal lining fluid; phase 1c also analyzed bronchial lining fluid.MTPS9579A did not meet the primary endpoint (hazard ratio = 0.90; 95% CI: 0.55–1.47; p = 0.6835); exacerbation rates in the placebo group were low. Serum and nasal MTPS9579A pharmacokinetics and tryptase levels were consistent with data from healthy volunteers. However, in phase 1c patients, compared to nasal levels, MTPS9579A bronchial concentrations were 6.8‐fold lower, and bronchial active and total tryptase levels were higher (119‐fold and 30‐fold, respectively). Pharmacokinetic/pharmacodynamic modeling predicted intravenous doses of 3800 mg every 4 weeks would be necessary to achieve 95% active tryptase inhibition from baseline.The MTPS9579A dose tested in the phase 2a study was insufficient to inhibit tryptase in bronchial lining fluid, likely contributing to the observed lack of efficacy. [ABSTRACT FROM AUTHOR]

Objectives: Lactic acid metabolism, a hallmark of carcinogenesis, may play potential roles in cervical carcinoma, assisting the prognosis prediction. Materials and Methods: A regression analysis was conducted to identify the ones with the most frequent variation in mutations and CNV changes in lactate metabolism‐related (L‐related) genes, after which a prognostic nomogram was built based on selected genes and clinical features by machine learning methods. Results: EGLN1, IL1, IL12RB1, ENO1, and 10 other genes had the most frequent changes and prognostic differences in overall survival (OS). The lactated associated risk (LAR) score model can distinguish the patients in OS (p = 0.046, HR = 101.9, 95%CI 1.1–9447.6), and together with clinical features has a higher AUC (AUC = 0.839). Furthermore, CD8+ T, activated CD4+ memory T and resting mast cells were significantly negatively associated with the LAR score. Conclusions: Lactic acid metabolism is closely related to the prognosis of cervical carcinoma, where the immune microenvironment may play an important role. [ABSTRACT FROM AUTHOR]

Summary: Irritable bowel syndrome (IBS) is a chronic gastrointestinal condition associated with altered bowel habits and recurrent abdominal pain, often triggered by food intake. Current treatments focus on improving stool pattern, but effective treatments for pain in IBS are still lacking due to our limited understanding of pathophysiological mechanisms. Visceral hypersensitivity (VHS), or abnormal visceral pain perception, underlies abdominal pain development in IBS, and mast cell activation has been shown to play an important role in the development of VHS. Our work recently revealed that abdominal pain in response to food intake is induced by the sensitization of colonic pain‐sensing neurons by histamine produced by activated mast cells following a local IgE response to food. In this review, we summarize the current knowledge on abdominal pain and VHS pathophysiology in IBS, we outline the work leading to the discovery of the role of histamine in abdominal pain, and we introduce antihistamines as a novel treatment option to manage chronic abdominal pain in patients with IBS. [ABSTRACT FROM AUTHOR]

Summary: The increasing prevalence of food allergy and related pathologies in recent years has underscored the need to understand the factors affecting adverse reactions to food. Food allergy is caused when food‐specific IgE triggers the release of histamine from mast cells. However, other food‐specific antibody isotypes exist as well, including IgG and IgA. IgA is the main antibody isotype in the gut and mediates noninflammatory reactions to toxins, commensal bacteria, and food antigens. It has also been thought to induce tolerance to food, thus antagonizing the role of food‐specific IgE. However, this has remained unclear as food‐specific IgA generation is poorly understood. Particularly, the location of IgA induction, the role of T cell help, and the fates of food‐specific B cells remain elusive. In this review, we outline what is known about food‐specific IgA induction and highlight areas requiring further study. We also explore how knowledge of food‐specific IgA induction can be informed by and subsequently contribute to our overall knowledge of gut immunity. [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis (AD) is a prevalent chronic inflammatory and highly pruritic skin condition characterized by the infiltration of immune cells, notably eosinophils and mast cells. Mast cells (MCs) critically participate in the complex pathogenesis of AD through multiple pathways and have recently garnered growing attention in research. Despite the abundance of related studies published over the years, a comprehensive bibliometric analysis on this topic remains lacking. Objective: Our objective was to perform an up‐to‐date bibliometric analysis of the literature focusing on the relationship between MCs and AD. This analysis would provide valuable insights through a thorough bibliometric review, enabling a clearer understanding of the current research landscape, pinpointing key studies, and detecting emerging trends within this field. Methods: We searched the Web of Science Core Collection (WoSCC) database on 15 July 2024. The data retrieval strategy was structured as follows: #1: TS = ("mast cells") OR TS = ("mast cell") OR TS = ("mastocyte"); #2: TS = ("atopic dermatitis") OR TS = ("atopic eczema") Final data: (#1 AND #2). A total of 2272 items published between 2001 and 2024 were included. Several scientometric visualization tools, including VOSviewer, R‐bibliometrix, CiteSpace and an online analytical platform, were utilized to conduct text mining and to visualize the bibliometric data, facilitating a comprehensive analysis of research trends and patterns. Results: Out of the initial 2272 articles retrieved, 2168 were selected for analysis after applying inclusion and exclusion criteria based on publication type. The findings indicate a steady and substantial exponential growth in the annual number of publications focused on the relationship between over the years. The South Korea (547/2168), USA (465/2168) and Japan (436/2168) were the major contributors within this field, collectively constituting more than half of the total publications. To clarify the underlying mechanisms and role of MCs in the pathogenesis of AD and to make MCs prime targets for therapeutic intervention have garnered the most attention in this field. According to references analysis, the research emphasis has shifted to developing MC‐related therapeutics and intervention and regulating the immune system of AD patients through modulating the activity of various immune cells. On the basis of keywords analysis, we outlined the following research frontiers and hotpots in the future: the role of oxidative stress in the pathogenesis; imbalance in the different types of T helper (Th) cells during immune response; skin barrier and barrier dysfunction; improving quality of life; sensory neurons; biological agents and small‐molecule drugs. Furthermore, IL‐13, IL‐4, NFKB1, BCGF‐1 and CD4 ranked as the top five genes that have received the most investigative attention in the intersection of MCs and AD. Conclusion: In a word, this analysis would greatly benefit from a thorough bibliometric review to gain a deeper understanding of the current research landscape, identify pivotal studies and pinpoint emerging trends in the field of MCs and AD. Meanwhile, our findings offered researchers a holistic perspective of ongoing developments, serving as a valuable resource for guiding future research and informing decision‐making for both researchers and policymakers in this area. [ABSTRACT FROM AUTHOR]

Background: Bronchoalveolar lavage (BAL) is a common procedure for evaluation of the equine lower airways. Time to resolution of post‐BAL inflammation has not been clearly defined. Hypothesis: Residual inflammation, evident by changes in immune cell populations and inflammatory cytokines, will resolve by 72 hours after BAL. Animals: Six adult, healthy, institution‐owned horses. Methods: Randomized, complete cross‐over design. Each horse underwent 3 paired BALs, including a baseline and then 48, 72, and 96 hours later, with a 7‐day washout between paired BALs. Each sample underwent cytological evaluation and cytokine concentrations were determined by a commercially available multiplex bead immunoassay. Statistical analysis was performed by multilevel mixed‐effects Poisson regression analysis. Data are reported as marginal means and 95% confidence interval (CI). Results: Neutrophil, eosinophil and mast cell percentages were not significantly different at any time points. Macrophage percentages were higher at 72 hours (45.0 [95% CI, 41.6‐48.4]%) and 96 hours (45.3 [95% CI, 42.9‐47.7]%) vs baseline (37.4 [95% CI, 33.5‐41.4]%; P <.001 and P =.01, respectively), and at 72 hours and 96 hours vs 48 hours (31.9 [95% CI, 28.1‐35.6]%; P <.001). Neutrophil percentage was not significantly increased at 48 hours (P =.11). Interleukin (IL)‐6 concentration was increased at 72 hours (5.22 [95% CI, 3.44‐6.99] pg/mL) vs 48 hours (4.38 [95% CI, 2.99‐5.78] pg/mL; P <.001). Conclusions and Clinical Importance: Significant lung inflammation was not detected at 72 and 96 hours, suggesting that repeating BAL at 72 hours or more can be done without concern of residual inflammation. [ABSTRACT FROM AUTHOR]

A 12‐year‐old male domestic cat with multiple subcutaneous mast cell tumours (MCTs) presented with a 2‐week history of pruritus and raw/bleeding skin from self‐trauma at Kagoshima University Veterinary Teaching Hospital. Polymerase chain reaction (PCR) and histopathological analyses revealed intertumoral heterogeneity among tumour locations based on the mutation status of KIT. In addition, the expression pattern of KIT was characterized. After failed treatment with vinblastine (2.0–2.2 mg/m2, intravenous administration, two doses in total) or nimustine (25 mg/m2, intravenous administration, two doses in total), toceranib (2.2–2.6 mg/kg, orally administered, every other day) was administered to treat recurrent MCTs harbouring the KIT exon eight internal tandem duplication mutation, achieving a complete response. However, toceranib resistance developed 2 months after treatment initiation. Subsequent PCR analysis was conducted to identify the mutational status of KIT in each MCT and to detect the presence of secondary mutations associated with the acquisition of toceranib resistance. Secondary KIT mutations (c.998G>C and c.2383G>C), which were not initially detected in tumour cells at diagnosis, were identified after the development of resistance to toceranib. This indicates that the tumour cells in feline MCTs in the same case have diverse characteristics. Our findings encourage further investigation into the development of therapeutic strategies for feline MCTs, particularly focusing on the heterogeneous nature of KIT/KIT and overcoming acquired resistance to toceranib. [ABSTRACT FROM AUTHOR]

Feline gastrointestinal eosinophilic sclerosing fibroplasia (FGESF) is a rare and poorly understood disease characterised by the infiltration of eosinophils and the development of fibrous tissue within the gastrointestinal tract of cats. A 2‐year‐old female neutered Ragdoll was presented for signs consistent with extrahepatic biliary tract obstruction (EHBO), including jaundice, hyporexia and lethargy. Marked progressive hyperbilirubinemia and mild anaemia were also present. Abdominal ultrasonography suggested a duodenal mass and pancreatitis as the cause of EHBO. Cytopathological results from fine needle aspirates detected mast cells and eosinophils in the duodenal mass and eosinophils in the spleen and the liver, suggestive of a possible mast cell tumour. A cholecystojejunostomy and a duodenotomy were performed to divert the biliary outflow and obtain biopsy samples, respectively. Eosinophilic sclerosing fibroplasia in the duodenal mass and fungal elements in an abdominal lymph node were reported on histopathological examination. A pan‐fungal PCR targeting ITS2 performed on DNA extracted from an abdominal lymph node detected Candida albicans. This report adds to the growing body of evidence that FGESF can occur in association with fungal infections. [ABSTRACT FROM AUTHOR]

This article discusses the role of IL-33, an alarmin cytokine, in regulating mast cell responses during food allergy. The IL-33 receptor, ST2, is expressed on mast cells, and genetic variations in the IL-33/ST2 axis are associated with disease susceptibility. The study used a mouse model of food allergy and found that IL-33 is critical for inducing mast cell responses to food antigens. Mice lacking ST2 showed decreased diarrhea, mast cell accumulation, and mast cell activation compared to wild-type mice. The study also found that IL-4 plays a role in mediating mast cell responses, as treatment with IL-4 reversed the attenuated mast cell activation in ST2-deficient mice. These findings provide insights into the potential interplay between IL-33 and IL-4 in the treatment of allergic diseases. [Extracted from the article]

This article explores the association between chronic urticaria (CU) and serological biomarkers, as well as the effects of omalizumab (OMZ) treatment on these biomarkers. The study found that CU is linked to elevated concentrations of MMP9 and CCL18, which are involved in skin ECM degradation and basophil migration, respectively. OMZ treatment was found to decrease vascular endothelial growth factor (VEGF) levels and alter the homeostasis of type I, IV, and VI collagens. The study also observed changes in the concentration of extracellular vesicles (EVs) in CU patients after OMZ treatment. These findings suggest potential candidates for further research in CU management. [Extracted from the article]

Chronic spontaneous urticaria (CSU) is a debilitating, inflammatory skin condition characterized by infiltrating immune cells. Available treatments are limited to improving the signs and symptoms. There is an unmet need to develop therapies that target disease‐driving pathways upstream of mast cell activation to inhibit or delay the progression of CSU and associated comorbidities. Here, we aim to define disease modification due to a treatment intervention and criteria that disease‐modifying treatments (DMTs) must meet in CSU. We have defined disease modification in CSU as a favorable treatment‐induced change in the underlying pathophysiology and, therefore, the disease course, which is clinically beneficial and enduring. A DMT must fulfil the following criteria: (1) prevents or delays the progression of CSU, (2) induces long‐term, therapy‐free clinical remission, which is the sustained absence of CSU signs and symptoms without the need for treatment, and (3) affects the underlying mechanism of CSU, as demonstrated by an effect on disease‐driving signals and/or a biomarker. DMTs in CSU should slow disease progression, achieve long‐lasting disease remission, target disease‐driving mechanisms, reduce mast cell‐activating IgE autoantibodies, target cytokine profile polarization, and normalize the gut microbiome and barrier. Treating CSU at the immune system level could provide valuable alternatives to pharmacotherapy in CSU management. Specific DMTs in CSU are yet to be developed, but some show potential benefits, such as inhibitors of Bruton's Tyrosine Kinase, IL‐4 and IL‐13. Future therapies could prevent CSU signs and symptoms, achieve long‐term clinical benefits after discontinuing treatment, and prevent associated concomitant disorders. [ABSTRACT FROM AUTHOR]

Background: Galectin‐9 (Gal‐9) has been implicated in allergic and autoimmune diseases, but its role and relevance in chronic spontaneous urticaria (CSU) are unclear. Objectives: To characterize the role and relevance of Gal‐9 in the pathogenesis of CSU. Methods: We assessed 60 CSU patients for their expression of Gal‐9 on circulating eosinophils and basophils as well as T cell expression of the Gal‐9 receptor TIM‐3, compared them with 26 healthy controls (HCs), and explored possible links with disease features including disease activity (urticaria activity score, UAS), total IgE, basophil activation test (BAT), and response to omalizumab treatment. We also investigated potential drivers of Gal‐9 expression by eosinophils and basophils. Results: Our CSU patients had markedly increased rates of circulating Gal‐9+ eosinophils and basophils and high numbers of lesional Gal‐9+ cells. High rates of blood Gal‐9+ eosinophils/basophils were linked to high disease activity, IgE levels, and BAT negativity. Serum levels of TNF‐α were positively correlated with circulating Gal‐9+ eosinophils/basophils, and TNF‐α markedly upregulated Gal‐9 on eosinophils. CSU patients who responded to omalizumab treatment had more Gal‐9+ eosinophils/basophils than non‐responders, and omalizumab reduced blood levels of Gal‐9+ eosinophils/basophils in responders. Gal‐9+ eosinophils/basophils were negatively correlated with TIM‐3+TH17 cells. Conclusion: Our findings demonstrate a previously unrecognized involvement of the Gal‐9/TIM‐3 pathway in the pathogenesis CSU and call for studies that explore its relevance. [ABSTRACT FROM AUTHOR]

Derived from the myeloid lineage, granulocytes, including basophils, eosinophils, and neutrophils, along with mast cells, play important, often disparate, roles across the allergic disease spectrum. While these cells and their mediators are commonly associated with allergic inflammation, they also exhibit several functions either promoting or restricting tumor growth. In this Position Paper we discuss common granulocyte and mast cell features relating to immunomodulatory functions in allergy and in cancer. We highlight key mechanisms which may inform cancer treatment and propose pertinent areas for future research. We suggest areas where understanding the communication between granulocytes, mast cells, and the tumor microenvironment, will be crucial for identifying immune mechanisms that may be harnessed to counteract tumor development. For example, a comprehensive understanding of allergic and immune factors driving distinct neutrophil states and those mechanisms that link mast cells with immunotherapy resistance, might enable targeted manipulation of specific subpopulations, leading to precision immunotherapy in cancer. We recommend specific areas of investigation in AllergoOncology and knowledge exchange across disease contexts to uncover pertinent reciprocal functions in allergy and cancer and allow therapeutic manipulation of these powerful cell populations. These will help address the unmet needs in stratifying and managing patients with allergic diseases and cancer. [ABSTRACT FROM AUTHOR]

The article discusses the presence of mouse IgG antibodies in the widely used mouse IgE clone SPE-7, which is used to study IgE biology and function. The study found that SPE-7 contains IgG2a/b-IgE complexes, which can alter the functional profile of IgE. The presence of IgG in SPE-7 was confirmed through various assays, including enzyme-linked immunosorbent assays (ELISA) and liquid chromatography-mass spectrometry (LC-MS). These findings challenge the concept that IgE exerts antigen-independent effects on mast cell degranulation and survival. The study suggests that the presence of contaminating IgGs in therapeutic IgE antibodies should be considered, as they may alter the functional and pharmacological profile of these antibodies. [Extracted from the article]

Background: Hypersensitivity reactions (HR) are common in mastocytosis. However, little is known about triggers and risk factors. The registry of the European Competence Network on Mastocytosis (ECNM) enables reliable studies in a larger cohort of mastocytosis patients. We assessed prevalence, triggers and risk factors of HR in adults with mastocytosis in the ECNM registry. Methods: Data were collected in 27 ECNM centers. We analyzed potential triggers (Hymenoptera venoms, food, drug, inhalant and others) and risk factors at diagnosis and during follow‐up. The study group consisted of 2485 adults with mastocytosis, 1379 women (55.5%) and 1106 men (44.5%). Median age was 48.2 years (range 18–91 years). Results: Nine hundred and forty eight patients (38.1%) reported one or more HR'. Most common triggers were Hymenoptera venoms in cutaneous mastocytosis (CM) and indolent systemic mastocytosis (ISM), whereas in advanced SM (advSM), most common elicitors were drugs, including nonsteroidal anti‐inflammatory agents and penicillin. In multivariate analyses, tryptase level < 90 ng/mL, <15% infiltration by mast cells in bone marrow biopsy‐sections, and diagnosis of ISM were identified as independent risk factors for HR. For drug‐induced HR, prominent risk factors were advSM and high tryptase levels. New reactions were observed in 4.8% of all patients during 4 years follow‐up. Conclusions: HR are mainly triggered by Hymenoptera venoms in patients with CM and ISM and by drugs in patients with advSM. Tryptase levels <90 ng/mL, mast cell bone marrow infiltration <15%, and WHO category ISM are predictors of HR. New HR occur in 4.8% of all patients within 4 years. [ABSTRACT FROM AUTHOR]

Background: Chronic spontaneous urticaria (CSU) is a common, debilitating skin disorder characterized by recurring episodes of raised, itchy and sometimes painful wheals lasting longer than 6 weeks. CSU is mediated by mast cells which are absent from peripheral blood. However, lineage−CD34hiCD117int/hiFcεRI+ cells in blood have previously been shown to represent a mast cell precursor. Methods: We enumerated FcεRI−, FcεRI+ and FcεRIhi lineage−CD34+CD117+ cells using flow cytometry in blood of patients with CSU (n = 55), including 12 patients receiving omalizumab and 43 not receiving omalizumab (n = 43). Twenty‐two control samples were studied. Disease control and patient response to omalizumab was evaluated using the urticaria control test. We performed single‐cell RNA sequencing (scRNA‐Seq) on lineage−CD34hiCD117hi blood cells from a subset of patients with CSU (n = 8) and healthy controls (n = 4). Results: CSU patients had more lineage−CD34+CD117+FcεRI+ blood cells than controls. Lineage−CD34+CD117+FcεRI+ cells were significantly higher in patients with CSU who had an objective clinical response to omalizumab when compared to patients who had poor disease control 90 days after initiation of omalizumab. scRNA‐Seq revealed that lineage−CD34+CD117+FcεRI+ cells contained both lymphoid and myeloid progenitor lineages, with omalizumab responsive patients having proportionally more myeloid progenitors. The myeloid progenitor lineage contained small numbers of true mast cell precursors along with more immature FcεRI− and FcεRI+ myeloid progenitors. Conclusion: Increased blood CD34+CD117+FcεRI+ cells may reflect enhanced bone marrow egress in the setting of CSU. High expression of these cells strongly predicts better clinical responses to the anti‐IgE therapy, omalizumab. [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]

Whether N6‐Methyladenosine (m6A)‐ and ferroptosis‐related genes act on immune responses to regulate glioma progression remains unanswered. Data of glioma and corresponding normal brain tissues were fetched from the TCGA database and GTEx. Differentially expressed genes (DEGs) were identified for GO and KEGG enrichment analyses. The FerrDb database was based to yield ferroptosis‐related DEGs. Hub genes were then screened out using the cytoHubba database and validated in clinical samples. Immune cells infiltrating into the glioma tissues were analysed using the CIBERSORT R script. The association of gene signature underlying the m6A‐related ferroptosis with tumour‐infiltrating immune cells and immune checkpoints in low‐grade gliomas was analysed. Of 6298 DEGs enriched in mRNA modifications, 144 were ferroptosis‐related; NFE2L2 and METTL16 showed the strongest positive correlation. METTL16 knockdown inhibited the migrative and invasive abilities of glioma cells and induced ferroptosis in vitro. NFE2L2 was enriched in the anti‐m6A antibody. Moreover, METTL16 knockdown reduced the mRNA stability and level of NFE2L2 (both p < 0.05). Proportions of CD8+ T lymphocytes, activated mast cells and M2 macrophages differed between low‐grade gliomas and normal tissues. METTL16 expression was negatively correlated with CD8+ T lymphocytes, while that of NFE2L2 was positively correlated with M2 macrophages and immune checkpoints in low‐grade gliomas. Gene signatures involved in the m6A‐related ferroptosis in gliomas were identified via bioinformatic analyses. NFE2L2 interacted with METTL16 to regulate the immune response in low‐grade gliomas, and both molecules may be novel therapeutic targets for gliomas. [ABSTRACT FROM AUTHOR]

This document is a research paper discussing the diagnosis of hypersensitivity to amoxicillin, a type of beta-lactam antibiotic. The authors conducted a study using a test called hMC-pMAT to evaluate its effectiveness in diagnosing amoxicillin hypersensitivity. The results showed that hMC-pMAT was comparable to other diagnostic tests, such as the basophil activation test (BAT), in clear cases of hypersensitivity. However, in more difficult cases and in patients with non-responsive basophils, hMC-pMAT did not provide additional value. The authors suggest that further research is needed to validate and generalize these findings, especially for patients with non-responsive basophils. [Extracted from the article]

Melasma is an acquired chronic pigmentary disorder affecting millions of individuals worldwide. However, the pathogenesis of melasma remains unclear. This article provides a comprehensive review of the pathophysiological changes occurring in the skin microenvironment of melasma lesions, which can be summarized as follows: (1) skin barrier dysfunction and abnormal synthesis, transport, and intracellular distribution of melanin in the epidermis; (2) basement membrane damage; (3) solar elastosis, vascular changes, senescent fibroblasts, mast cell infiltration, and sebocyte participation in the dermis; and (4) systemic factors such as sex hormones and oxidative stress. Furthermore, potential therapeutic strategies are introduced to provide novel perspectives for fundamental and clinical research related to melasma. [ABSTRACT FROM AUTHOR]

Type I hypersensitivity, also known as classical allergy, is mediated via allergen‐specific IgE antibodies bound to type I FcR (FcεRI) on the surface of mast cells and basophils upon cross‐linking by allergens. This IgE‐mediated cellular activation may be blocked by allergen‐specific IgG through multiple mechanisms, including direct neutralization of the allergen or engagement of the inhibitory receptor FcγRIIb which blocks IgE signal transduction. In addition, co‐engagement of FcεRI and FcγRIIb by IgE‐IgG‐allergen immune complexes causes down regulation of receptor‐bound IgE, resulting in desensitization of the cells. Both, activation of FcεRI by allergen‐specific IgE and engagement of FcγRIIb by allergen‐specific IgG are driven by allergen‐binding. Here we delineate the distinct roles of antibody affinity versus avidity in driving these processes and discuss the role of IgG subclasses in inhibiting basophil and mast cell activation. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion The field of drug development is witnessing a remarkable surge in the development of innovative strategies. There is a need to develop technological platforms capable of generating human data prior to progressing to clinical trials.Here we introduce a new flexible solution designed for the comprehensive monitoring of the natural human skin ecosystem's response to immunogenic drugs over time. Based on unique bioengineering to preserve surgical resections in a long survival state, it allows for the first time a comprehensive analysis of resident immune cells response at both organ and single‐cell levels.Upon injection of the mRNA‐1273 COVID‐19 vaccine, we characterized precise sequential molecular events triggered upon detection of the exogenous substance. The vaccine consistently targets DC/macrophages and mast cells, regardless of the administration route, while promoting specific cell–cell communications in surrounding immune cell subsets.Given its direct translational relevance, this approach provides a multiscale vision of genuine human tissue immunity that could pave the way toward the development of new vaccination and drug development strategies. [ABSTRACT FROM AUTHOR]

White adipose tissue (WAT) is a robust energy storage and endocrine organ critical for maintaining metabolic health as we age. Our aim was to identify cell‐specific transcriptional aberrations that occur in WAT with aging. We leveraged full‐length snRNA‐Seq and histology to characterize the cellular landscape of human abdominal subcutaneous WAT in a prospective cohort of 10 younger (≤30 years) and 10 older individuals (≥65 years) balanced for sex and body mass index (BMI). The older group had greater cholesterol, very‐low‐density lipoprotein, triglycerides, thyroid stimulating hormone, and aspartate transaminase compared to the younger group (p < 0.05). We highlight that aging WAT is associated with adipocyte hypertrophy, increased proportions of lipid‐associated macrophages and mast cells, an upregulation of immune responses linked to fibrosis in pre‐adipocyte, adipocyte, and vascular populations, and highlight CXCL14 as a biomarker of these processes. We show that older WAT has elevated levels of senescence marker p16 in adipocytes and identify the adipocyte subpopulation driving this senescence profile. We confirm that these transcriptional and phenotypical changes occur without overt fibrosis and in older individuals that have comparable WAT insulin sensitivity to the younger individuals. [ABSTRACT FROM AUTHOR]

ABSTRACT Canine cutaneous mast cell tumours (MCTs) are currently staged based on the World Health Organization (WHO) classification, which has remained unchanged since its initial formulation. Our study aimed to assess the reliability of a novel pTNM staging system, which incorporates tumour extent (T), lymph node involvement (N), presence of distant metastases (M) and the two‐tier histologic grade. We analysed medical records of dogs with one or more cutaneous/subcutaneous completely staged MCT, undergoing tumour excision with lymphadenectomy, unless distant metastases were present, in which cases, medical therapy was administered. Dogs were categorized into three stages: I (T1‐2N0M0), II (T1‐2N1M0) and III (distant metastases). Stages I and II were further divided based on histologic grade into ‘low’ and ‘high’. Substage b was defined as the presence of tumour diameter of ≥3 cm and/or ulceration. Of 226 dogs, 87 (38.5%) were in Stage I (I‐low, n = 75; I‐high, n = 12), 107 (47.3%) in Stage II (II‐low, n = 59; II‐high, n = 48), and 32 (14.2%) in Stage III. The newly proposed staging system was able to significantly stratify the population for both time to progression and tumour‐specific survival. Compared to Stage I‐low, the risk of progression increased significantly for Stage I‐high (18.3 times), Stage II‐low (8.5 times), Stage II‐high (41.5 times) and Stage III (110.3 times). The staging system was highly prognostic for both cutaneous and subcutaneous MCTs. Prospective validation studies are essential to compare this new system with the current WHO staging and further validate its accuracy and clinical utility. [ABSTRACT FROM AUTHOR]

This article explores the differences in mast cell activation between anaphylaxis and desensitization in human peanut allergy. The study used human mast cells and sera from peanut-allergic individuals to investigate the functional differences in mast cell activation after anaphylaxis and desensitization. The findings suggest that desensitization reduces the overall activation and release of interleukin 8 (IL-8) compared to anaphylaxis. The study also found that refractoriness, or temporary antigen-specific resistance, occurs independently of the initial activation modality. Further research is needed to understand the immune response to allergen-specific immunotherapy in vivo. [Extracted from the article]

Background: Anti‐IgE immunotherapy with monoclonal antibodies represents a breakthrough in treatment of severe allergic diseases. However, drawbacks such as short half‐life and high price are not negligible. Our objective is to develop an anti‐IgE vaccine based on virus‐like particles (VLPs) which can induce long‐lasting neutralizing IgG anti‐IgE antibodies reducing allergic responses without causing intrinsic mast cell activation due to IgE cross‐linking. Methods: The vaccines were made by chemically coupling three synthetic mouse IgE‐Fc fragments to plant‐derived immunologically optimized CuMVTT VLPs. The immunogenicity of the vaccines was tested by immunizing naive or allergic mice either with the coupled vaccines or the VLP control followed by systemic or local allergen challenge. Results: Mice immunized with the vaccines exhibited high titers of anti‐IgE antibodies in the sera and high levels of anti‐IgE secreting plasma cells in lymphoid organs. Moreover, free IgE in serum were reduced by the induced anti‐IgE antibodies; therefore, less IgE was bound to FcεRI on the surface of basophils. In line with these reduced IgE levels on effector cells after vaccination, immunized mice were protected from challenge with allergens. Importantly, despite presence of anti‐IgE antibodies, no signs of acute or chronic allergic response were seen in immunized allergic mice. Conclusion: The generated vaccines can effectively induce anti‐IgE antibodies that did not cause allergic responses in sensitized mice but were able to decrease the level of free and cell bound IgE and protected sensitized animals from allergic responses upon allergen challenge. [ABSTRACT FROM AUTHOR]

Dermographism is a common subtype of chronic urticaria. It generally manifests as a linear wheal after scratching or friction, with or without angioedema. The pathophysiology is not clear, but currently, we believe that the stimulation of the skin by mechanical stress leads to the activation of mast cells, which provoke the release of histamine and pro‐inflammatory mediators, ultimately forming wheal along the stressed area. The gold standard for diagnosis is a medical history and provocation test or dermatographic test. As one of the subtypes of chronic urticaria, the Urticaria Control Test (UCT), Chronic Urticaria Quality of Life questionnaire (CU‐Q2oL), and Dermatology Life Quality Index (DLQI) are also effective tools for evaluating disease control in dermographism patients. In addition to avoiding triggers, nonsedating H1 antihistamines are the first‐line medications recommended by EAACI and other guidelines; for those who do not respond to standard doses, the recommended dosage can be increased up to 4 times. When necessary, the off‐label use of omalizumab can be considered, and some drugs with potential therapeutic effects are still being explored. However, there is still a lack of biomarkers for predicting disease severity, efficacy, and prognosis. Here, we review what we know about dermographism and some points that need exploration in the future. [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]

Chronic spontaneous urticaria (CSU), atopic dermatitis (AD), psoriasis and rosacea are highly prevalent inflammatory skin conditions which impose a significant burden on patients' quality of life. Their pathophysiology is likely multifactorial, involving genetic, immune and environmental factors. Recent advancements in the field have demonstrated the key role of mast cells (MC) in the pathophysiology of these conditions. The Mas‐related G protein‐coupled receptor X2 (MRGPRX2) has emerged as a promising non‐IgE‐mediated MC activation receptor. MRGPRX2 is predominately expressed on MC and activated by endogenous and exogenous ligands, leading to MC degranulation and release of various pro‐inflammatory mediators. Mounting evidence on the presence of endogenous MRGPRX2 agonists (substance P, cortistatin‐14, LL37, PAMP‐12 and VIP) and its high expression among patients with CSU, AD, rosacea, psoriasis and chronic pruritus emphasizes the pathogenic role of MRGPRX2 in these conditions. Despite the currently available treatments, there remains a pressing need for novel drug targets and treatment options for these chronic inflammatory skin conditions. Here, we reviewed the pathogenic role of MRGPRX2 and its potential as a novel therapeutic target and provided an update on future research directions. [ABSTRACT FROM AUTHOR]

Background: Although diabetic gastroenteropathy (DGE) is associated with small intestinal bacterial overgrowth (SIBO), most studies have evaluated SIBO with a hydrogen breath test, which may be affected by altered transit in DGE. The risk factors for the consequences of SIBO in DGE are poorly understood. We aimed to evaluate the prevalence of, risk factors for, and gastrointestinal symptoms associated with SIBO in patients with DGE. Methods: In 75 patients with DGE and dyspepsia, we tested for SIBO (≥105 colony forming units /mL of aerobic and/or anaerobic bacteria in a duodenal aspirate) and assessed gastric emptying (GE) of solids, symptoms during a GE study and during an enteral lipid challenge (300 kcal/2 h), and daily symptoms with a Gastroparesis Cardinal Symptom Index diary for 2 weeks. Symptoms and GE were compared in patients with versus without SIBO. Key Results: Of 75 patients, 34 (45%) had SIBO, which was not associated with the use of proton pump inhibitors, daily symptoms, GE, or symptoms during a GE study. During enteral lipid challenge, severe nausea (p = 0.006), fullness (p = 0.02) and bloating (p = 0.009) were each associated with SIBO. Twenty patients (59%) with versus 13 (32%) without SIBO had at least one severe symptom during the lipid challenge (p = 0.006). Conclusions & Inferences: Among patients with DGE 45% had SIBO, which was associated with symptoms during enteral lipid challenge but not with delayed GE, symptoms during a GE study, or daily symptoms. Perhaps bacterial products and even fatty acids are recognized by and activate mast cells that drive the increased lipid sensitivity in SIBO. [ABSTRACT FROM AUTHOR]

Background: Bronchoalveolar lavage (BAL) cytology results from 1 lung might not be representative of both lungs. Objectives: To determine whether the lung site sampled would influence the horse's BAL cytology profile, and if a pooled BAL sample would be superior with regard to BAL cytology diagnosis in a cohort of healthy and subclinical asthmatic warmblood horses. Animals: Fifty‐nine horses in 2021 and 70 horses in 2022, the follow‐up included 53 of the same in each year. Methods: A cross‐sectional study with follow‐up included BAL cytology samples from individual lungs and from pooled BAL samples. The BAL samples were enumerated and differential cell count were applied to categorize the horses as control or with airway inflammation (AI). Results: Bronchoalveolar lavage mast cell count was higher in left lung compared to right lung (2021; median 1.6 [range, 0.6‐3.3] vs 1.2 [0.7‐1.5] P =.009, 2022; median 3.1 [2.1‐4.2] vs 2.4 [1.7‐3.4], P <.001) and compared to pooled samples (2022; median 2.6 [1.7‐3.7], P <.001). Between year 2021 and 2022, 17 of the horses had changes in BAL cytology from control to AI or vice versa. Conclusions and Clinical Importance: Pooled BAL sample was the least reliable for detecting AI, and was not representative of the overall lung condition. [ABSTRACT FROM AUTHOR]