Search Results (192)

Mast cell degranulation and other interacting and linked cells, including T-lymphocytes, macrophages, eosinophils, and platelets, as well as a range of inflammatory mediators produced during an anaphylactic or allergic reaction, constitute the main causes of Kounis syndrome. Acute ischemia episodes, coronary spasm, atheromatous plaque erosion/rupture, and platelet activation can all be caused by histamine, tryptase, arachidonic acid derivatives, and chymase in the Kounis syndrome cascade. Kounis syndrome can be triggered by a variety of factors, including medications, hymenopteran stings, metals, foods, environmental exposures, illnesses, and immunizations. In addition, some unusual, rare, intriguing, and significant causes of Kounis syndrome have been discovered recently, namely the “kiss of death”, where human kissing and pet kissing can induce fatal Kounis syndrome. Moreover, the clinical conundrum is that several of the main drugs and substances used to treat myocardial infarction and Kounis syndrome, such as adrenaline (epinephrine), aspirin, atropine, clopidogrel, corticosteroids, heparins, protamine sulfate, and hirudotherapy can also initiate it. Therefore, physicians should be aware of this clinical discrepancy to prevent catastrophic consequences. Full article

This study explores immunophenotypic and angiogenic profiles in salivary gland tumors (SGTs), focusing on epithelial–mesenchymal dynamics and immune–stromal interactions. Immunohistochemical analysis of E-cadherin, Vimentin, mast cell tryptase (MCT), CD300a, CK18, CD31, and vascular endothelial growth factor (VEGF) was performed in normal salivary tissue, pleomorphic adenomas (PA), and squamous cell carcinomas (SCCs) to assess epithelial plasticity, mast cell (MC) involvement, and vascular remodeling. Normal glands showed compartmentalized E-cadherin (epithelial) and Vimentin (mesenchymal) expression, with stromal MCs positive for MCT and CD300a. PA exhibited reduced E-cadherin, increased Vimentin, and atypical co-localization of CK18 with MCT/CD300a in ductal cells, indicating immune–epithelial plasticity. SCC displayed epithelial–mesenchymal transition (EMT), architectural disruption, and reduced MCT/CD300a. Notably, diminished MCT may reflect either decreased MCs density or prior degranulation, with possible diffuse MCT in stroma. Angiogenic profiling showed maximal CD31 in PA and minimal in SCC, while VEGF peaked in normal tissue, suggesting deregulated angiogenesis. SGT progression involves immune–epithelial plasticity, vascular deregulation, and stromal reprogramming. Immune marker localization within epithelial cells challenges histogenetic models and may inform prognostic assessment and targeted therapeutic strategies. Full article

The cochlea is susceptible to damage from ototoxic agents such as cisplatin, yet the mechanisms underlying cochlear injury remain incompletely understood. Mast cells (MCs), key immune players in allergic and inflammatory responses, have recently been identified in the rodent cochlea and implicated in cisplatin-induced ototoxicity. Our study investigated the role of MC degranulation in cochlear damage and evaluated the activation capacity of cochlear-resident MCs. Bone marrow-derived MCs (BMMCs) were cultured and induced to degranulate via IgE-anti-DNP/DNP stimulation, and the supernatants were applied to cochlear explants. Cochlear explants were also treated with Compound 48/80 (CP48/80) or cisplatin to assess MC activation. Morphological changes were assessed and hair cells (HC) quantified via phalloidin staining, while ELISA measured mediator release. Supernatants from degranulated BMMC induced a dose-dependent HC loss and tissue damage. A significant chymase and tryptase release was triggered by CP48/80 from cochlear MCs, with chymase elevation detected even at low concentrations. Cochlear MCs were rapidly activated by cisplatin exposure, elevating chymase and histamine levels, and the effects were attenuated by the MC stabilizer sodium cromolyn. Notably, tryptase remained undetectable post-cisplatin treatment, suggesting tissue-specific MC responses. These findings establish MC degranulation as an early event in cisplatin-induced cochlear injury, mediated by chymase and histamine. Our study highlights MCs as potential therapeutic targets for mitigating ototoxicity and underscores the need to explore MC-driven pathways in hearing loss. Full article

Chronic kidney disease (CKD) affects as many as 10% of the population, which translates to about 850 million globally. Even though genetics, diabetes, and hypertension contribute to CKD, the underlying pathologic processes remain poorly understood. Mast cells (MCs) are unique tissue immune cells capable of secreting numerous biologically active molecules. MCs have been associated with kidney diseases and poor CKD outcomes, but they have received limited attention in CKD research. MCs are typically located perivascularly and are identified through kidney biopsies, which limits their diagnostic utility. MC-specific biomarkers such as histamine and the proteases chymase and tryptase show potential, but signature biomarker profiles are needed. While MC biomarkers have been studied in non-renal diseases, their clinical relevance in kidney disease remains underexplored. This review aims to clarify the role of MCs in kidney diseases, such as diabetic nephropathy, IgA nephropathy, hypertensive nephropathy, pruritus, parathyroidism, renal amyloidosis, and lupus nephritis, as well as in conditions such as kidney fibrosis, inflammation, and kidney transplant rejection. Evidence indicates an increased number of MCs, as judged by increased urine levels of histamine, chymase, IL-33, metalloproteinase-9 (MMP-9), and tryptase. In conclusion, MCs are involved in the pathogenesis of CKD and may represent new targets for early diagnosis, prevention, and treatment. Full article

Background: Phosphaturic mesenchymal tumours secreting fibroblast growth factor 23 (hereinafter referred to as FGF23+ PMT) are rare neoplasms that can cause hypophosphataemic osteomalacia, owing to excessive FGF23 production. Mast cells (MCs) play a key role in tumour biology by modulating proliferative activity of atypical cells, resistance to innate and acquired immunity, angiogenesis, and metastatic behaviour. However, MCs associated with FGF23+ PMT have not previously been investigated. This study, to our knowledge, is the first to characterise features of the tumour microenvironment through spatial phenotyping of the immune and stromal landscape, together with histotopographic mapping of intercellular MC interactions with other subcellular populations in FGF23+ PMT. Methods: Histochemical staining (haematoxylin and eosin, toluidine blue, Giemsa solution, picro-Mallory protocol, silver impregnation), as well as monoplex and multiplex immunohistochemical staining with spatial phenotyping, were performed to detect atypical FGF23-secreting cells, immune cells (CD3, CD4, CD8, CD14, CD20, CD38, CD68, or CD163), stromal components (CD31, α-SMA, or vimentin), and specific MC proteases (tryptase, chymase, or carboxypeptidase A3). Bioinformatics analysis using artificial intelligence technologies was applied for spatial profiling of MC interactions with tumour, immunocompetent, and stromal cells in the tumour microenvironment. Results: Bioinformatic analysis of the entire tumour histological section, comprising over 70,000 cells stained using monoplex and multiplex immunohistochemical protocols, enabled identification of more than half of the cell population. The most abundant were CD14+ (30.7%), CD163+ (23.2%), and CD31+ (17.9%) cells. Tumour-associated MCs accounted for 0.7% of the total pool of immunopositive cells and included both mucosal and connective tissue subpopulations, predominantly of the tryptase + chymase-CPA3-specific protease phenotype. This pattern reflected combined multidirectional morphogenetic processes in the patient’s FGF23+ PMT. More than 50% of MCs were colocalized with neighbouring cells of the tumour microenvironment within 20 μm, most frequently with monocytes (CD14+CD68+), M2 macrophages (CD68+CD163+), and endothelial cells (CD31+). In contrast, colocalization with atypical FGF23-secreting cells was rare, indicating minimal direct effects on tumour cell activity. Interaction with T lymphocytes, including CD8+, was also infrequent, excluding their activation and the development of antitumour effects. Mapping of MC histotopography validated the hypothesis of their inductive role in monocyte differentiation into M2 macrophages and probable polarisation of macrophages from M1 into M2, thereby contributing to slow tumour growth. MCs were further involved in extracellular matrix remodelling and participated in the formation of pro-osteogenic niches within the FGF23+ PMT microenvironment, leading to pathological osteoid development. Conclusions: This study demonstrated active MC participation in the evolution of the FGF23+ PMT microenvironment. The findings may be applied in translational medicine to develop novel algorithms for personalised therapy in patients with FGF23-secreting tumours, offering an alternative when surgical removal of the tumour is not feasible. Full article

Background: Mast cells, key effectors of the innate immune system, are known to participate in various stages of tumor progression, including inflammation, angiogenesis, and extracellular matrix remodeling. Their role in melanoma, particularly in relation to Breslow thickness, pT stage, and AJCC staging, remains unclear. This study aims to quantitatively and phenotypically assess mast cell infiltration in cutaneous melanoma at different stages of progression, focusing on Tryptase- and Chymase-positive subtypes. Methods: This retrospective multicenter study included 124 patients with cutaneous melanoma (AJCC 8th edition, stages IA–IIIC). Histological sections were stained with hematoxylin and eosin, and mast cells were visualized using toluidine blue and immunohistochemistry with anti-Tryptase and anti-Chymase antibodies. Mast cells were counted manually in intratumoral and peritumoral regions by two independent observers. Quantitative data were analyzed using non-parametric tests and presented as median [Q1–Q3]. Results: Histological examination of 124 melanoma samples confirmed typical features of cutaneous melanoma, with nodular melanoma being the most common subtype (68 cases, 54.8%) and the lower extremities identified as the predominant tumor location (47 cases, 37.9%). Toluidine blue staining verified the presence of mast cells in both intratumoral and peritumoral compartments, with the highest density observed in early-stage melanomas. Immunohistochemical analysis identified both Tryptase+ and Chymase+ mast cells. The intratumoral number of Tryptase+ cells declined from 17 [14–19] per HPF at AJCC stage IA to 6 [5–7] per HPF at stage IIIC, while Chymase+ mast cells decreased from 14 [11–16] per HPF to 2 [1–3] per HPF over the same stages. Peritumoral counts also showed a downward trend, although less pronounced. Overall, the most significant reduction was observed in Chymase+ mast cells, suggesting their potential role as markers of melanoma progression. Conclusions: This study highlights the dynamic changes in mast cell populations in cutaneous melanoma, with a pronounced decrease in Chymase⁺ mast cells as the tumor progresses. Further research is needed to explore the mechanistic role of mast cells and their phenotypic shifts in melanoma progression. Full article

Leeches are aquatic annelids of significant medicinal value, known to produce a variety of antithrombotic proteins. However, the extent of interspecies variation in these bioactive components remains poorly understood. In this study, next-generation sequencing and the Pichia pastoris eukaryotic expression system were employed to systematically analyze the diversity of leech-derived tryptase inhibitor (LDTI) genes and their functional activities across four dominant medicinal leech species: Hirudinaria manillensis, Hirudo nipponia, Whitmania pigra, and Whitmania laevis. Our results revealed a slightly higher genetic variation in LDTI genes and their protein among non-hematophagous leeches (W. pigra and W. laevis) compared to hematophagous species (H. manillensis and H. nipponia). Selection analysis indicated purifying selection in H. manillensis (ω = 0.47), while the other species exhibited either neutral or weak positive selection (ω ≥ 1). LDTI expression levels were significantly higher in hematophagous leeches, with peak expression observed in H. manillensis (transcripts per million = 2942.07 ± 1593.12). In vitro chromogenic substrate-based anticoagulant assays of recombinant proteins confirmed anticoagulation activity across all species, with H. manillensis displaying the most potent inhibition. These findings demonstrate the antithrombotic potential of all four species, regardless of their feeding ecology. Moreover, H. manillensis emerges as the optimal candidate for therapeutic development, owing to its superior LDTI sequence conservation, expression levels, and specific anticoagulant activity per unit concentration. Full article

Mast cells (MC) are key effector cells in allergic diseases and are increasingly recognized for their roles in the immunopathogenesis of tuberculosis (TB). In allergic conditions, MCs are hyperactivated, driving T-helper Type 2 (Th2)-skewed immune responses that may antagonize the T-helper Type 1 (Th1)-mediated immunity essential for controlling Mycobacterium tuberculosis (Mtb) infection. This immunological imbalance may contribute to increased TB susceptibility, altered granuloma dynamics, and accelerated fibrotic remodeling. Histopathological and in vivo studies have revealed that MCs are recruited to TB lesions, where they release a spectrum of mediators, including histamine, IL-17A, TNF-α, TGF-β, tryptase, and chymase. These mediators can either support initial immune defense or promote chronic inflammation and tissue damage, depending on context and regulation. Moreover, individuals with chronic allergic diseases such as asthma and allergic rhinitis may experience worse TB outcomes due to their baseline immune dysregulation. Environmental exposures (e.g., air pollution, smoking), genetic polymorphisms (e.g., IL-4 −589C/T, IL-13 R130Q), and gut-lung axis disturbances further modulate MC activity and TB pathogenesis. This review synthesizes current findings on MC involvement in TB, particularly in allergic settings, and highlights the need for epidemiological studies and mechanistic research. It also explores the promise of host-directed therapies (HDTs) that target MCs or their mediators, such as antihistamines, MC stabilizers, leukotriene inhibitors, and cytokine modulators, as novel adjuncts to standard TB treatment. Personalized approaches that consider immune profiles, genetic risk, and comorbid allergies may improve TB outcomes and inform future clinical guidelines. Full article

Background: Due to the new COVID-19 vaccine types used in the COVID-19 vaccination program, significant levels of uncertainty and vaccine hesitancy arose due to fears about anaphylactic reactions, especially in patients with allergies. This study aimed to analyze how patients with significant allergies receiving specific immunotherapy (SIT) reacted to COVID-19 vaccines in real life. Methods: We assessed 57 patient charts of individuals with allergies receiving SIT for documented allergies, for their comorbidities, total IgE and tryptase levels, and Hospital Anxiety and Depression Scale (HADS) scores. Questionnaires regarding COVID-19 vaccination status and reported adverse reactions were analyzed. Results: Patients were more frequently male (58%) and had a mean age of 43 years, and the majority (60%) had already experienced an anaphylactic reaction in the past, most commonly to the allergen of the current SIT. In total, 93% received COVID-19 vaccinations. More than half of the patients (57%) reported at least one adverse reaction after COVID-19 vaccination. Out of these patients, 97% reacted in an unspecific way, with symptoms of general illness. One potential allergic reaction, classified as a grade 1 anaphylactic reaction, was documented. The patient with the potential allergic reaction was significantly more concerned before receiving the vaccination and had experienced possible allergic reactions to other vaccinations in the past. The remaining patients with unspecific reactions after vaccination had also experienced such adverse reactions in the past to other vaccinations. Antihistamine premedication was associated with fewer unspecific reactions after COVID-19 vaccination. Conclusions: Vaccinations in patients with significant allergies and prior anaphylactic reactions are, overall, safe. Prior allergic reactions after other vaccinations could be a potential risk for reaction after COVID-19 vaccinations, whereas antihistamine intake could be beneficial in reducing side effects after COVID-19 vaccinations in patients with allergies. Prospective studies on this topic are needed. Full article

This narrative review explains the history of anaphylactic or hypersensitivity reactions, their connection to the cardiovascular system, and Kounis syndrome, which is linked to hypersensitivity. Additional subjects discussed include immunoglobulin E and serum tryptase, common pathways of allergic and nonallergic cardiovascular events, current perspectives on Kounis syndrome, allergic myocardial infarction, allergic angina, and the impact of COVID-19 and its vaccination on Kounis syndrome. Kounis syndrome is a distinct kind of acute vascular disease that affects the coronary, cerebral, mesenteric, peripheral, and venous systems. Kounis syndrome is currently used to describe coronary symptoms linked to disorders involving mast cell activation and inflammatory cell interactions, such as those involving T-lymphocytes and macrophages, which further induce allergic, hypersensitive, anaphylactic, or anaphylactic insults. Platelet activating factor, histamine, neutral proteases like tryptase and chymase, arachidonic acid products, and a range of cytokines and chemokines released during the activation process are among the inflammatory mediators that cause it. Proinflammatory cytokines are primarily produced by mast cells in COVID-19 infections. Mast cell-derived proteases and eosinophil-associated mediators are also more prevalent in the lung tissues and sera of COVID-19 patients. As a modern global threat to civilization, COVID-19 is linked to chemical patterns that can activate mast cells; therefore, allergic stimuli are usually the reason. Virus-associated molecular patterns can activate mast cells, but allergic triggers are typically the cause. By activating SARS-CoV-2 and other toll-like receptors, a variety of proinflammatory mediators, including IL-6 and IL-1β, are released, potentially contributing to the pathology of COVID-19. Full article

Microglia, the brain’s resident innate immune cells, play a fundamental role in maintaining neural homeostasis and mediating responses to injury or infection. Upon activation, microglia undergo morphological and functional changes, including phenotypic switching between pro- and anti-inflammatory types and the release of different inflammatory mediators. These processes contribute to neuroprotection and the pathogenesis of various central nervous system (CNS) disorders. Mast cells, although sparsely located in the brain, exert a significant influence on neuroinflammation through their interactions with microglia. Through degranulation and secretion of different mediators, mast cells disrupt the blood–brain barrier and modulate microglial responses, including alteration of microglial phenotypes. Notably, mast cell-derived factors, such as histamine, interleukins, and tryptase, activate microglia through various pathways including protease-activated receptor 2 and purinergic receptors. These interactions amplify inflammatory cascades via various signaling pathways. Previous studies have revealed an exceedingly complex crosstalk between mast cells and microglia suggesting a bidirectional regulation of CNS immunity, implicating their cooperation in both neurodegenerative progression and repair mechanisms. Here, we review some of the diverse communication pathways involved in this complex interplay. Understanding this crosstalk may offer novel insights into the cellular dynamics of neuroinflammation and highlight potential therapeutic targets for a variety of CNS disorders. Full article

Specific venom immunotherapy (VIT) in patients with hymenoptera venom allergy (HVA) represents a well-studied approach to reduce the severity of a possible anaphylactic reaction. Currently, data on mechanisms of tolerance induction at the cellular level within the first hours of therapy are lacking. To address this, total and unoccupied high-affinity IgE receptor (FcεRI) numbers per basophil, soluble FcεRI (sFcεRI) and serum tryptase levels were measured before and after the first day of VIT induction in HVA patients. Additionally, basophil activation tests (BATs) were performed at those time points. In the early phase of VIT induction, no significant change in total FcεRI receptor density on basophils was observed, but a significant increase in unoccupied FcεRI was noticeable, predominantly in patients with high total IgE and low baseline unoccupied FcεRI density. No meaningful difference in serum tryptase levels or sFcεRI levels was observed after VIT induction. BATs showed heterogeneous results, often unchanged before and after VIT (in 47% of the cases), sometimes increased (in 40%) and only rarely decreased EC₅₀ sensitivity (in 13%). Changes in the BAT EC₅₀ correlated with FcεRI receptor density changes in basophils. In summary, VIT induction led to an increased ratio of unoccupied-to-total FcεRI without notable tryptase or sFcεRI serum elevation, pointing towards subthreshold cell activation with receptor internalization and recycling. However, the mostly unchanged or even increased basophil sensitivity in EC₅₀ calls for further research to clarify the clinical relevance of these rapid receptor modulations. Full article

Background: Patients with mastocytosis may present with exacerbated respiratory symptoms and lung diseases resulting from mast cell mediator release. However, their prevalence and severity level remain under debate. The study aims to analyze the prevalence of respiratory symptoms and the usefulness of lung function tests like spirometry, diffusing capacity of the lung for carbon monoxide (DLCO), and high-resolution computed tomography (HRCT) of the chest in mastocytosis patients presenting with dyspnea, cough, and exercise intolerance. Methods: We included 104 patients with mastocytosis and 71 healthy controls. Data collection encompassed patient interview, clinical examination, spirometry, DLCO, and chest HRCT. Diagnosis of mastocytosis included bone marrow biopsies and serum tryptase measurements. Results: Compared to controls, patients with mastocytosis exhibited significantly lower values in FEV1/VC ratio, absolute DLCO/VA, predicted DLCO/VA, absolute DLCOcSB, and predicted DLCOcSB (p < 0.001). Commonly reported respiratory symptoms included dyspnea (36.5%), chest tightness (22.1%), and wheezing (9.6%). Airway obstruction was identified in 7.7% of patients; however, it appeared to be independent of the mastocytosis subtype. A decreased DLCO/VA ratio was observed in 4.8% of patients, but HRCT did not reveal any evidence of underlying lung disease. Conclusions: Mastocytosis appears to be a risk factor for the occurrence and exacerbation of respiratory symptoms. However, airway obstruction and impairment of the alveolar–capillary membrane seem to occur independently of the clinical subtype of mastocytosis. Additionally, the causal relationship between pulmonary involvement, mast cell infiltration of the alveolar–capillary membrane, and the systemic circulation of mast cell mediators remains unclear and requires further research. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) has recently become the leading cause of chronic liver disease and can progress to hepatocellular carcinoma (HCC) through multiple pathogenic mechanisms. Protease-activated receptor 2 (PAR2) is a G-protein-coupled receptor activated by proteases such as trypsin, tryptase or coagulation factors VII and Xa. Recent studies have shown that PAR2 expression is increased in the liver of patients with MASLD or liver fibrosis. Its activation is linked to metabolic dysfunction through several pathways, including SREBP1c activation, AMPK inhibition and Akt-induced insulin resistance. Inhibition of PAR2 has been effective in reducing MASLD progression in different animal models. Notably, PAR2 blockade has also been effective in more advanced stages of the disease by dampening chronic inflammation and fibrogenesis through the inhibition of hepatic stellate cell activation and of TGF-β and SerpinB3 production. PAR2 also plays a role in cancer development, promoting tumour proliferation, angiogenesis and expression of immune checkpoint inhibitors (like PD-L1, CD47 and CD24). Due to its multifaceted involvement in liver disease, PAR2 is emerging as a key therapeutic target in this clinical context. This review aims to summarise current knowledge on PAR2′s role in MASLD and its potential as a therapeutic target. Full article

The incidence of fatal anaphylaxis is increasing, but there is still no recognized “golden standard” for forensic diagnosis. Due to its non-specific symptoms, especially cardiovascular symptoms without cutaneous changes, it can easily be misdiagnosed as acute myocardial infarction. Here, we established rat models (n = 12) of fatal anaphylaxis (FA), acute myocardial infarction (AMI), and coronary atherosclerosis with anaphylaxis (CAA). The untargeted metabolomics of plasma and 16S rRNA sequencing of fecal matter was performed, and a random forest was used to identify potential biomarkers. Three metabolites (tryptophan, trans-3-indole acrylic acid, and imidazole acetic acid) and three microbial genera (g_Prevotellaceae_Ga6A1_group, g_UCG_008, and g_Eubacterium_hallii_group) were identified as potential biomarkers for distinguishing anaphylaxis and non-anaphylaxis. The classification model of plasma metabolites showed a much better discriminatory performance than that of microbial genus, serum IgE, and tryptase. The performance of the microbial genera was superior to the serum IgE but inferior to the serum tryptase. Forensic samples of fatal anaphylaxis and non-anaphylaxis deaths (n = 12) were collected for untargeted metabolomics detection. The results showed that among the three identified metabolic biomarkers, tryptophan has better stability in cadaveric blood samples. Its diagnostic performance (AUC = 87.1528) was superior to serum IgE and tryptase, making it more suitable as a postmortem biomarker of fatal anaphylaxis. Full article