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Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease resulting in decreased quality of life. Histamine and specifically the H4 receptor play a key role in the inflammatory process in AD and serve as targets for novel therapeutic approaches. Objective: In the present study we aimed to elucidate the immunopathological mechanisms with which the H4 receptor impacts TH2 cells and contributes to AD pathophysiology. Methods: Total CD4+ T cells obtained from healthy or AD individuals and in vitro differentiated TH2 cells were cultured under different conditions and the mRNA expression or protein production of target molecules were determined using quantitative real‐time PCR and ELISA. Results: H4 receptor mRNA expression was upregulated concentration dependent upon IL‐4 stimulation in in vitro differentiated TH2 cells progressively during the differentiation. Transcriptomic analysis of in vitro differentiated TH2 versus TH1 cells revealed that the H4 receptor among other genes represents one of the highly upregulated genes in TH2 cells. Most importantly, increased amounts of IL‐5 and IL‐13 mRNA expression were detected in in vitro differentiated TH2 cells as well as protein secretion in the presence of histamine or of the H4 receptor‐selective‐agonist when compared to the untreated control. Conclusion: We show for the first time an H4 receptor dependent upregulation of the pro‐inflammatory cytokines IL‐5 and IL‐13 in human TH2 cells by histamine. This suggests that the blockade of the H4 receptor may lead to downregulation of these cytokines and amelioration of AD symptoms as reported in first clinical studies. [ABSTRACT FROM AUTHOR]

This article provides an update on the diagnosis, pathogenesis, and treatment of chronic spontaneous urticaria (CSU). CSU is a form of chronic urticaria characterized by the presence of urticarial lesions most days of the week and no identifiable cause. The article presents an algorithm for the diagnosis of CSU and discusses its association with autoimmunity. The recommended treatments for CSU include high-dose antihistamines, omalizumab, and cyclosporine. Other potential treatments are also being studied. The article emphasizes the importance of properly conducted clinical trials and highlights medications that are not recommended due to low success rates or inadequate study design. [Extracted from the article]

Histamine, mast cell, basophil Keywords: basophil; histamine; mast cell EN basophil histamine mast cell 1714 1716 3 06/02/23 20230601 NES 230601 In the early 1970s, the specialty of Allergy and Clinical Immunology in Italy was in its infancy, with few groups within Internal Medicine Departments. REFERENCES 1 Stellato C, de Crescenzo G, Patella V, Mastronardi P, Mazzarella B, Marone G. Human basophil/mast cell releasability. [Extracted from the article]

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease resulting in decreased quality of life. Histamine and specifically the H 4 receptor play a key role in the inflammatory process in AD and serve as targets for novel therapeutic approaches., Objective: In the present study we aimed to elucidate the immunopathological mechanisms with which the H 4 receptor impacts TH2 cells and contributes to AD pathophysiology., Methods: Total CD4 + T cells obtained from healthy or AD individuals and in vitro differentiated TH2 cells were cultured under different conditions and the mRNA expression or protein production of target molecules were determined using quantitative real-time PCR and ELISA., Results: H 4 receptor mRNA expression was upregulated concentration dependent upon IL-4 stimulation in in vitro differentiated TH2 cells progressively during the differentiation. Transcriptomic analysis of in vitro differentiated TH2 versus TH1 cells revealed that the H 4 receptor among other genes represents one of the highly upregulated genes in TH2 cells. Most importantly, increased amounts of IL-5 and IL-13 mRNA expression were detected in in vitro differentiated TH2 cells as well as protein secretion in the presence of histamine or of the H 4 receptor-selective-agonist when compared to the untreated control., Conclusion: We show for the first time an H 4 receptor dependent upregulation of the pro-inflammatory cytokines IL-5 and IL-13 in human TH2 cells by histamine. This suggests that the blockade of the H 4 receptor may lead to downregulation of these cytokines and amelioration of AD symptoms as reported in first clinical studies., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Eotaxin at 10 nM significantly enhanced basophil histamine release triggered by anti-IgE antibody and C5a (Figure 1A); release was similarly enhanced in highly pure (purity: ~90%) basophils (Figure 1B). Keywords: allergy; basophils; eotaxin (CCL11); histamine; leukotriene C4 EN allergy basophils eotaxin (CCL11) histamine leukotriene C4 3549 3552 4 11/01/21 20211101 NES 211101 ACKNOWLEDGEMENTS The authors thank Drs Kei Onuma, Ryo Hatano (Juntendo University) and Hiroshi Kawasaki (JCHO Yugawara Hospital) for kindly providing us with anti-CCR3 hybridoma, Ms Sayaka Igarashi for helpful advice on the experimental procedures, Dr Hirokazu Sakasegawa for his critical reading of this manuscript, and Ms Yasuko Asada for her excellent secretarial work. [Extracted from the article]

The proper protocol for IHC therapy for remission induction in CSU seems to be a weekly injection regimen until remission is reached. Abbreviations CSU Chronic spontaneous urticaria Df Dermatophagoides farina Dp Dermatophagoides pteronyssinus IHC immunoglobulin/histamine complex The primary treatment of chronic spontaneous urticaria (CSU) focuses on symptomatic control.1 Recently, remission of CSU by several drugs, including cyclosporine A and omalizumab, has been reported.2,3 Previous report suggests that Immunoglobulin/histamine complex (IHC) to inhibit antigen-induced histamine release from basophils and mast cells have histaminopexic effects, and may be effective in treating chronic urticaria.4 Our previous report documented remission in four cases by continuing immunoglobulin/histamine therapy until remission was reached.4 This was a retrospective cohort study (May 2017 to May 2021) and evaluated 134 CSUs; 114 patients were treated with IHC (IH Group), and 20 patients were treated with only H1 antihistamines (AH Group) (Table S1). [Extracted from the article]

B and C, H2R mRNA expression in IL-4 stimulated M2 macrophages, D and E, H4R mRNA expression in IL-4 stimulated M2 macrophages, F and G, H4R mRNA expression in IL-13 stimulated M2 macrophages. Expression of histamine receptors H2R and H4R are predominantly regulated via the IL-4/IL-13 receptor type II on human M2 macrophages Keywords: atopic dermatitis; histamine; macrophages EN atopic dermatitis histamine macrophages 2886 2890 5 09/03/21 20210901 NES 210901 ACKNOWLEDGEMENTS The authors would like to thank Brigitta Koether for excellent technical assistance. [Extracted from the article]

Antagonizing histamine H SB 1 sb receptors inhibited the concentration-response curves and the initial 15 minutes of responses induced by submaximal bolus dose challenges, indicating that the early response of both treatments was mediated by histamine. Keywords: asthma; drug allergy; histamine; mast cells; "omics" and systems biology EN asthma drug allergy histamine mast cells "omics" and systems biology 2270 2273 4 07/02/21 20210701 NES 210701 Mast cells (MCs) can be activated immunologically by allergen and non-immunologically via the Mas-related G protein-coupled receptor member X2 (MRGPRX2).1 With the emerging interest of MRGPRX2, we compared the airway smooth muscle (ASM) response and release of mediators in airways exposed to the human MRGPRX2 agonist compound 48/80 (C48/80) and house dust mite (HDM). Asthma, drug allergy, histamine, mast cells, "omics" and systems biology. [Extracted from the article]

Most of these differential responses were due to stronger activation in HCs vs AR patients, except for the right anterior insula, right middle occipital gyrus, right middle/superior frontal gyrus, and left cerebellum, where a stronger activation was observed in AR patients. Further research in a larger group of patients might be useful to investigate brain responses in severe AR patients and to better understand the psycho-emotional impact of chronic allergic inflammation. In allergic rhinitis (AR) patients, nasal allergen deposition leads to mast cell activation with release of allergic mediators such as histamine. In this proof-of-concept study, 8 house dust mite (HDM) AR patients and 7 non-allergic healthy controls (HC) were recruited at the outpatient clinic for Otorhinolaryngology of University Hospitals Leuven. [Extracted from the article]

Histamine is known to be stable in the plasma obtained after centrifugation up to 4 days at RT for patients and controls.9 According to these results, we suggest that whole blood samples can be stored at +4°C up to 72 hours for histamine and 7 days for tryptase when the laboratory is not available immediately. Tryptase release is considered a robust marker of mast cell degranulation but is not informative in mild reactions and often normal during food-induced allergic reactions.1 Histamine is released at the early beginning of the reaction and may be useful when tryptase levels are normal or not informative. Keywords: histamine; pre-analytic; tryptase; whole blood EN histamine pre-analytic tryptase whole blood 1579 1583 5 05/17/21 20210501 NES 210501 Immediate hypersensitivity reactions are related to mast cell and/or basophil activation. Increased tryptase is defined as >=1.2 × basal value + 2 µg.L SP -1 sp .4 In our hands, tryptase uncertainties of measurement for low and high concentrations (9 µg.L SP -1 sp and 38.2 µg.L SP -1 sp ) are 17% and 16%, respectively, in accordance with published results.5 Plasma histamine concentrations were measured by a radioimmunoassay (Beckman Coulter, ImmunoTech). [Extracted from the article]

The H4R is highly expressed on eosinophils from AD patients and IL-4 upregulates expression and function via the JAK/STAT pathway Taken together, we show for the first time that the H SB 4 sb R mRNA is upregulated via IL-4 and IL-13 in human eosinophils and that IL-4 receptor-induced upregulation is mediated via the JAK/STAT pathway. Moreover, we demonstrated that eosinophils from the circulation of AD patients showed a significantly higher basal expression of H SB 4 sb R and a higher upregulation after IL-4 stimulation compared to eosinophils from healthy subjects or psoriasis patients (Figure 1J-L). [Extracted from the article]

Histamine down-regulates the FCERI -chain expression in human IL-4-activated M2 macrophages However, the regulation of FCERI -chain expression was not directly related to IL-4 stimulation in their study.6 Thus, we show here for the first time that IL-4 and also IL-13 up-regulate FCERI -chain mRNA expression in human M2 macrophages. The histamine-mediated down-regulation of the FCERI -chain expression in IL-4-activated M2 macrophages may reduce IgE/FCERI antigen sensing and signal transduction thereby balancing the inflammatory conditions in allergic reactions. [Extracted from the article]

Systemic mastocytosis (SM) is a disease characterized by increased number of aberrant mast cells in one or several organs and increased systemic levels of mast cell (MC) mediators.1 Indolent SM (ISM) is the most common form of SM, constituting approximately 80% of the patients diagnosed with SM. Keywords: histamine; IgE; mast cells EN histamine IgE mast cells 1909 1911 3 05/31/22 20220601 NES 220601 ACKNOWLEDGEMENTS We thank Ingrid Delin for technical assistance with the analysis of PGD SB 2 sb . [Extracted from the article]

Background: Several factors may contribute to the circadian variability of clinical manifestations in asthma and allergy. Basophils play a pivotal role in allergic inflammation. However, evidence for a functional clock governing the effector function of these cells is sparse and contradictory. We have systematically sampled the 24‐hour response of basophils to IgE‐ and non‐IgE‐dependent ligands in asthma to understand their possible contribution to the diurnal variations of allergic symptoms. Methods: Leukocytes were collected every 4 hours for 24 hours from 10 patients with moderate, persistent asthma and 10 matched, nonallergic controls, and then incubated with concentrations of anti‐IgE, formyl‐methionyl‐leucylphenylalanine (fMLP), or the Ca2+ ionophore, A23187. Histamine release (HR) was tested for time‐of‐day‐ or disease‐related variability by conventional statistics and for 24‐hour rhythmicity by the cosinor method. Results: HR induced by anti‐IgE was significantly increased at 08:00 vs. 20:00 in basophils from asthmatics but not controls. No significant differences were seen at any time in the response to A23187, while the response to fMLP was significantly higher at 08:00 vs. 20:00 in controls but not asthmatics. The basophil response to anti‐IgE, but not fMLP or A23187, varied significantly across the 24 hours in asthma, and its amplitude, percent rhythm, and acrophase were comparable to those of peak expiratory flow or serum cortisol. Conclusion: Using an integrated statistical approach, we show that basophil responsiveness undergoes significant circadian variability and that distinct patterns of rhythmicity can be recognized depending on the signal delivered, the activation parameters assessed, and the disease status. [ABSTRACT FROM AUTHOR]

Background: Histamine is an important immunomodulator influencing both the innate and adaptive immune system. Certain host cells express the histidine decarboxylase enzyme (HDC), which is responsible for catalysing the decarboxylation of histidine to histamine. We and others have shown that bacterial strains can also express HDC and secrete histamine; however, the influence of bacterial‐derived histamine on the host immune responses distant to the gut is unclear. Methods: The Escherichia coli BL21 (E coli BL21) strain was genetically modified to express the Morganella morganii (M morganii)‐derived HDC gene (E coli BL21_HTW). E coli BL21 and E coli BL21_HTW were gavaged to ovalbumin (OVA) sensitized and challenged mice to investigate the effect of bacterial‐derived histamine on lung inflammatory responses. Results: Oral administration of E coli BL21_HTW, which is able to secrete histamine, to wild‐type mice reduced lung eosinophilia and suppressed ex vivo OVA‐stimulated cytokine secretion from lung cells in the OVA respiratory inflammation mouse model. In histamine receptor 2 (H2R)‐deficient mice, administration of histamine‐secreting bacteria also reduced inflammatory cell numbers in bronchoalveolar lavage (BAL). However, the suppressive effect of bacterial‐derived histamine on BAL inflammation was lost in HDC‐deficient mice. This loss of activity was associated with increased expression of histamine degrading enzymes and reduced histamine receptor expression. Conclusion: Histamine secretion from bacteria within the gut can have immunological consequences at distant mucosal sites, such as within the lung. These effects are influenced by host histamine receptor expression and the expression of histamine degrading enzymes. [ABSTRACT FROM AUTHOR]

Background: Food‐induced anaphylaxis is a serious allergic reaction caused by Fcε‐receptor activation on mast cells (MCs). The exact mechanisms breaking oral tolerance and the effector pathways driving food allergy remain elusive. As complement is activated in food‐induced anaphylaxis, we aimed to assess the role of C5a in disease pathogenesis. Methods: Oral antigen‐induced food‐induced anaphylaxis was induced in BALB/c wild‐type (wt) and C5ar1−/− mice. Readouts included diarrhea development, changes in rectal temperature, hematocrit, antigen‐specific serum IgE, MCPT‐1, and intestinal MC numbers, as well as FcεR1‐mediated MC functions including C5a receptor 1 (C5aR1) regulation. Further, histamine‐mediated hypothermia and regulation of endothelial tight junctions were determined. Results: Repeated oral OVA challenge resulted in diarrhea, hypothermia, increased hematocrit, high OVA‐specific serum IgE, and MCPT‐1 levels in wt mice. Male C5ar1−/− mice were completely whereas female C5ar1−/− mice were partially protected from anaphylaxis development. Serum MCPT‐1 levels were reduced gender‐independent, whereas IgE levels were reduced in male but not in female C5ar1−/− mice. Mechanistically, IgE‐mediated degranulation and IL‐6 production from C5ar1−/−BMMCs of both sexes were significantly reduced. Importantly, FcεR1 cross‐linking strongly upregulated C5aR1 MC expression in vitro and in vivo. Finally, C5ar1−/− male mice were largely protected from histamine‐induced hypovolemic shock, which was associated with protection from histamine‐induced barrier dysfunction in vitro following C5aR targeting. Conclusions: Our findings identify C5aR1 activation as an important driver of IgE‐mediated food allergy through regulation of allergen‐specific IgE production, FcεR1‐mediated MC degranulation, and histamine‐driven effector functions preferentially in male mice. The C5a/C5aR1 axis controls the production of allergen‐specific IgE in male mice. FcεR1 aggregation upregulates C5aR1 expression in mast cells which amplifies IgE‐driven mediator release. C5aR1 signaling controls histamine‐mediated effector functions in vivo and in vitro. [ABSTRACT FROM AUTHOR]

Background: Histaminolytic activity mediated by diamine oxidase (DAO) is present in plasma after induction of severe anaphylaxis in rats, guinea pigs, and rabbits. Heparin released during mast cell degranulation in the gastrointestinal tract might liberate DAO from heparin‐sensitive storage sites. DAO release during anaphylaxis has not been demonstrated in humans. Methods: Plasma DAO, tryptase, and histamine concentrations of four severe anaphylaxis events were determined at multiple serial time points in two patients with systemic mastocytosis. The histamine degradation rates were measured in anaphylaxis samples and in pregnancy sera and plasma with comparable DAO concentrations. Results: Mean DAO (132 ng/mL) and tryptase (304 ng/mL) concentrations increased 187‐ and 4.0‐fold, respectively, over baseline values (DAO 0.7 ng/mL, tryptase 76 ng/mL) during severe anaphylaxis. Under non‐anaphylaxis conditions, DAO concentrations were not elevated in 29 mastocytosis patients compared to healthy volunteers and there was no correlation between DAO and tryptase levels in mastocytosis patients. The histamine degradation rate of DAO in plasma from mastocytosis patients during anaphylaxis is severely compromised compared to DAO from pregnancy samples. Conclusion: During severe anaphylaxis in mastocytosis patients, DAO is likely released from heparin‐sensitive gastrointestinal storage sites. The measured concentrations can degrade histamine, but DAO activity is compromised compared to pregnancy samples. For accurate histamine measurements during anaphylaxis, DAO inhibition is essential to inhibit further histamine degradation after blood withdrawal. Determination of DAO antigen levels might be of clinical value to improve the diagnosis of mast cell activation. Diamine oxidase (DAO) antigen increases more than 100‐fold in plasma during severe anaphylaxis and degrades histamine (HIS) in vivo and in vitro but its activity is reduced compared to DAO in pregnancy plasma. Only immediate DAO inhibition after blood withdrawal allows accurate histamine measurements in plasma. Determination of DAO antigen levels might help to diagnose mast cell (MC) activation. [ABSTRACT FROM AUTHOR]

Background: Basophils are commonly associated with allergic responses because of their ability to produce large amounts of pro‐Th2 cytokines and histamine. However, the mechanisms through which bone marrow‐resident basophils (BMRB) become fully competent cytokine and histamine producers in response to IgE crosslinking are poorly understood. Here, we sought to determine the role of IL‐3 in promoting pro‐Th2 basophils. Methods: BMRB and basophils exposed to IL‐3 in vitro and in vivo were evaluated for their production of Th2 cytokines and histamine in response to FcεRI crosslinking on both protein and gene expression levels. In vivo relevance of our findings was assessed in a model of ovalbumin‐induced allergic asthma using IL‐3–deficient and wild‐type mice in a protocol of adoptive basophil transfer. Results: We show that BMRB and basophils previously exposed to IL‐3 differ in their ability to generate cytokines (IL‐4, IL‐6, IL‐13, and GM‐CSF) and histamine in response to FcεRI crosslinking, reflecting two stages of maturation. Exposure to IL‐3 initiated an autocrine loop of endogenous IL‐3 production that enhanced histamine and cytokine production upon FcεRI crosslinking. This increased responsiveness required calcium flux and was dependent on calcineurin and store‐operated calcium channels. Our findings are of pathophysiological relevance, as assessed by the failure of IL‐3–deficient mice to develop airway hyperreactivity, which could be restored by adoptive transfer of IL‐3–derived basophils recovered from wild‐type mice. Conclusion: IL‐3–dependent basophils promote Th2 allergic AHR, which designates the IL‐3/basophil axis as a promising therapeutic target for the treatment of basophil‐dependent asthma. FcεRI crosslinking on IL‐3–derived basophils induces concomitant histamine and cytokine synthesis depending on calcineurin and store‐operated calcium entry. Autocrine IL‐3 is essential for enhancing the responsiveness of bone marrow basophils to FcεR1 crosslinking. IL‐3–deficient mice are unable to develop asthmatic hyperreactivity, which can be fully restored by the adoptive transfer of IL‐3–producing basophils. [ABSTRACT FROM AUTHOR]

Keywords: histamine; mast cells; urticaria EN histamine mast cells urticaria 1830 1832 3 07/14/20 20200701 NES 200701 Chronic spontaneous urticaria (CSU) is defined as the presence of urticaria for over 6 weeks and is distinct from the inducible (physical) urticarias. About 40% of patients have IgG antibody to the IgE receptor (or IgE, itself), 25% have IgG antithyroid antibodies and 30% a positive ANA. When serum of patients is injected into skin (the autologous skin test), hive formation is seen (when positive) without adding antigen and reflects IgG anti-IgE receptor rather than IgE antibody. [Extracted from the article]

Abstract: Background: Histamine intolerance is thought to trigger manifold clinical symptoms after ingesting histamine‐rich food due to reduced activity of diamine oxidase (DAO). No study has hitherto systematically assessed daily fluctuations of histamine levels and DAO activities in symptomatic patients. The aim of the study was to investigate the presence of histamine intolerance, to therefore establish day profiles of histamine levels and DAO activities, and to compare the results between patients with suspected histamine intolerance, food allergy and healthy controls. Methods: We determined day profiles of histamine plasma levels and DAO serum activities in 33 patients with suspected histamine intolerance, in 21 patients with proven food allergy and in 10 healthy control patients. Clinical symptoms, food intolerances and further clinical and laboratory chemical parameters were evaluated. Results: Twenty‐four percent (8 of 33) suspected histamine‐intolerant patients showed elevated histamine levels during the day. That might be caused by constantly and significantly reduced DAO activities in these patients compared to food‐allergic and control patients. The remaining 25 patients presented normal histamine levels and DAO activities, but an increased prevalence of multiple food intolerances compared to the other subgroup of suspected histamine‐intolerants. There was no correlation between subjective complaints and serological histamine parameters in patients with suspected histamine intolerance. Conclusions: We determined by daily profiling that decreased DAO activities correlated with elevated histamine levels in a subgroup of suspected histamine‐intolerants. This finding discriminates these patients from food intolerant individuals with similar clinical symptoms and strongly suggests the presence of histamine intolerance. [ABSTRACT FROM AUTHOR]

Background Histamine is a key immunoregulatory mediator and can dampen proinflammatory responses via activation of histamine receptor 2 (H2R). The aim of this study was to determine the role of H2R in modulating lung inflammatory responses. Methods H2R was blocked using famotidine or activated using dimaprit in both the ovalbumin ( OVA) and house dust mite extract ( HDM) murine models of respiratory inflammation. H2R-deficient animals and CD1d/H2R-deficient animals were utilized to examine the CD1d presentation of lipid antigens (αGalCer or OCH) to invariant natural killer T ( iNKT) cells. Results Famotidine treatment resulted in more severe airway disease in the OVA model, while dimaprit treatment significantly reduced disease severity. Both OVA and HDM-induced airway diseases were more severe in H2R-deficient animals. Flow cytometric analysis of lung tissue from H2R-deficient animals revealed increased numbers of CD1d+ dendritic cells and increased numbers of iNKT cells. In vitro, αGalCer-stimulated iNKT cells from H2R-deficient mice secreted higher levels of IL-4, IL-5, and GM- CSF. In vivo, αGalCer or OCH administration to the lung resulted in enhanced mucus secretion, inflammatory cell recruitment, and cytokine production in H2R-deficient or famotidine-treated animals, while dimaprit dampened the lung iNKT cell response to αGalCer. Removal of iNKT cells in H2R-deficient ( CD1d−/−H2R−/−) animals normalized the lung response to HDM. Conclusion The deliberate activation of H2R, or its downstream signaling molecules, may represent a novel therapeutic target for chronic lung inflammatory diseases, especially when CD1d-mediated presentation of lipid antigens to iNKT cells is contributing to the pathology. [ABSTRACT FROM AUTHOR]

Background Recent data suggest that Bruton's tyrosine kinase ( BTK) is an emerging therapeutic target in IgE receptor (Ig ER)-cross-linked basophils. Methods We examined the effects of four BTK inhibitors (ibrutinib, dasatinib, AVL-292, and CNX-774) on IgE-dependent activation and histamine release in blood basophils obtained from allergic patients (n=11) and nonallergic donors (n=5). In addition, we examined the effects of these drugs on the growth of the human basophil cell line KU812 and the human mast cell line HMC-1. Results All four BTK blockers were found to inhibit anti-IgE-induced histamine release from basophils in nonallergic subjects and allergen-induced histamine liberation from basophils in allergic donors. Drug effects on allergen-induced histamine release were dose dependent, with IC50 values ranging between 0.001 and 0.5 μmol/L, and the following rank order of potency: ibrutinib> AVL-292>dasatinib> CNX-774. The basophil-targeting effect of ibrutinib was confirmed by demonstrating that IgE-dependent histamine release in ex vivo blood basophils is largely suppressed in a leukemia patient treated with ibrutinib. Dasatinib and ibrutinib were also found to counteract anti-IgE-induced and allergen-induced upregulation of CD13, CD63, CD164, and CD203c on basophils, whereas AVL-292 and CNX-774 showed no significant effects. Whereas dasatinib and CNX-774 were found to inhibit the growth of HMC-1 cells and KU812 cells, no substantial effects were seen with ibrutinib or AVL-292. Conclusions BTK-targeting drugs are potent inhibitors of IgE-dependent histamine release in human basophils. The clinical value of BTK inhibition in the context of allergic diseases remains to be determined. [ABSTRACT FROM AUTHOR]

Background Atopic dermatitis ( AD) is a common skin disorder. Its diagnosis relies on clinical judgment. Mild and untypical manifestations may cause diagnostic difficulties. Biomarkers for the differential diagnostic workup of AD are needed. Objective To test whether the results of skin provocation with cowhage, an established model of histamine-independent pruritus, and histamine are different in AD patients and healthy subjects and whether these tests may be used as diagnostic markers of AD. Methods Twenty-two AD patients and 18 healthy controls were subjected to topical cowhage provocation and skin prick testing with histamine and assessed for differences in the quality, intensity, and persistence of itch, for wheal diameter, volume, and flare size and intensity. Results Patients with AD, compared with healthy controls, exhibited significantly smaller histamine-induced flares ( P < 0.01) and markedly longer itch persistence after provocation with cowhage ( P < 0.01). Both parameters showed good diagnostic properties for AD (area under the receiver operating characteristic ( ROC) curve 0.78 and 0.80, respectively). The persistence of cowhage-induced itch for at least 30 min and a histamine-induced flare of less than 2 cm in diameter were reliable thresholds for the diagnosis of AD. If combinations of the results of both tests were used, their sensitivity and specificity of diagnosing AD were up to 91% and 94%, respectively. Conclusion The clinical benefit of cowhage and histamine skin provocation tests should be investigated in further studies. Long persistence of cowhage-induced itch and diminished histamine-induced flare in nonlesional skin may support diagnosis of AD. [ABSTRACT FROM AUTHOR]

Background: Food allergy affects up to 10% of the pediatric population. Despite ongoing efforts, treatment options remain limited. Novel models of food allergy are needed to study response patterns downstream of IgE-crosslinking and evaluate drugs modifying acute events. Here, we report a novel human ex vivo model that displays acute, allergen-specific, IgE-mediated smooth muscle contractions using precision cut intestinal slices (PCIS)., Methods: PCIS were generated using gut tissue samples from children who underwent clinically indicated surgery. Viability and metabolic activity were assessed from 0 to 24 h. Distribution of relevant cell subsets was confirmed using single nucleus RNA sequencing. PCIS were passively sensitized using plasma from peanut allergic donors or peanut-sensitized non-allergic donors, and exposed to various stimuli including serotonin, histamine, FcɛRI-crosslinker, and food allergens. Smooth muscle contractions and mediator release functioned as readouts. A novel program designed to measure contractions was developed to quantify responses. The ability to demonstrate the impact of antihistamines and immunomodulation from peanut oral immunotherapy (OIT) was assessed., Results: PCIS viability was maintained for 24 h. Cellular distribution confirmed the presence of key cell subsets including mast cells. The video analysis tool reliably quantified responses to different stimulatory conditions. Smooth muscle contractions were allergen-specific and reflected the clinical phenotype of the plasma donor. Tryptase measurement confirmed IgE-dependent mast cell-derived mediator release. Antihistamines suppressed histamine-induced contraction and plasma from successful peanut OIT suppressed peanut-specific PCIS contraction., Conclusion: PCIS represent a novel human tissue-based model to study acute, IgE-mediated food allergy and pharmaceutical impacts on allergic responses in the gut., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background Specific allergen immunotherapy (SIT) is an effective allergy treatment, but it is unclear whether SIT is effective for atopic eczema (AE). We undertook a systematic review to assess SIT efficacy and safety for treating AE. Methods We searched databases, ongoing clinical trials registers, and conference proceedings up to July 2015. Randomized controlled trials (RCTs) of SIT using standardized allergen extracts, compared with placebo/control, for treating AE in patients with allergic sensitization were eligible. Results We identified 12 eligible trials with 733 participants. Interventions included subcutaneous (six trials), sublingual (four trials), oral or intradermal SIT in children/adults allergic to house dust mite (10 trials), grass pollen or other inhalants. Risk of bias was moderate, with high loss to follow-up and nonblinding as the main concerns. For our primary outcomes, three studies (208 participants) reported no significant difference - patient-reported global disease severity improvement RR 0.75 (95% CI 0.45, 1.26); and eczema symptoms mean difference −0.74 on a 20-point scale (95% CI −1.98, 0.50). Two studies (85 participants) reported a significant difference - SIT improved global disease severity RR 2.85 (95% CI 1.02, 7.96); and itch mean difference −4.20 on a 10-point scale (95% CI −3.69, −4.71). Meta-analysis was limited due to extreme statistical heterogeneity. For some secondary outcomes, meta-analyses showed benefits for SIT, for example investigator-rated improvement in eczema severity RR 1.48 (95% CI 1.16, 1.88; six trials, 262 participants). We found no evidence of adverse effects. The overall quality of evidence was low. Conclusion We found no consistent evidence that SIT is effective for treating AE, but due to the low quality of evidence further research is needed to establish whether SIT has a role in AE treatment. [ABSTRACT FROM AUTHOR]

Background The utility of measuring histamine and prostaglandin metabolites in the urine of patients with mastocytosis has not been critically examined in a large series of patients. This study examined the relationship between the extent of increase in urinary excretion of 11β-prostaglandinF2α and N-methyl histamine, with serum tryptase, whole blood serotonin, and bone marrow findings including morphology, percentage involvement, and abnormal mast cell phenotype. Methods This was a retrospective analysis of 90 patients who were continuously enrolled in the study for a period of 6 years (2008-2014). We recorded serum tryptase, whole blood serotonin, levels of urinary mast cell metabolites 11β-prostaglandinF2α and N-methyl histamine ( NMH), and bone marrow findings. Results Urinary mast cell metabolites 11β-prostaglandinF2α and N-methyl histamine correlated with levels of serum tryptase, mast cell burden in the bone marrow, the presence of mast cell aggregates, and atypical mast cells on bone marrow biopsy. Whole blood serotonin did not have a significant correlation with the serum tryptase or mast cell burden in the bone marrow. Urinary NMH was significantly different between c-kit D816V-positive and c-kit D816V-negative patients, while 11β-prostaglandinF2α was not. Urinary 11β-prostaglandinF2α 24-h excretion >3500 ng and NMH levels >400 μg/gm Cr corresponded with the high degree of bone marrow biopsies positive for atypical mast cells, the presence of aggregates, and c-kit mutation. Conclusions Easily obtained and quantified urinary metabolites of histamine (greater than twice the upper limit of normal) and prostaglandin D2 (>3.4 times the upper limit of normal) correlate well with bone marrow findings of mastocytosis. [ABSTRACT FROM AUTHOR]

Growing evidence identifies histamine as a key player in allergic responses, but the reports relating serum histamine to tolerance are scarce and inconclusive. This study investigated the relationship of circulating histamine to the tolerant phenotype in allergic beekeepers. The results showed a positive correlation between the serum levels of histamine and specific immunoglobulin G4 (sIgG4) to honeybee venom, but not with total IgE or sIgE. Interestingly, both sIgG4 and histamine levels were negatively correlated with the time since the last bee sting. In contrast to total IgE and sIgE, serum sIgG4 and histamine levels followed comparable patterns, being higher in tolerant/recently stung individuals and lower in the least frequently stung subgroup. The data obtained in this pilot study associated, for the first time, serum histamine levels with allergen tolerance in allergic individuals and provided the lead for further considering the putative immunomodulatory properties of histamine in allergic responses. [ABSTRACT FROM AUTHOR]

It remains poorly understood how symptoms in allergic rhinitis are most severe during overnight or early in the morning. The circadian clock consisting of a network of several 'clock genes' including Clock drives daily rhythms in physiology. This study showed that allergen-induced surface CD203c expression on basophils in seasonal allergic rhinitis caused by Japanese cedar pollen exhibited a time-of-day-dependent variation associated with temporal variations in canonical circadian clock gene expression. We also found that bone-marrow-derived basophils ( BM basophils) generated from wild-type mice exhibited a time-of-day-dependent variation in IgE-mediated IL-4 and histamine production, which was not observed in BM basophils generated from Clock-mutated mice. Therefore, allergen-specific basophil reactivity shows daily variations depending on the circadian clock activity in basophils, which could partly explain temporal symptomatic variations in allergic rhinitis. Additionally, circadian variations in CD203c expression should be considered for interpretation of this biomarker in clinical research. [ABSTRACT FROM AUTHOR]

In this article, the author opines on the urticaria and angioedema as the common diseases perceived by the dermatologists. The author opines on these diseases which could be distinguished by their gross appearance, speed of onset, duration, anatomic location, and severity of symptoms, urticaria is mediated by mast cells with histamine, and chronic angioedema. The author also provides his views on self-treatment by healthcare professionals.

Histamine is a biogenic amine with extensive effects on many cell types, mediated by the activation of its four receptors ( H1 R- H4 R). Distinct effects are dependent on receptor subtypes and their differential expression. Within the gastrointestinal tract, histamine is present at relatively high concentrations, particularly during inflammatory responses. In this review, we discuss the immunoregulatory influence of histamine on a number of gastrointestinal disorders, including food allergy, scombroid food poisoning, histamine intolerance, irritable bowel syndrome, and inflammatory bowel disease. It is clear that the effects of histamine on mucosal immune homeostasis are dependent on expression and activity of the four currently known histamine receptors; however, the relative protective or pathogenic effects of histamine on inflammatory processes within the gut are still poorly defined and require further investigation. [ABSTRACT FROM AUTHOR]

Background The most intriguing function attributed to interleukin-31 ( IL-31) is its ability to induce pruritus in pathologic conditions, such as atopic dermatitis ( AD). As of today, this feature of IL-31 was tested in vivo only in animal models. Methods Ten patients with AD and 10 healthy controls were challenged with IL-31 and NaCl (negative control) by skin prick testing. Twenty additional healthy controls were subjected to skin prick testing with histamine. Itch and local inflammatory responses of the skin were assessed for up to 72 h. Results All of the histamine-challenged subjects developed immediate pruritus (i.e. within the first 5 min). In contrast, only one IL-31- and two of the NaCl-challenged subjects reported immediate itch at the provocation site (short lasting, for 2-6 min). Nine subjects (five patients with AD) reported late itch responses to IL-31 challenges with a mean delay of 143 min. No subject reported late itch responses to histamine or NaCl testing. There was no significant difference in IL-31-induced itch start time, duration and intensity between patients with AD and healthy volunteers. Conclusion IL-31 does not induce immediate itch responses in humans. The late onset of IL-31-induced itch supports the notion that IL-31 exerts its pruritic effect indirectly via keratinocytes and secondary mediators, rather than through its receptors on cutaneous nerves. [ABSTRACT FROM AUTHOR]

Background Cold contact urticaria ( CCU) is characterized by itchy wheal and flare responses due to the release of histamine and other pro-inflammatory mediators after exposure to cold. The treatment of choice is nonsedating antihistamines, dosages of which may be increased up to fourfold if standard doses are ineffective. Here, we assess the effects of a standard 20 mg dose and up-dosing to 40 and 80 mg of bilastine in reducing the symptoms of CCU and inflammatory mediator release following cold challenge. Methods Twenty patients with CCU were included in this randomized, crossover, double-blind, placebo-controlled 12-week study. They received placebo, 20, 40 or 80 mg of bilastine daily each for 7 days with 14-day washout periods. The primary readout was change in critical temperature thresholds ( CTT). Secondary readouts were changes in pruritus, levels of histamine IL-6, IL-8 and TNF-α collected by skin microdialysis and safety and tolerability of bilastine. Results Bilastine 20 mg was highly effective ( P < 0.0001) in reducing CTT. Up-dosing to 80 mg significantly ( P < 0.04) increased its effectiveness. At this dose, 19 of 20 (95%) patients responded to treatment, with 12 of 20 (60%) becoming symptom free. Only one patient was refractory to treatment. Microdialysis levels of histamine, IL-6 and IL-8 assessed 1-3 h after cold challenge were significantly ( P < 0.05) decreased following up-dosing with 80 mg bilastine. Bilastine treat-ment was well tolerated without evidence of increased sedation with dose escala-tion. Conclusions Bilastine was effective in reducing the symptoms of patients with CCU. Increased efficacy of bilastine with fourfold up-dosing was without sedation and supports urticaria treatment guidelines. [ABSTRACT FROM AUTHOR]

Background Monocyte differentiation into dendritic cells or macrophages and recruitment to peripheral organs in chronic inflammatory diseases are directed by allergen challenge via Fcε RI as well as the nature of soluble factors in the microenvironment. High-affinity receptor for IgE stimulation of effector cells results in the release of histamine, which acts on various histamine receptors ( HR) 1-4, expressed by immune cells. Methods We examined the effect of Fcε RI stimulation of human monocytes on H1 R expression and function of differentiating cells. The m RNA levels of H1 R, H2 R and histidine decarboxylase of differentiating cells were detected by quantitative real-time PCR. Expression of CD1c, CD11c, CD68 and CD163 was detected by flow cytometry. Amount of histamine, IL-6 and IL-12p70 in the cell culture was measured with the help of cytometric bead arrays or ELISA assays. Numbers of H1 R-expressing macrophages were evaluated by immunofluorescence double staining of CD68 and H1 R on human skin sections. Results We demonstrated that Fcε RI stimulation promotes the generation of H1 R-expressing macrophage-like cells with enhanced histamine biosynthesis and H1 R-mediated proinflammatory properties. Supporting our in vitro findings, high numbers of H1 R-expressing CD68pos macrophages were detected in the dermis of atopic dermatitis ( AD) skin lesions. Conclusion Our observations point to a close histamine-/ HR-mediated activation of dermal macrophages, leading to modified cell differentiation and responsiveness via H1 R, which might contribute to the aggravation of allergic skin inflammation in AD. [ABSTRACT FROM AUTHOR]

An autoimmune subset of chronic spontaneous urticaria is increasingly being recognized internationally, based on laboratory and clinical evidence that has accrued over the last 20 years. This evidence has been reviewed by a taskforce of the Dermatology section of the European Academy of Allergy and Clinical Immunology. Functional autoantibodies in chronic urticaria ( CU) patient sera have been demonstrated against Ig E and Fcε RIα by basophil and mast cell histamine release assays and by basophil activation assays. Antibody specificity has been confirmed by immunoassay, but there is a poor correlation between functionality and immunoreactivity. Approximately 25% of CU patients have a positive basophil histamine release assay and show autoreactivity (a positive autologous serum skin test), whereas 50% are negative regarding both. Functionality of CU sera appears to be complement dependent on mast cells but not exclusively on basophils. Basophil activation by CU sera is predominantly restricted to Ig G1 and Ig G3 subclasses. Circumstantial evidence for CU being an autoimmune disease comes from an observed association with other autoimmune diseases, a strong association between serum functionality and HLA- DR4 haplotype and the good response of CU patients to immunotherapies. It was proposed that a study should be undertaken to prospectively validate potentially relevant clinical criteria (from the history, examination and routinely available clinical investigations) against a new 'gold standard' for the diagnosis of ACU (positive autoreactivity, functional bioassay and immunoassay) to define preliminary criteria sets for the diagnosis of ACU based on clinical and laboratory features with highest individual sensitivity and specificity. [ABSTRACT FROM AUTHOR]