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Background: Histamine is a crucial mediator in the development of anaphylaxis. Although histamine is promptly degraded because of its short half-life in plasma, basophils, which release histamine, remain in the blood for days. To explore basophils as a potential marker and their involvement in the pathogenesis of anaphylaxis, we evaluated the intracellular histamine concentration and the degree of basophil activation in anaphylaxis patients., Methods: We conducted a case-control study enrolling anaphylaxis patients and healthy controls. Basophil activation was evaluated by flow cytometry using up-regulation of CD203c expression., Results: We enrolled 23 patients and measured their blood histamine concentration. Basophil activation was analyzed in seven of 23 patients. The median intracellular histamine concentrations at admission were significantly lower in patients compared with controls (16.4 ng/mL [interquartile range {IQR}, 2.70 to 34.0] vs. 62.3 ng/mL [IQR, 46.0 to 85.1]; p < 0.0001). The median basophil number at admission was also significantly lower in patients compared with controls (2.21 cell/μL [IQR, 0.75 to 12.3] vs. 21.0 cell/μL [IQR, 19.5 to 28.9]; p = 0.027). CD203c expression was not up-regulated in any of the seven patients in vitro, but it was up-regulated in response to anti-IgE stimulation in vitro in two patients at admission and four patients at follow-up., Conclusions: Anaphylaxis is associated with a decrease in intracellular histamine, and a reduced number and reactivity of peripheral basophils. Impaired basophil function and a decrease in their number and intracellular histamine levels in the circulation may reflect the underlying mechanism, suggesting that basophils may be a marker of anaphylaxis., (Copyright © 2019 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

IL-4 plays a crucial role in the pathogenesis of allergic diseases, such as the induction of IgE synthesis and the development of mast cells. To further understand the effect of IL-4 on mast cells in skin, we utilized a mast cell/fibroblast co-culture system as an in vitro model of dermal mast cells. IL-4 induced mast cell growth in the culture with fibroblasts. Immunoblot analysis revealed that IL-4 activated Stat6 in both mast cells and fibroblasts. The over-expression of dominant-negative Stat6 in fibroblasts in the presence of IL-4 decreased the histamine content per mast cell, but not the number of mast cells. In contrast, the over-expression of constitutively-active Stat6 in fibroblasts increased the histamine content per mast cell, indicating that the activation of Stat6 in fibroblasts supports the maturation of mast cells co-cultured with fibroblasts.

Sweating aggravates itch in atopic dermatitis, but the mechanism is unclear. In this study, we examined the involvement of type I hypersensitivity in the aggravation of atopic dermatitis by sweating. Skin tests with autologous sweat were positive in 56 of 66 patients (84.4%) with atopic dermatitis, but only in 3 of 27 healthy volunteers (11.1%). Sweat samples from both patients and healthy volunteers induced varying degrees of histamine release from basophils of patients with atopic dermatitis. However, the histamine release was impaired by removal of IgE on the basophils. Incubation of basophils with myeloma IgE before sensitization with serum of patients blocked the ability to release histamine-induced sweat. IgE antibody against antigen(s) in sweat may be present in serum of patients with atopic dermatitis. Key words:

Chronic spontaneous urticaria (CSU) is a common skin disorder characterized by daily or almost daily recurring skin edema and flare with itch and pruritus anywhere on the body for more than 6 weeks. Although basophil- and mast cell-released inflammatory mediators, such as histamine, play important roles in the pathogenesis of CSU, the detailed underlying mechanism is not clear. Since several auto-antibodies, IgGs which recognize IgE or the high-affinity IgE receptor (FcεRI) and IgEs against other self-antigens, are detected in CSU patients, they are considered to activate both mast cells in the skin and basophils circulating in the blood. In addition, we and other groups demonstrated that the coagulation and complement system also contribute to the development of urticaria. Here, we summarized the behaviors, markers and targets of basophils in relation to the coagulation–complement system, and for the treatment of CSU. [ABSTRACT FROM AUTHOR]

Background: Sweat aggravates atopic dermatitis (AD). In patients with AD, type-I hypersensitivity to sweat may be shown by histamine release from patients' basophils in response to the semi-purified sweat antigen (QR), and the presence of specific immunoglobulin E (IgE) binding to MGL_1304, the component of QR. However, there has been no information on the immunological changes of type-I hypersensitivity to the sweat antigen in patients with well-controlled AD using topical corticosteroids (TCSs) and/or biologics as treatments. Method: Histamine-releasing tests using patients' basophils and QR and the detection of serum IgE against MGL_1304 and mite allergen Der f 1 were performed in patients with AD who were well controlled by topical TCS with/without dupilumab for 53–96 weeks. Results: In total, 14 patients were enrolled. Seven patients received TCS therapy alone (TCS group), and seven patients received TCS with dupilumab therapy (dupilumab group). In all participants, the level of specific IgE against MGL_1304 decreased after treatments, but histamine release from basophils in response to QR did not show a statistically significant reduction; rather, it increased. In the dupilumab group, all changes in histamine release induced by QR (increase), the IgE level against MGL_1304 (decrease), and that against Der f 1 (decrease) were statistically significant, whereas the TCS group showed no significant change in any of them. Conclusion: The well-controlled condition for 53–96 weeks resulted in no reduction of the hyperreactivity of basophils against in patients with AD, even with the treatment with dupilumab. This study suggests persistent basophil hyperreactivity to sweat antigen over a year or longer. [ABSTRACT FROM AUTHOR]

We previously reported that about 80 % of patients with atopic dermatitis and 60 % with cholinergic urticaria revealed type I allergy against sweat, by means of skin test against autologous sweat and/or histamine-release test for peripheral blood basophils with semi-purified sweat antigen. In this study, we developed an assay for sera to neutralize histamine-releasing activity of semi-purified sweat antigen. The semi-purified sweat antigen was pre-incubated with serially diluted sera for 30 min at 37 °C and was subjected to histamine-release activity. Histamine release-neutralization (HRN) activities were calculated by measuring the amount of histamine release from basophils in the presence or absence of semi-purified sweat antigen. Of 62 subjects, 39 showed positive histamine release (≥5 %) from their basophils in response to semi-purified sweat antigen, and sera of 34 out of 39 subjects (87.2 %) were also positive in HRN activity (≥10 %). The specificity of the HRN assay was 0.522. Moreover, HRN activities in sera were largely correlated with degrees of histamine release from peripheral blood basophils of the same donors in response to sweat antigen. To identify the substance that neutralizes histamine-release activity, we removed IgE and IgG from the sera of HRN (+) subjects by column chromatography. The HRN activities in 30 out of 42 sera were largely reduced by the removal of IgG. On the other hand, sera of four subjects lost HRN activity by the removal of IgE, suggesting that the majority of HRN (+) subjects have serum IgG against the sweat antigen as well as IgE bound to peripheral basophils. Thus, the HRN assay maybe useful for the screening of type I allergy against sweat antigen. [ABSTRACT FROM AUTHOR]

Background: Since the first report of a dog that developed severe systemic symptoms in response to a second injection of sea anemone toxin by Richet and Portier in 1902, no clear human cases of anaphylaxis related to exposure to sea anemones has been reported in the literature. Methods: A 24-year-old man with an episode of local urticaria on his first contact with a sea anemone (Stichodactyla haddoni), developed dyspnea, severe urticaria and hypotension on exposure to water containing the dead bodies of the organism. To study whether this reaction was mediated by antigen-specific IgE, we performed a histamine release test with blood, Western blotting with serum and lymphocyte proliferating test with peripheral blood mononuclear cells of the patient, for the homogenate of sea anemones. Results: The homogenate of sea anemones induced histamine release from the blood of the patient, but it also induced histamine release from the blood of control subjects. Moreover, it also caused hemolysis of blood of all donors. However, Western-blotting demonstrated the presence of an 86 kd protein-specific IgE in the serum of the patient. Conclusions: Protein antigen (s) in sea anemones may cause anaphylactic shock under the influence of the cytolytic effects and/or lymphocyte-stimulating activity elicited by the toxin of sea anemones. [ABSTRACT FROM AUTHOR]

Basophils and mast cells have high affinity IgE receptors (FcεRI) on their plasma membrane and play important roles in FcεRI-associated allergic diseases, such as pollen allergy, food allergy, chronic spontaneous urticarial (CSU), and atopic dermatitis (AD). To date, several reports have revealed that high IgE antibody concentrations activate mast cells—which reside in tissue—in the absence of any antigens (allergens). However, IgE antibody-induced activation of basophils—which circulate in blood—has not been reported. Here, we investigated whether IgE antibodies may regulate functions of human peripheral basophils without antigens in vitro. We successfully removed IgE antibodies bound to FcεRI on the surface of human peripheral basophils by treating with 0.1% lactic acid. We also demonstrated that high IgE antibody concentrations (>1 μM) induced histamine release, polarization, and CD203c upregulation of IgE antibody-stripped basophils. Thus, high IgE antibody concentrations directly activate basophils, which express IgE-free FcεRI on the cell surface. This mechanism may contribute to the pathogenesis of patients with AD and CSU who have higher serum IgE concentrations compared to healthy donors. [ABSTRACT FROM AUTHOR]

Chronic spontaneous urticaria (CSU) is a common skin disorder characterized by daily or almost daily recurring skin edema and flare with itch. Recently, the activation of the blood coagulation cascade has been suggested to be involved in CSU, but the trigger of the coagulation cascade remains unclear. In this article, we review recent understanding of the relationship between the pathogenesis of CSU and extrinsic coagulation reactions. In CSU, vascular endothelial cells and eosinophils may play a role as TF-expressing cells for activating the extrinsic coagulation pathway. Moreover, the expression of TF on endothelial cells is synergistically enhanced by the activation of Toll-like receptors and histamine H 1 receptors. The activated coagulation factors may induce plasma extravasation followed by degranulation of skin mast cells and edema formation recognized as wheal in CSU. Molecules involved in this cascade could be a target for new and more effective treatments of urticaria. [ABSTRACT FROM AUTHOR]

Background: Most urticarias are induced by vasoactive mediators such as histamine released from mast cells. Although mast cells are activated by allergens through cross-linking of cell-surface-bound IgE, this mechanism does not appear to explain most cases of chronic urticaria, which, when allergic, infectious, drug-induced, or physical causes cannot be identified, are classified as idiopathic. Methods: We recruited 26 patients with chronic idiopathic urticaria, in whom intradermal injection of autologous serum caused a wheal-and-flare response. Serum from four patients that induced marked histamine release from basophils from a donor with very low serum IgE levels was studied with respect to the IgE dependence of the histamine release, the activity of the IgG fractions, and the neutralizing effect of a recombinant preparation of the soluble extracellular domain of the α subunit of the high-affinity IgE receptor (sFcεRIα). Results: The histamine-releasing activity of the serum was abolished by passive sensitization of basophils with myeloma IgE, enhanced after dissociation of IgE by treatment with lactic acid, and induced by IgG fractions from the serum of all four patients. Preincubation of the serum and isolated IgG with sFcεRIα resulted in almost complete neutralization. Conclusions: Histamine-releasing IgG autoantibodies against the α subunit of the high-affinity IgE receptor are present in the circulation of some patients with chronic urticaria. Autoantibody-induced cross-linking of IgE receptors may be an important mechanism in the pathogenesis of chronic urticaria and other diseases mediated by mast cells. (N Engl J Med 1993;328:1599-604.) [ABSTRACT FROM AUTHOR]

Tingling dermal pain triggered by sweating impairs the lives of patients with cholinergic urticaria and generalized anhidrosis. However, dermal pain evoked by sweating stimuli has been under investigated. To clarify characteristics of tingling dermal pain on sweating, we retrospectively evaluated clinical and histopathological manifestations in 30 patients having the main problem of dermal pain on sweating, and the efficacy of treatments. Dermal pain upon sweating affected mostly young males. It accompanied eruptions upon sweating and/or hypohidrosis in 24 patients, while 6 patients had dermal pain independently of hypohidrosis or eruptions. Dermal pain appeared immediately upon exposure to sweating stimuli, and disappeared within mostly 30 or 10 min. Hypohidrosis was not necessarily generalized but localized or absent. Histological analysis revealed that dermal pain could occur even without morphological changes and inflammation of sweat glands. Hypersensitivity to sweat contents was found only in 26% of patients. Sweat histamine and increase of plasma histamine after thermal induction in patients were significantly higher than those in healthy subjects. Effectiveness of steroid pulse therapy was demonstrated for dermal pain with hypohidrosis. Medications acting on nervous systems and regular sweat-inducing activities for promoting perspiration were also effective. Short-lasting tingling dermal pain appears immediately upon exposure to sweating stimuli, regardless of developing eruptions and/or presence of hypohidrosis, but possibly in association with sweat and plasma histamine. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: The histamine releasing test which detects histamine released from basophils in vitro is safe, sensitive and widely used for clinical examination in the field of allergy. However, basophils of certain individuals do not release histamine, because of dysfunctions in their intracellular signal transduction (non-responder). To overcome potential shortcomings of the histamine releasing test, we applied surface plasmon resonance (SPR) to detect the activation of basophils. Methods: Basophils of patients with allergy, and those of non-allergic volunteers were isolated from peripheral blood. A batch of basophils obtained from a healthy volunteer was treated with lactic acid and IgE of a patient with atopic dermatitis in order to replace their endogenous IgE. They were fixed on the sensor chip of the SPR apparatus, pretreated with or without various inhibitors for intracellular signal transduction, and exposed to the antigens or anti-lgE antibody. Results: When basophils were sensitized with antigen specific IgE, they immediately caused the increase of resonance angle (AR) in response to either anti-lgE antibody or corresponding antigens, even when they did not release histamine. Moreover, the dose dependent reactions of basophils were reflected by the increase of AR as well as the release of histamine. The increase of AR in response to anti-lgE antibody was reduced by pre-treatment of basophils with inhibitors for intracellular signal transduction, but not more than the level for histamine release. Conclusions: SPR biosensors may be superior to the histamine release test for studying functions of human basophils including those not releasing histamine. [ABSTRACT FROM AUTHOR]

Previous studies identified autoantibodies against the IgE high affinity receptor α-chain, FcεRIα, in sera of selected patients with severe chronic idiopathic urticaria. We have now determined the incidence of anti-FcεRIα autoantibodies in a group of 163 patients. Intradermal injection of autologous serum caused skin reactions indicative of mast cell degranulation in 98 (60%) patients. Based on histamine release from IgE-sensitized and nonsensitized basophil leukocytes of healthy donors, we detected anti- FcεRIα autoantibodies in sera from 38 (23%) urticaria patients and evidence for anti-IgE antibodies in a further nine patients. The sera that released histamine from basophils induced histamine release (4- 34%, n = 12) from mast cells in incubated skin slices. Protein-G affinity chromatography of sera demonstrated that mast cell histamine release was IgG- mediated. Preincubation of sera or the IgG fraction with a recombinant α-chain of FcεRIα inhibited histamine release from mast cells and basophils. Further studies with the mouse anti-human FcεRIα antibody 29C6 showed that mast cells and basophils were similarly sensitive to IgG-mediated direct cross-linking of FcεRIα, with 0.01-1.0 μ/ml 29C6 evoking histamine release in each case. These studies demonstrate that circulating levels of anti-FcεRIα autoantibodies mediate histamine release from skin mast cells in vitro and, taken together with in vivo evidence of mast cell degranulation following intradermal injection of autologous serum, support the concept that anti-FcεRIα autoantibodies are relevant to the pathogenesis of severe chronic urticaria in about 25% of patients. [ABSTRACT FROM AUTHOR]