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Background: Type I allergy to sweat is involved in the pathogenesis of atopic dermatitis (AD) and cholinergic urticaria (CholU), with MGL_1304 from Malassezia globosa being the major causative antigen. Currently, no standard diagnostic test exists for sweat allergy that uses serum., Methods: The ImmunoCAP (iCAP) system to measure antigen-specific IgE was developed using recombinant MGL_1304 (rMGL_1304). Using a positive histamine release test (HRT) against the semi-purified sweat antigen (QR) as a criterion for diagnosing sweat allergy, the diagnostic usefulness of anti-MGL_1304 IgE detected through iCAP was analyzed in comparison with conventional anti-Malassezia antigen m227 IgE (anti-m227 IgE)., Results: The iCAP system with rMGL_1304 detected anti-MGL_1304 IgE in serum samples without detection of non-specific reactions. In 93 patients with AD or CholU, of which 58 were HRT-positive, anti-MGL_1304 IgE titers correlated with histamine release levels in HRT against QR better than anti-m227 IgE titers. The cutoff value for sweat allergy diagnosis was 1.55 U A /mL for anti-m227 IgE (sensitivity: 79.3 %; specificity: 65.7 %) and 0.671 U A /mL for anti-MGL_1304 IgE (sensitivity: 84.5 %; specificity: 80.0 %). Clinical features of AD and CholU were partially associated with anti-m227 IgE and anti-MGL_1304 IgE titers but not with histamine release in HRT using QR., Conclusions: Anti-MGL_1304 IgE detection using iCAP is simple and can help diagnosis of sweat allergy with better accuracy than conventional anti-Malassezia antigen IgE., (Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Background: 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., Methods: 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., Results: 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., Conclusions: 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., (Copyright © 2022 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Autoantibodies (AAbs) against immunoglobulin E (IgE) antibodies (Abs) and their high-affinity receptor alpha subunits (FcεRIα) are key factors in the elicitation of type IIb autoimmune chronic spontaneous urticaria (type IIb aiCSU). In this study, we aimed to develop a new method to detect functional anti-FcεRIα and anti-IgE AAbs, which can crosslink the plural FcεRІα molecules and IgE Abs on the surface of mast cells and basophils, in sera from aiCSU patients using the amplified luminescence proximity homogeneous assay (Alpha)., Methods: Sera were obtained from 14 aiCSU patients, as diagnosed by recurrent chronic spontaneous urticaria episodes and positive results for the autologous serum skin test and/or histamine release test (HRT). The AAbs to FcεRIα and IgE Abs were determined in sera from aiCSU patients using enzyme-linked immunosorbent assay (ELISA) and Alpha by cross-linking (AlphaCL) of IgE Abs and/or FcεRІα., Results: Serum anti-FcεRIα and anti-IgE AAb levels were not significantly different between aiCSU patients and healthy subjects in ELISA. Anti-FcεRIα AAbs were detected in 10 of 14 aiCSU patients who displayed positive (5/5) and negative (5/9) results in the HRT for anti-FcεRIα AAbs by AlphaCL, whereas no signals were observed in healthy subjects. Additionally, anti-IgE AAbs were detected in two of four aiCSU patients who displayed positive results in the HRT for anti-IgE AAbs., Conclusions: A new assay method using AlphaCL can detect anti-FcεRIα and anti-IgE AAbs with FcεRIα- and IgE-crosslinking abilities in sera from aiCSU patients. This simple and practical assay method may be available as a diagnostic tool for urticaria patients., (Copyright © 2021 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Recurrent angioedema (RecAE) has a substantial impact on patients' daily lives. However, there have been no disease-specific patient-reported outcomes (PROs) available in Japan to measure disease activity and health-related QoL impairment in such patients., Methods: Japanese versions of the Angioedema Activity Score (AAS) and the Angioedema Quality of Life Questionnaire (AE-QoL) were examined for their validity and reliability. By using these questionnaires, the relationship between disease activity and QoL impairment among the Japanese population of RecAE were analyzed in real-world setting., Results: The Japanese AAS and AE-QoL domains showed good internal consistency of 0.967 and > 0.835. For known group validity, AAS28 and AE-QoL total scores were higher in more severe patients than those with milder disease and QoL impairment, respectively. AAS28 showed strong correlation with indexes of disease activity, while the AE-QoL total score correlated with Dermatology Life Quality Index (DLQI). Sufficient reproductivity of the AAS and AE-QoL was shown by their intraclass correlation coefficients of 0.890 and 0.700. The Japanese population is characterized by the total score of AAS28, 34.3 ± 38.8 (mean ± SD); and AE-QoL, 38.7 ± 25.2. Each domain score of AE-QoL was 32.4 ± 29.7 in "Functioning", 35.0 ± 27.8 in "Fatigue/mood", 50.7 ± 30.6 in "Fears/shame", or 24.7 ± 29.8 in "Food". Changes in AAS28 and AE-QoL positively correlated to Patient global assessment of disease activity and DLQI, respectively., Conclusions: The Japanese AAS and AE-QoL are valid and reliable instruments for Japanese patients with RecAE, and active disease affecting QoL. They help assess disease activity and QoL of RecAE in routine patient care and clinical trials., (Copyright © 2021 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

IgE and mast cells play a pivotal role in various allergic diseases, including asthma, allergic rhinitis, and urticaria. Treatment with omalizumab, a monoclonal anti-IgE antibody, has significantly improved control of these allergic diseases and introduced a new era for the management of severe allergic conditions. About 10 years of experience with omalizumab treatment for severe allergic asthma confirmed its effectiveness and safety, reducing symptoms, frequency of reliever use, and severe exacerbations in patients with intractable conditions. Omalizumab is particularly useful in childhood asthma, where atopic conditions often determine clinical courses of asthma. Recently, omalizumab is approved for the treatment of chronic spontaneous urticaria (CSU) with the fixed dose of 300 mg. Although the mechanisms underlying the actions of omalizumab in CSU are not fully clarified, nearly 90% of patients with CSU showed a complete or a partial response to omalizumab treatment. Furthermore, omalizumab is just approved for the treatment of severe Japanese cedar pollinosis (JC) based on the successful results of an add-on study of omalizumab for inadequately controlled severe pollinosis despite antihistamines and nasal corticosteroids. For proper use of omalizumab to treat severe JC, co-administration of antihistamines is necessary, while patients should meet the criteria including strong sensitization to Japanese cedar pollen (≥class 3) and poor control under standard treatment. In the management of severe allergic diseases using omalizumab, issues including cost and concerns about relapse after its discontinuation should be overcome. At the same time, possibilities for application to other intractable allergic diseases should be considered., (Copyright © 2020 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Fish roe allergy is a common health problem in countries where sea food is a major part of the diet, such as Japan. β'-component (β'-c) in fish roe has been identified as a major antigen for patients who show hypersensitivity to various fish roes. However, little is known about causative antigens for patients reactive to fish roe of specific species., Methods: Serum and basophils were obtained from patients who had reactivity to roes of Gadus chalcogrammus (GC) and/or other fish species. GC roe specific antigens were analyzed by immunoblotting, histamine release assay (HRA) and mass spectrometry. Recombinant-fragments of vitellogenin (Vg) were obtained by the Escherichia coli expression system., Results: Serum IgE of a patient with specific reactions to GC roe bound to 15, 28, 40 and 70 kDa-proteins in GC roe extract. Mass spectrometry analysis revealed that proteins in these bands contained fragments corresponding to Vg. Immunoblotting of Vg immunoprecipitated by rabbit anti-Vg antiserum from the extract revealed 15, 28 and 54 kDa fragments bound by the patient's IgE. These bindings were inhibited by the pretreatment of recombinant phosvitin (rPv) and β'-c (rβ'-c). Fractions obtained by native gel electrophoresis containing 15, 28 and 54 kDa proteins, but not the other fractions, induced significant histamine release from the patient's basophils. Sera of the other patients with GC roe specific-IgE showed IgE binding to rPv and/or rβ'-c., Conclusions: The 15, 28 and 54 kDa-fragments of Vg which include structures of Pv and β'-c, could be antigens for GC roe specific type-I-hypersensitivity., (Copyright © 2019 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Sweat allergy is defined as a type I hypersensitivity against the contents of sweat, and is specifically observed in patients with atopic dermatitis (AD) and cholinergic urticaria (CholU). The allergic reaction is clinically revealed by positive reactions in the intradermal skin test and the basophil histamine release assay by sweat. A major histamine-releasing antigen in sweat, MGL_1304, has been identified. MGL_1304 is produced at a size of 29 kDa by Malassezia (M.) globosa and secreted into sweat after being processed and converted into the mature form of 17 kDa. It induces significant histamine release from basophils of patients with AD and/or CholU with MGL_1304-specific IgE, which is detected in their sera. Patients with AD also show cross-reactivity to MGL_1304-homologs in Malassezia restricta and Malassezia sympodialis, but MGL_1304 does not share cross antigenicity with human intrinsic proteins. Malassezia or its components may penetrate the damaged epidermis of AD lesions and interact with the skin immune system, resulting in the sensitization and reaction to the fungal antigen. As well as the improvement of impaired barrier functions by topical interventions, approaches such as anti-microbial treatment, the induction of tolerance and antibody/substance neutralizing the sweat antigen may be beneficial for the patients with intractable AD or CholU due to sweat allergy. The identification of antigens other than MGL_1304 in sweat should be the scope for future studies, which may lead to better understanding of sweat allergy and therapeutic innovations., (Copyright © 2018 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

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., (Copyright © 2017 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Non-steroidal anti-inflammatory drugs (NSAIDs), especially aspirin, and food additives (FAs) may exacerbate allergic symptoms in patients with chronic idiopathic urticaria and food-dependent exercise-induced anaphylaxis (FDEIA). Augmentation of histamine release from human mast cells and basophils by those substances is speculated to be the cause of exacerbated allergic symptoms. We sought to investigate the mechanism of action of aspirin on IgE-mediated histamine release., Methods: The effects of NSAIDs, FAs or cyclooxygenase (COX) inhibitors on histamine release from human basophils concentrated by gravity separation were evaluated., Results: Benzoate and tartrazine, which have no COX inhibitory activity, augmented histamine release from basophils similar to aspirin. In contrast, ibuprofen, meloxicam, FR122047 and NS-398, which have COX inhibitory activity, did not affect histamine release. These results indicate that the augmentation of histamine release by aspirin is not due to COX inhibition. It was observed that aspirin augmented histamine release from human basophils only when specifically activated by anti-IgE antibodies, but not by A23187 or formyl-methionyl-leucyl-phenylalanine. When the IgE receptor signaling pathway was activated, aspirin increased the phosphorylation of Syk. Moreover, patients with chronic urticaria and FDEIA tended to be more sensitive to aspirin as regards the augmentation of histamine release, compared with healthy controls., Conclusions: Aspirin enhanced histamine release from basophils via increased Syk kinase activation, and that the augmentation of histamine release by NSAIDs or FAs may be one possible cause of worsening symptoms in patients with chronic urticaria and FDEIA.

Background: Dermographic urticaria (DU) is characterized by strong itch and wheals induced by mechanical scratching. H(1)-receptor antagonists may reduce symptoms of DU to some extent, but other treatments being used for chronic spontaneous urticaria, such as H(2)-receptor antagonists and corticosteroids, are not usually effective for DU., Case Summary: We here report six cases of antihistamine-resistant DU treated with oral ciclosporin. Four cases suffering from severe itches that spontaneously occurred before the appearance of wheals in response to scratching were substantially improved by use of ciclosporin for 21, 16, 32, and 8 months, and one of them reached complete remission. Two cases did not obtain a benefit from the treatment, because of insufficient effects and/or side effects., Discussion: Oral ciclosporin may be of value as a potential treatment of anti-histamine-resistant DU.