Allergology International
Online ISSN : 1440-1592
Print ISSN : 1323-8930
ISSN-L : 1323-8930
Current issue
Displaying 1-23 of 23 articles from this issue
Editorials
Invited Review Articles
Review Series: T Follicular Helper Cells and IgE
  • Joshua F.E. Koenig
    2025 Volume 74 Issue 1 Pages 4-12
    Published: 2025
    Released on J-STAGE: January 21, 2025
    JOURNAL FREE ACCESS

    IgE antibodies raised against innocuous environmental antigens cause allergic diseases like allergic rhinitis, food allergy, and allergic asthma. While some allergies are often outgrown, others (peanut, shellfish, tree nut) are lifelong in the majority of individuals. Lifelong allergies are the result of persistent production of allergen-specific IgE. However, IgE antibodies and the plasma cells that secrete them tend to be short-lived. Persistent allergen-specific IgE titres are thought to be derived from the continued renewal of IgE plasma cells from memory B cells in response to allergen encounters. The initial generation of allergen-specific IgE is driven by B cell activation by IL-4 producing Tfh cells, but the cellular and molecular mechanisms of the long-term production of IgE are poorly characterized. This review investigates the mechanisms governing IgE production and Tfh activation in the primary and recall responses, towards the objective of identifying molecular targets for therapeutic intervention that durably inactivate the IgE recall response.

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  • Pablo F. Cañete, Di Yu
    2025 Volume 74 Issue 1 Pages 13-19
    Published: 2025
    Released on J-STAGE: January 21, 2025
    JOURNAL FREE ACCESS

    Atopy is considered the epidemic of the 21st century, and while decades of research have established a direct link between Th2 cells driving pathogenic IgE-mediated allergic disease, only in the past years have T follicular helper (Tfh) cells emerged as pivotal drivers of these responses. In this review, we will examine the molecular mechanisms governing the IgE response, with a particular emphasis on the key cytokines and signaling pathways. We will discuss the exclusion of IgE-producing B cells from germinal centers and explore the recently established role of follicular T cell function and heterogeneity in driving or curtailing these immune responses. Additionally, we will assess the current state of major monoclonal antibodies and allergen immunotherapies designed to counteract Th2-driven inflammation, as well as reflect on the need to investigate how these biologics impact Tfh cell activity, differentiation, and function, as these insights could pave the way for much-needed therapeutic innovation in the treatment of allergic diseases.

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  • Alexander L. Dent
    2025 Volume 74 Issue 1 Pages 20-24
    Published: 2025
    Released on J-STAGE: January 21, 2025
    JOURNAL FREE ACCESS

    Allergen-specific IgE is a major mediator of allergic responses and contributes greatly to allergic disease in the human population. Therapies that inhibit the production of IgE would be useful for lessening the burden of allergic disease. A great deal of research has focused on how IgE responses are regulated, and several factors that promote the production of allergic IgE have been characterized. T follicular helper (TFH) cells expressing IL-4 are required for the development of IgE expressing B cells in the germinal center (GC). Ig somatic hypermutation and B cell selection in the GC leads to the development of high affinity allergen-specific IgE that promotes anaphylaxis, a severe form of allergic response. T follicular regulatory (TFR) cells are also found in the GC response and act with TFH cells in the selection of high affinity IgE + B cells. This review examines the current literature on IgE responses and TFR cells. In mouse studies, TFR cells have a suppressive role on IgE responses in allergic airway disease, however TFR cells also play a helper role in the IgE response in food allergy. In human studies, TFR cells correlate with a decreased allergic response but evidence for a direct suppressive role of TFR cells on IgE in vivo is lacking. TFR cells may represent a new target for allergy therapies, but caution must be exercised to promote the suppressor activity of TFR cells and not the helper activity of TFR cells on IgE responses.

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  • Mitsuhiro Akiyama, Waleed Alshehri, Sho Ishigaki, Koichi Saito, Yuko K ...
    2025 Volume 74 Issue 1 Pages 25-32
    Published: 2025
    Released on J-STAGE: January 21, 2025
    JOURNAL FREE ACCESS

    Human T follicular helper (Tfh) cells play a crucial role in orchestrating B cell differentiation, maturation, and immunoglobulin class switching. Recent studies have underscored the presence of Bcl-6 + Tfh cells not only in secondary lymphoid organs but also within tertiary lymphoid structures at inflammatory sites, emphasizing their pivotal role in disease pathogenesis. Furthermore, Tfh cells have been found to transit between lesion sites, lymph nodes, and peripheral blood, as revealed by T cell receptor repertoire analysis. Among Tfh subsets, Tfh2 cells have emerged as central orchestrators in driving the production of IgE and IgG4 from B cells. Their critical role in diseases such as allergy, malignancy, and IgG4-related disease highlights their profound impact on balancing inflammation and immune tolerance. Our current review provides the molecular characteristics of human Tfh cells, the differentiation pathways of Tfh subsets, mechanisms by which Tfh subsets induce IgE and IgG4 production, and their clinical implications in allergy, malignancy, and IgG4-related disease.

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Review Articles
  • Werner J. Pichler
    2025 Volume 74 Issue 1 Pages 33-41
    Published: 2025
    Released on J-STAGE: January 21, 2025
    JOURNAL FREE ACCESS

    Delayed drug hypersensitivity reactions (dDHRs) are iatrogenic diseases, which are mostly due to non-covalent interactions of a drug with the immune receptors HLA and/or TCR causing T-cell activation. This is also known as pharmacological interaction with immune receptors or p-i. P-i activation differs from classical antigen-driven immune reactions: a) drug binding induces structural changes in TCR-HLA proteins which make them look like allo-like TCR-HLA-complexes, able to elicit allo-like stimulations of T cells with cytotoxicity and IFNγ production, notably without the involvement of innate immunity; b) drug binding to TCR and/or HLA can increase the affinity of TCR-HLA interactions, which may affect signaling and IL-5 production by CD4+ T cells, and thus contribute to eosinophilia commonly found in dDHRs or induce oligoclonal T cell expansions; c) Both, antigen and p-i stimulations can induce eosinophil- or neutrophil-rich inflammations; but these stimulations should be distinguished as their underlying mechanism and development differ; and d) p-i stimulation can – like graft versus host reactions – result in long-lasting T-cell activations, which can lead to viremia, occasional autoimmunity, or a new syndrome characterized by multiple drug hypersensitivity (MDH).

    In summary, dDHRs are not allergic reactions but represent peculiar T-cell activations, similar to allo-like stimulations. Understanding and considering the p-i mechanism is needed for preventive measures and optimal treatments of dDHR. In addition, it may help to understand TCR signaling, alloreactivity, and may even open a new way of specific immune stimulations.

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  • Yukinori Kato, Taiyo Morikawa, Shigeharu Fujieda
    2025 Volume 74 Issue 1 Pages 42-50
    Published: 2025
    Released on J-STAGE: January 21, 2025
    JOURNAL FREE ACCESS

    Pollen-food allergy syndrome (PFAS) is caused by cross-reaction of a specific pollen antigen with the corresponding food allergen in sensitized individuals. The manifestations are usually limited to oral symptoms; however, sometimes, rhinitis, respiratory and skin symptoms, and anaphylactic shock may occur. In PFAS pathogenesis, when food containing protein antigens (pan-allergens) with high homology to pollen antigens is ingested, mast cells bound to pollen antigen-specific IgE distributed in the oral mucosa cross-react with the food antigen, causing a local type I allergic reaction. The prevalence of PFAS depends on the geographic conditions, such as the type and amount of pollen in the area. PFAS is prevalent in all regions owing to the wide variety of pollen antigens implicated in the disease, such as alder and grass pollen, even outside of the birch habitat area. Basic research on PFAS is expected to significantly contribute to elucidating the pathogenesis and development of therapeutic strategies for PFAS. Currently, effective treatment for patients with PFAS that allows safe consumption of raw foods is lacking, and avoiding the intake of causative foods is the basis of prevention. Furthermore, allergen immunotherapy for PFAS has not yet been established, but various attempts are underway to develop it into a novel treatment strategy. This review highlights the current research landscape on the pathophysiology, epidemiology, and clinical aspects of PFAS. We outline the research gaps that should be addressed to improve the outcomes of patients with PFAS.

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  • Hiroaki Hayashi, Makoto Ishii, Yoshinori Hasegawa, Masami Taniguchi
    2025 Volume 74 Issue 1 Pages 51-65
    Published: 2025
    Released on J-STAGE: January 21, 2025
    JOURNAL FREE ACCESS

    Characteristic symptoms of NSAID-exacerbated respiratory disease (N-ERD) include asthma, chronic eosinophilic rhinosinusitis with nasal polyposis, cysteinyl LT (CysLT) overproduction and NSAIDs hypersensitivity. Some N-ERD patients present with episodic treatment-resistant extra-respiratory symptoms (CysLT-associated coronary artery vasospasm, gastroenteritis, or skin rash). Even when using standard treatments for respiratory and extra-respiratory symptoms, including systemic corticosteroids and aspirin desensitization, it is difficult to control the clinical symptoms and severe type 2 inflammation involved with mast cells, eosinophils, ILC2s, and platelet activation. Few treatment options are applicable in a clinical setting. Therefore, identifying effective treatments is essential for managing N-ERD patients who suffer from these conditions. Our previous observational study demonstrated 12-month omalizumab treatment of N-ERD was clinically effective against respiratory symptoms. Despite the remaining eosinophilia, omalizumab significantly reduced urinary LTE4 and PGD2 metabolites to near normal levels at steady state. Based on the preliminary study, we demonstrated that omalizumab induced tolerance to aspirin in N-ERD patients 3 months after therapy initiation and suppressed activation of mast cells during 24 h of initiation in a randomized manner. Moreover, omalizumab had significant efficacy against extra-respiratory symptoms at baseline (lacking aspirin exposure) as well as throughout aspirin challenge. This review addresses the latest discoveries related to N-ERD pathogenesis and the significant effectiveness of omalizumab on N-ERD as a mast cell stabilizer. Our findings regarding omalizumab-associated mast cell inhibitory effects are indirect evidence that mast cell dysregulation and, possibly, IgE are pivotal components of N-ERD.

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Original Articles
  • Tsukasa Okamoto, Mariko Hanafusa, Taketomo Abe, Takashi Shimamura, Mas ...
    2025 Volume 74 Issue 1 Pages 66-71
    Published: 2025
    Released on J-STAGE: January 21, 2025
    JOURNAL FREE ACCESS
    Supplementary material

    Background: The latest guidelines on hypersensitivity pneumonitis (HP) categorise the disease as either fibrotic or non-fibrotic because of the greater clinical utility of this stratification. However, the prevalence and incidence of fibrotic and non-fibrotic HP are unknown. This study assessed the exact prevalence and incidence of fibrotic and non-fibrotic HP in Japan in 2021.

    Methods: For adults, the study hospitals were selected by stratified random sampling according to numbers of beds. The sampling rate was set at about 20%. The questionnaire survey was submitted to the target hospitals. For pediatric cases, a survey was distributed to all members of the Japanese Society of Pediatric Pulmonology and Japanese Society of Pediatric Allergy and Clinical Immunology.

    Results: Regarding adult cases, in total, 575 facilities responded to the survey, resulting in a response rate of 36.4%. The estimated prevalence and incidence of fibrotic HP were 6.3 and 2.5 per 100,000 population, respectively, versus 3.6 and 2.0 per 100,000 population, respectively, for non-fibrotic HP. Both fibrotic and non-fibrotic HP were more prevalent in southern Japan (Kyushu) and less prevalent in northern Japan (Hokkaido). The incidence of non-fibrotic HP was significantly lower in December than in the other months (relative risk ratio = 0.36, p < 0.001). Three cases of fibrotic HP and five cases of non-fibrotic HP were identified in children.

    Conclusions: This study determined the prevalence and incidence of fibrotic and non-fibrotic HP in Japan for the first time.

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  • Yuta Koike, Sayaka Kuwatsuka, Daisuke Motooka, Hiroyuki Murota
    2025 Volume 74 Issue 1 Pages 72-77
    Published: 2025
    Released on J-STAGE: January 21, 2025
    JOURNAL FREE ACCESS
    Supplementary material

    Background: Systemic inhibition of pro-inflammatory cytokines affects the skin microbiome; however, the impact of systemic anti-inflammatory therapy on the skin fungal microbiome is poorly understood. To examine the effects of cytokine inhibition on the fungal community on human skin and oral mucosa, we analyzed the composition of the skin mycobiome before and after IL-23 inhibition.

    Methods: The study enrolled 15 psoriasis patients. Swab samples were collected from the psoriasis-free skin of antecubital fossa, post-auricular, and the tongue surface before and after 16 weeks of treatment with anti-IL-23 antibodies. Fungal DNA was sequenced by ITS1 metagenomic analysis, and taxonomic classification was performed.

    Results: Data from samples collected from the antecubital fossa revealed that the α diversity of the skin mycobiome decreased significantly after treatment with anti-IL-23 antibodies (p = 0.0120). Fungal DNAs were not amplified in 6/15 swab samples after 16 weeks of IL-23 inhibition; by contrast, sufficiently detected in all 15 samples before treatment (p = 0.0554). A comparison of 9/15 paired samples containing well-detected reads revealed that the percentage of genus Malassezia in the mycobiome fell significantly after treatment with IL-23 inhibitors (before, 29.3% ± 9.9%; after; 8.5% ± 3.4%, p = 0.0137). The mycobiome on post-auricular skin and on the tongue surface showed no marked changes after IL-23 inhibition.

    Conclusions: Taken together, the data suggest that inhibition of systemic IL-23 provokes dysbiosis of the mycobiome at the antecubital fossa skin, a finding characterized by reduced fungal diversity and a reduction in the percentage of the genus Malassezia.

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  • Shusuke Yazawa, Yuzo Suzuki, Yuko Tanaka, Koshi Yokomura, Masato Kono, ...
    2025 Volume 74 Issue 1 Pages 78-85
    Published: 2025
    Released on J-STAGE: January 21, 2025
    JOURNAL FREE ACCESS
    Supplementary material

    Background: Hypersensitivity pneumonitis (HP) is a complex and heterogenous interstitial lung disease (ILD) that occurs in susceptible individuals due to certain inhaled antigens. Fibrotic-HP is a major underlying disease of progressive pulmonary fibrosis. Therefore, in addition to the radiological features of HP, quantitatively measuring fibrosis is important to evaluate disease severity and progression. The present study aimed to compare three-dimensional computed tomography (3D-CT)-derived lung volumes (LVs) of patients with HP and determine its association with mortality risk.

    Methods: In this retrospective and multicenter cohort study, 126 patients diagnosed with HP (fibrotic, n = 72 and non-fibrotic, n = 54) with a confidence level higher than moderate were enrolled. Each lobe LV was measured using 3D-CT at the time of diagnosis and standardized using predicted forced vital capacity. The 3D-CT LV was compared with those of 42 controls and 140 patients with idiopathic pulmonary fibrosis (IPF).

    Results: Compared to patients with fibrotic-HP, the standardized total LV was significantly higher in controls and patients with non-fibrotic-HP and was similar in patients with IPF. Longitudinal analyses demonstrated that approximately half of the patients with fibrotic-HP had an annual decrease in total LV. Decreased total and lower-lobe LVs were associated with shorter survival, and were independently associated with mortality together with ongoing exposure to inciting antigens. A composite model consisting of ongoing exposure to inciting antigens and total or lower-lobe LV successfully classified mortality risk into three groups.

    Conclusions: Quantitatively measuring standardized LV can help determine disease severity, progression, and mortality risk in patients with fibrotic-HP.

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  • Michiko Yonehara, Yuji Nakagawa, Yuji Ayatsuka, Yuko Hara, Jun Shoji, ...
    2025 Volume 74 Issue 1 Pages 86-96
    Published: 2025
    Released on J-STAGE: January 21, 2025
    JOURNAL FREE ACCESS

    Background: Artificial intelligence (AI) is a promising new technology that has the potential of diagnosing allergic conjunctival diseases (ACDs). However, its development is slowed by the absence of a tailored image database and explainable AI models. Thus, the purpose of this study was to develop an explainable AI model that can not only diagnose ACDs but also present the basis for the diagnosis.

    Methods: A dataset of 4942 slit-lamp images from 10 ophthalmological institutions across Japan were used as the image database. A sequential pipeline of segmentation AI was constructed to identify 12 clinical findings in 1038 images of seasonal and perennial allergic conjunctivitis (AC), atopic keratoconjunctivitis (AKC), vernal keratoconjunctivitis (VKC), giant papillary conjunctivitis (GPC), and normal subjects. The performance of the pipeline was evaluated by determining its ability to obtain explainable results through the extraction of the findings. Its diagnostic accuracy was determined for 4 severity-based diagnosis classification of AC, AKC/VKC, GPC, and normal.

    Results: Segmentation AI pipeline efficiently extracted crucial ACD indicators including conjunctival hyperemia, giant papillae, and shield ulcer, and offered interpretable insights. The AI pipeline diagnosis had a high diagnostic accuracy of 86.2%, and that of the board-certified ophthalmologists was 60.0%. The pipeline had a high classification performance, and the area under the curve (AUC) was 0.959 for AC, 0.905 for normal subjects, 0.847 for GPC, 0.829 for VKC, and 0.790 for AKC.

    Conclusions: An explainable AI model created by a comprehensive image database can be used for diagnosing ACDs with high degree of accuracy.

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  • Akiko Nakaoka, Takayasu Nomura, Atsushi Suzuki, Kazuyoshi Ozeki, Hiroh ...
    2025 Volume 74 Issue 1 Pages 97-104
    Published: 2025
    Released on J-STAGE: January 21, 2025
    JOURNAL FREE ACCESS
    Supplementary material

    Background: Epidemiological studies have identified associations between gastroesophageal reflux (GER) and cow's milk allergy (CMA) in infants. However, the role of GER in the development of CMA remains poorly understood. Our primary objectives were to develop a mouse model that suggests GER as a potential pathogenic mechanism for CMA and to elucidate the immunological mechanisms that connect lung innate immunity with CMA.

    Methods: Mice were exposed to cow's milk (CM) treated with hydrochloric acid through repeated aspiration into their airways. Subsequently, they were challenged by intraperitoneal injection of CM extract. The immunological mechanisms were investigated using comprehensive single-cell RNA sequencing (scRNA-seq) analysis of the lungs, combined with the use of genetically modified mice.

    Results: Mice exposed to CM mixed with hydrochloric acid via airway sensitization developed CMA, as evidenced by the production of antigen-specific IgE and IgG antibodies, and the induction of anaphylaxis upon systemic antigen administration. In contrast, aspiration of CM alone did not induce CMA. scRNA-seq analysis revealed potential roles of alveolar macrophages in response to hydrochloric acid. Mice lacking the TLR4 pathway were protected from developing CMA.

    Conclusions: We have developed a novel mouse model for CMA that utilizes the natural antigen and follows the physiological airway sensitization pathway, thus potentially resembling clinical scenarios. This model, named the acidified milk aspiration-induced allergy model, has the potential to shed light on the role of early innate immunity by analyzing a more physiological model.

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  • Marine Peyneau, Mathilde Zeller, Virginie Paulet, Benoît Noël, Marie-H ...
    2025 Volume 74 Issue 1 Pages 105-114
    Published: 2025
    Released on J-STAGE: January 21, 2025
    JOURNAL FREE ACCESS
    Supplementary material

    Background: In many countries, neuro-muscular blocking agents (NMBAs) are the first cause of perioperative anaphylaxis. Epidemiological studies identified pholcodine, a quaternary ammonium-containing opiate as one of the sensitization sources. However, NMBA anaphylaxis exists in countries where pholcodine was unavailable, prompting the hypothesis of other sensitizing molecules, most likely quaternary ammonium compounds (QACs).

    Indeed, QACs are commonly used as disinfectants, antiseptics, preservatives, and detergents. Occupational exposure to QACs has been reported as a risk factor for NMBA anaphylaxis, but little is known about the sensitization mechanism and the capacity of these molecules to elicit an immune response. We aimed to establish the immunogenicity of QACs representative of the main existing chemical structures.

    Methods: We measured the sensitization potential of seven QACs (two polyquaterniums, three alkyl-ammoniums and two aromatic ammoniums) by using two standard dendritic cells (DCs) models (THP-1 cell line and monocyte derived-dendritic cells). The allergenicity of the sensitizing compounds was further tested in heterologous and autologous T-cell-DC co-culture models.

    Results: Amongst the seven molecules tested, four could modulate activation markers on DCs, and thus can be classified as chemical sensitizers (polyquaterniums-7 and -10, ethylhexadecyldimethylammonium and benzethonium). This activation was accompanied by the secretion of pro-inflammatory and maturation cytokines. Furthermore, activation by polyquaternium-7 could induce T-cell proliferation in heterologous and autologous coculture models, demonstrating that this molecule can induce a specific CD4+ T cell response.

    Conclusions: We provide evidence at the cellular level that some QACs can elicit an immune response, which could be in line with the hypothesis of these molecules' role in NMBA sensitization.

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  • Ilona Shurmelova, Agata Baldyga, Eva Grekowitz, Susanne Kimeswenger, W ...
    2025 Volume 74 Issue 1 Pages 115-125
    Published: 2025
    Released on J-STAGE: January 21, 2025
    JOURNAL FREE ACCESS

    Background: Skin reaction patterns vary across patients with cholinergic urticaria (CholU), but their definition, prevalence, and clinical significance remain ill characterized.

    Methods: Patients with CholU underwent pulse-controlled ergometry provocation testing to analyze skin reaction patterns and their correlation with location, onset, severity, sweating behaviour, clinical features, disease control, and quality of life (QoL) impairment.

    Results: Based on the size, color, spacing, and shape of wheals as well as their surrounding skin responses, we identified six distinct types of CholU skin reactions, which differed in prevalence, from 83% (Type I) to 11% (Type VI) of patients affected. Almost all patients (94%) had ≥1 type of skin reaction pattern. Sweating was reduced in the majority of CholU patients and most prominently reduced in patients with Type VI skin signs (very small, round, red, widely spaced wheals with surrounding anemic halo), which emerged exclusively on the extremities. Type V skin signs (large, irregular, anemic, widely spaced wheals with moderate size erythema) were associated with the most severe clinical presentation and poorest QoL.

    Conclusions: Our analysis showed that most patients have more than one type of skin reaction patterns and that different skin signs are linked to distinct features. Future studies should determine any links between treatment response and types of skin signs in CholU.

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  • Amin Kraiem, Erica Pelamatti, Sophie Grosse-Kathoefer, Hilal Demir, Ut ...
    2025 Volume 74 Issue 1 Pages 126-135
    Published: 2025
    Released on J-STAGE: January 21, 2025
    JOURNAL FREE ACCESS
    Supplementary material

    Background: Solubility is a common feature of allergens. However, the causative relationship between this protein-intrinsic feature and sensitization capacity of allergens is not fully understood. This study aimed to proof the concept of solubility as a protein intrinsic feature of allergens.

    Methods: The soluble birch pollen allergen Bet v 1 was covalently coupled to 1 μm silica particles. IgE-binding and -cross-linking capacity was assessed by inhibition ELISA and mediator release assay, respectively. Alterations in adjuvanticity by particle-loading were investigated by activation of dendritic cells, mast cells and the Toll-like receptor 4 pathway as well as by Th2 polarization in an IL-4 reporter mouse model. In BALB/c mice, particle-loaded and soluble Bet v 1 were compared in a model of allergic sensitization. Antigen uptake and presentation was analysed by restimulating human Bet v 1-specific T cell lines.

    Results: Covalent coupling of Bet v 1 to silica particles resulted in an insoluble antigen with retained IgE-binding and -cross-linking capacity and no increase in adjuvanticity. In vivo, particle-loaded Bet v 1 induced significantly lower Bet v 1-specific (s)IgE, whereas sIgG1 and sIgG2a levels remained unaffected. The ratio of Th2 to Th1 cells was significantly lower in mice sensitized with particle-loaded Bet v 1. Particle-loading of Bet v 1 resulted in a 24-fold higher T cell activation capacity in Bet v 1-specific T cell lines, indicating more efficient uptake and presentation than of soluble Bet v 1.

    Conclusions: Our results show that solubility is a decisive factor contributing to the sensitization capacity of allergens. The reduction in sensitization capacity of insoluble, particle-loaded antigens results from enhanced antigen uptake and presentation compared to soluble allergens.

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  • Hidetoshi Takahashi, Atsushi Fukunaga, Koremasa Hayama, Takayoshi Sasa ...
    2025 Volume 74 Issue 1 Pages 136-143
    Published: 2025
    Released on J-STAGE: January 21, 2025
    JOURNAL FREE ACCESS
    Supplementary material

    Background: In Japan, urticaria is a common skin disorder with chronic spontaneous urticaria (CSU) being the most frequent subtype. This study evaluated the safety of ligelizumab (anti-IgE monoclonal antibody) in Japanese CSU patients.

    Methods: This was a Phase 3 multicenter, open-label, single-arm 52-week study in adult Japanese patients with CSU inadequately controlled with locally approved doses of H1-antihistamines. The primary objective reported the safety of ligelizumab 120 mg subcutaneously every 4 weeks, by evaluation of treatment emergent adverse events (TEAE). Secondary objectives evaluated efficacy by absolute change from baseline (CFB) in weekly urticaria activity score (UAS7), and the proportion of patients with UAS7 = 0, and dermatology life quality index (DLQI) = 0-1 over time.

    Results: From a total of 66 CSU patients (80.3% females; mean ± SD age 46.4 ± 13.2 years; mean ± SD baseline UAS7 28.7 ± 6.5) enrolled, 53 patients (80.3%) reported ≥1 TEAE during the study, with no severe or serious adverse events, no anaphylaxis events and low frequency of TEAEs leading to treatment discontinuations (6.1%). Absolute mean CFB of UAS7 showed a rapid onset of response at Week 4 (−14.2) with further improvement until end of treatment at Week 52 (−22.9). The proportion of patients achieving UAS7 = 0 improved over time (14.5% at Week 4; 50.0% at Week 52). A sizable proportion of patients achieved DLQI 0-1 with the first dose of ligelizumab (38.5%), and improvements observed throughout the study until Week 52 (68.8%).

    Conclusions: Treatment with ligelizumab 120 mg was well-tolerated with mild to moderate adverse events and was efficacious in Japanese patients.

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  • Kenji Mizumura, Yasuhiro Gon, Norihiro Harada, Shiho Yamada, Asami Fuk ...
    2025 Volume 74 Issue 1 Pages 144-155
    Published: 2025
    Released on J-STAGE: January 21, 2025
    JOURNAL FREE ACCESS
    Supplementary material

    Background: The therapeutic effectiveness of dupilumab for severe asthma in real-world settings is yet to be prospectively investigated across multiple institutions, and uncertainties persist regarding predictive factors for its effectiveness. We aimed to assess the effectiveness of dupilumab and identify predictors of its effectiveness in real-world settings using two type-2 biomarkers: FeNO concentration and blood eosinophil count.

    Methods: This prospective multicenter study included 103 patients with severe asthma. Exacerbations and respiratory functions were monitored for 24 weeks. Asthma control was evaluated using the Asthma Control Questionnaire-5. Clinical symptoms and their impact on cough and sputum were assessed using the Cough and Sputum Assessment Questionnaire (CASA-Q). Subgroup analyses of type-2 biomarkers were conducted based on FeNO levels and blood eosinophil counts at baseline.

    Results: Treatment with dupilumab led to a reduction in exacerbations and enhancement in asthma control, FEV1, and CASA-Q scores. FEV1 improvement was correlated with enhancement in the sputum domain of the CASA-Q. Patients exhibiting elevated FeNO levels and blood eosinophil counts demonstrated more significant enhancements in FEV1. CASA-Q sputum domain scores were significantly higher in the group with elevated eosinophil counts. Regression analysis revealed that FeNO levels and blood eosinophil counts are significant predictors of FEV1 improvement, with blood eosinophil counts also predicting sputum improvement in patients treated with dupilumab.

    Conclusions: Type-2 biomarkers may act as indicators of improvement in FEV1 and sputum outcomes among patients with severe asthma undergoing dupilumab treatment in real-world settings.

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  • Hisashi Sasaki, Jun Miyata, Yusuke Kawashima, Ryo Konno, Masaki Ishika ...
    2025 Volume 74 Issue 1 Pages 156-165
    Published: 2025
    Released on J-STAGE: January 21, 2025
    JOURNAL FREE ACCESS
    Supplementary material

    Background: Aspergillus fumigatus is a pathogenic fungus known to be associated with severe asthma and allergic bronchopulmonary mycosis. However, the precise mechanisms underlying airway inflammation remain unclear. In this study, we investigated the direct modulation of human eosinophils by A. fumigatus and identified the specific mechanism of airway inflammation.

    Methods: Eosinophils isolated from healthy subjects were stimulated with extracts of A. fumigatus. Multi-omics analysis, comprising transcriptomic and proteomic analyses, was performed. The expression of specific factors was evaluated using quantitative real-time polymerase chain reaction and flow cytometry. Mechanistic analyses were performed using NOD2 inhibitor and N-acetyl-L-cysteine (NAC).

    Results: The A. fumigatus extract changed the expression of adhesion molecules (CD62L and CD11b) and CD69 on the surface of eosinophils, without affecting their viability, via nucleotide-binding oligomerization domain-containing protein 2 (NOD2) but not protease activity. Investigation using kinase inhibitors showed that A. fumigatus extract-induced modulation was partly mediated via p38 mitogen-activated protein kinases. Multi-omics analysis revealed that A. fumigatus-induced gene and protein expression profiles were characterized by the upregulation of oxidative stress-related molecules, including heat shock proteins (HSP90AA1, HSP90AB1, SRXN1, and HMOX1). NOD2 inhibitor and NAC differentially inhibited A. fumigatus-induced inflammatory changes. Additional multi-omics analysis identified that NOD2 signaling induced gene signatures different from those of interleukin (IL)-5 and elicited synergistic change with IL-5.

    Conclusions: A. fumigatus modulates human eosinophils via NOD2 and oxidative stress-mediated signaling. NOD2 signaling potentiated IL-5-induced activation, suggesting its pathogenic role in type 2 inflammation. NOD2 inhibitors and antioxidants can have therapeutic potential against A. fumigatus-related allergic disorders.

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