BACKGROUND:We have recently reported the preclinical characterization of a recombinant birch pollen allergy vaccine based on a fusion protein, AB-PreS, consisting of allergen-derived peptides fused to the hepatitis B virus (HBV)-derived PreS surface protein as immunological carrier. OBJECTIVE:To investigate in a clinical study the usefulness of the AB-PreS vaccine, termed GNR-127, for allergen-specific immunotherapy of birch pollen allergy. METHODS:Stage 1 of the study, an open-label Phase I study, determined among three doses (20 μg: n = 6; 40 μg: n = 6; 80 μg: n = 6) administered as Aluminum-hydroxide-adsorbed vaccines subcutaneously five times in monthly intervals, the highest tolerated doses. In the following Stage 2, randomized patients (placebo: n = 45; 40 μg: n = 43; 80 μg: n = 44) received in a single-blind, placebo-controlled Phase II study monthly up to five pre-seasonal injections. Safety monitoring followed the Medical Dictionary for Regulatory Activities (MedDRA); efficacy parameters were determined according to the European Academy for Allergy and Clinical Immunology (EAACI) guidelines; allergen-specific antibodies and basophil sensitivity were determined by ELISA and basophil activation testing, respectively. RESULTS:A dose-dependent reduction of the combined symptom medication score (CSMS) (40 μg: 17.41%; 80 μg: 24.13%) over placebo was observed which was significant for the 80 μg group and accompanied by the strongest induction of Bet v 1-specific IgG (median 20-fold increase) and a blunting of the seasonally boosted IgE response and basophil sensitivity. The vaccine showed an acceptable safety profile despite high administered doses. CONCLUSION:A pre-seasonal course of 5 monthly injections of GNR-127 80 μg improved symptoms of birch pollen allergy accompanied by a robust Bet v 1-specific IgG response, paving the road for a Phase III efficacy study. TRIAL REGISTRATION:ClinicalTrials.gov (Identifier: NCT07155499).
BACKGROUND:Atopic dermatitis (AD) is characterized by pruritus, epidermal hyperplasia, and lichenification that significantly impairs quality of life. Nemolizumab, an anti-IL-31Rα monoclonal antibody, is approved for treating moderate-to-severe AD in patients aged > 12 years. This study investigated nemolizumab's molecular mechanisms using patient samples from the ARCADIA 1 (NCT03985943) and 2 (NCT03989349) trials. METHODS:Tape-strips were collected from the lesional and non-lesional skin of 71 nemolizumab-treated and 39 placebo-treated patients, all receiving background topical corticosteroids ± topical calcineurin inhibitors, at baseline and after 16 weeks of treatment for bulk RNAseq analysis. Single cell RNAseq was performed on a subset of untreated patients and used as a reference to map bulk RNA-seq DEGs, providing cellular context for treatment-associated transcriptional changes. RESULTS:Bulk RNAseq revealed significant transcriptomic modulation following 16 weeks of nemolizumab treatment (797 downregulated/142 upregulated genes), while placebo-treated patients showed minimal changes. Nemolizumab treatment attenuated expression of pruritus-related genes (e.g., OSMR, TRPV3, HRH1, KLK6/7/9) and genes involved in epidermal hyperplasia and ECM remodeling (e.g., COL1A1/12A1, IGFBP3). Inflammatory pathways were also modulated, with downregulation of Th17- and Th1-related genes (e.g., S100A7/8/9, PI3, MX1, OASL). Pathway-level analysis demonstrated normalization of pruritus and inflammatory gene signatures, including Th2 and Th22 pathways. Subgroup analysis showed that patients with severe baseline pruritus (PPNRS ≥ 7) had higher baseline expression of immune-related genes and experienced greater downregulation following treatment compared to patients with moderate baseline itch. Single-cell mapping of differentially expressed genes suggested enrichment of these genes in keratinocyte, fibroblast, endothelial, and nerve cell subpopulations. Clinically, improvements in EASI and pruritus scores (PPNRS) correlated with decreased expression of fibrosis- and pruritus-associated genes. CONCLUSION:Our findings provide molecular evidence supporting nemolizumab's therapeutic efficacy across multiple disease domains, including pruritus, inflammation, and epidermal hyperplasia, highlighting its role in AD treatment and management.
BACKGROUND:Seasonal allergic rhinitis (SAR) has been so far classified according to frequency and severity by retrospective information based on the ARIA (Allergic Rhinitis and its Impact on Asthma) classification. Electronic symptom diaries (e-Diaries) are feasible tools to collect prospective patient-reported data. OBJECTIVE:To test the consistency between prospectively recorded symptoms and retrospective ARIA classification and to generate a new SAR classification based on prospective e-Diary data. METHODS:Within the @IT.2020 multicentre observational study, we recruited 815 children and adults with SAR in nine study centres from Mediterranean countries. Participants recorded daily organ-specific (Rhinoconjunctivitis Total Symptom Score; RTSS) and general symptoms (visual analogue scale, VAS) plus quality-of-life measures via an e-Diary app. Retrospective clinical questionnaires were performed at the beginning (T0) and end (T1) of the pollen season. Unsupervised clustering analyses around medoids were implemented to classify SAR by prospective patient-reported data. RESULTS:One third (56/164, 34.1%) and almost half (173/366, 47.3%) of the patients retrospectively over- or underestimated the frequency of their symptoms, respectively. A moderate correlation was found between SAR severity reported at T1 and prospectively recorded symptom severity. An unsupervised clustering approach was able to identify distinct groups (mild, moderate, severe cluster) of patients based on the prospective severity of organ-specific (RTSS) and overall symptoms (VAS), as well as quality of life criteria. CONCLUSIONS:A significant recall bias regarding frequency and severity of symptoms emerged by comparing the retrospective ARIA classification with prospectively recorded data by an e-Diary. A prospective approach to SAR classification, inspired by the retrospective ARIA classification, may facilitate a more precise evaluation of the patient for improved disease management.
BACKGROUND:Anaphylaxis is classically framed around IgE-FcεRI, yet a subset of severe reactions engages an IgG-FcγR-mediated arm whose consequences for mucosal barrier integrity and epithelial repair remain undefined under recurrence. We propose that mucosal surfaces sustain function during severe anaphylaxis through coordinated operation of immunological composition, structural integrity and reparative capacity-which we term mucosal allostasis-and asked whether the two pathways diverge along this framework. METHODS:BALB/c mice were resolved into IgE- and IgG-mediated arms using a hybrid active/passive (ASA-PSA) sensitisation model and subjected to acute or recurrent severe anaphylaxis, with pharmacological reversal enabling matched rechallenge. Lung, small intestine, colon and serum were profiled across cytokine, mediator, junctional, repair and bacterial 16S rDNA panels; ILC subsets and junctional integrity were resolved by flow cytometry and immunohistochemistry. RESULTS:Despite comparable systemic clinical severity, the two pathways diverged sharply at the mucosal level. IgE-mediated recurrence preserved junctional expression and mounted a coordinated AREG/EGF/periostin/TFF3/MUC2 repair programme, whereas IgG-mediated recurrence dismantled both: Claudin-1, Occludin, ZO-1 and E-cadherin declined in tissue and rose reciprocally in serum, repair mediators failed to engage where junctional injury was greatest, and bacterial DNA translocation rose 48-fold, alongside a type 2/regulatory to inflammatory shift and an ILC2 to ILC1/NCR+ ILC3 reorganisation. CONCLUSION:Recurrent IgE- and IgG-mediated severe anaphylaxis diverge into two mechanistically opposite allostatic phenotypes. IgG-mediated recurrence produces an allostatic collapse in which structural failure proceeds uncoupled from reparative engagement, identifying barrier-repair coupling as a candidate axis for intervention in refractory anaphylaxis.
IgE-mediated food allergy is a global health issue with rising prevalence that cannot be explained by genetic change alone, strongly suggesting that environmental exposures are a key driver. The external exposome encompasses several exposures that influence the developing immune system and modify food allergy risk. Environmental exposure to food allergens in household dust is increasingly recognized as a risk factor for sensitization, whereas early oral introduction promotes tolerance. Early-life microbial exposures, especially those associated with rural and farming environments, may protect against food allergies by stimulating innate immune pathways and shaping the gut microbiome. Co-exposures to microbial adjuvants can further alter risk in a timing-dependent manner. Epidemiological birth cohort studies have linked exposure to air pollutants, such as particulate matter and nitrogen dioxide, to food sensitization and allergy. Synthetic chemicals represent an emerging risk factor by disrupting epithelial barrier integrity and immune regulation. Ultra-processed food consumption and dietary additives may further increase risk by altering gut permeability and immune function. Significant gaps remain in our understanding of the most relevant environmental exposures affecting food allergy risk. Future research using longitudinal cohort designs and exposome-wide approaches is essential for developing evidence-based strategies to prevent food allergy.
Over the past several decades, there have been significant advances in our understanding of both immunological and pharmacological mechanisms of adverse drug reactions (ADRs). Immune-mediated drug reactions (IMDRs) represent a small proportion of ADRs and are caused by a pathological activation of the immune system or inflammatory pathways. Drugs can act as an antigen or may directly interact with the immune system or inflammatory pathways, making immune-mediated drug reactions observed in contemporary practice not sufficiently explained by the Gell and Coombs (G&C) framework. Moreover, the phenotype alone is neither pathognomonic nor sufficient to infer the endotype. The proposed nomenclature integrates chrono-morphological phenotypes, mechanistic endotypes and characteristics of the involved drug. In this nomenclature, IMDRs are classified, according to the nature of interaction with the immune system, in: (i) drug allergy that encompasses antigen-driven reactions-diagnosed by tests detecting sensitisation-and (ii) drug hypersensitivity that includes the heterogeneous broad group of drug-directly-driven reactions. This framework supports precision medicine, aligns terminology with mechanisms, and provides a common language for interdisciplinary communication, pharmacovigilance, and drug development. It accommodates emerging therapeutic classes and remains adaptable to future discoveries in immunopathogenesis and biomarker development.
BACKGROUND:Respiratory tract colonization by the pathogenic airway bacteria Haemophilus influenzae, Streptococcus pneumoniae, and/or Moraxella catarrhalis has been linked to the pathogenesis of childhood asthma and exacerbations, but the underlying mechanisms remain unclear. OBJECTIVE:To investigate the association of H. influenzae, S. pneumoniae, and M. catarrhalis with airway immune responses during acute early-life asthma-like episodes and examine how these responses differ between children with and without asthma. METHODS:The study included 476 asthma-like episodes from 271 children aged 0 to 4 years from the COPSAC2010 mother-child cohort. Levels of 17 immune mediators covering Type-1, -2, and -17 and regulatory pathways were assessed in upper airway mucosal lining fluid while hypopharyngeal aspirates were collected for bacterial cultures and nasopharyngeal aspirates for viral PCR. Asthma was prospectively assessed until age 6 years. RESULTS:Detection of H. influenzae during asthma-like symptoms was associated with elevated IL-1β, TNF-α, and IL-2, alongside decreased CXCL10 levels. Similar immune profiles were observed in children with and without asthma by age 3. Detection of S. pneumoniae and M. catarrhalis were not associated with significant changes in immune mediator levels; however, children with asthma by age 3 exhibited elevated IL-1β levels during detection of S. pneumoniae, a pattern not observed in children without asthma. No significant differences in mediator levels were observed in children with and without asthma at age 6. CONCLUSION:Children with pathogenic bacterial detection in the airways during acute asthma-like episodes exhibit an increased proinflammatory immune response marked by increased IL-1β, IL-2 and TNF-α, which may promote chronic inflammation, possibly contributing to asthma development and exacerbations.
BACKGROUND:IgE-mediated food allergy burdens individuals, families and healthcare systems. Randomised controlled trials indicate early introduction and regular consumption of common food allergens in infancy can reduce food allergy risk. Few studies have explored parental and healthcare professional experiences. This systematic review examines their perspectives applying a theory-informed behavioural analysis identifying key barriers influencing food allergen introduction. METHOD:A systematic search of seven databases was conducted in November 2025. All study designs and published primary research papers were included and screened against the inclusion/exclusion criteria. Quantitative findings were summarised narratively and analysed alongside qualitative data. All findings were synthesised concurrently using an integrated thematic synthesis following the Thomas and Harden approach. Quality appraisal was assessed. RESULTS:Twenty-five studies were included. Four themes were identified: (1) Practical barriers to introducing the allergenic foods, (2) perceived risk and fear of allergic reactions and safety, (3) navigating and making sense of food allergy prevention information, particularly conflicting advice for parents and (4) food allergy prevention advice, guidance awareness, interpretation and implementation. CONCLUSION:Effective food allergy prevention requires early, consistent support for parents from suitably trained healthcare professionals. Advice should be evidence-based, simple, culturally relevant and accessible, promoting realistic and healthy infant and family foods and diets.
BACKGROUND:Hazelnut and walnut allergy may cause severe reactions, but the clinical relevance of individual seed storage proteins, including recently available vicilins, remains incompletely defined. METHODS:We performed an observational analysis of a consecutive tertiary-care cohort of 114 patients with tree nut allergy, including 70 with walnut allergy and 44 with hazelnut allergy. Clinical severity was classified as mild, moderate, or severe. Specific IgE to selected hazelnut and walnut components was assessed by ImmunoCAP. We evaluated sensitisation frequencies, severity-stratified molecular profiles, and the diagnostic contribution of newly available vicilins in a singleplex format, vicilin co-sensitisation patterns by network and heatmap analyses, ROC performance for severe reactions, and parsimonious multivariable logistic regression models adjusted for age and sex. RESULTS:Severe reactions were more frequent in hazelnut than in walnut allergy (43.2% vs. 24.3%). Cor a 14, Cor a 9, and Cor a 16 showed the clearest severity-related gradients in hazelnut allergy, and Jug r 1 and Jug r 2 in walnut allergy. Co-sensitisation was strongest between the type 2 vicilins Cor a 16 and Jug r 2. Cor a 16 showed the highest AUC among hazelnut components (0.72), with overlapping performance for Cor a 14 and Cor a 9, whereas Jug r 1 performed best among walnut components (AUC 0.89). After adjustment for age and sex, severe reactions remained associated with Cor a 14, Jug r 1, and Jug r 2. CONCLUSIONS:In this tertiary-care cohort, individual seed storage proteins differed in their associations with reaction severity. Cor a 14 and Jug r 1 showed the strongest adjusted associations, while type 2 vicilins dominated co-sensitisation patterns. Overall, these findings support the clinical value of molecule-resolved diagnostics and suggest that integrating multiple vicilin components may improve molecular stratification of tree nut allergy, although external validation is required.
BACKGROUND:Sensitization to birch pollen is a major contributor to allergic rhinitis in Europe, with sensitization rates in many countries from 10% to 20% of the general population. Growing evidence suggests that air pollution enhances the allergenicity of pollen; however, the clinical consequences of this co-exposure remain poorly understood. This study investigated whether air pollution intensifies birch pollen allergenicity and assessed its effects on symptom severity and basophil activation in allergic and non-allergic individuals. METHODS:Fifty birch-allergic patients and twenty-five non-atopic controls were examined over two consecutive pollen seasons (2023-2024). Daily nasal, ocular, and asthma symptoms were recorded using a mobile application. Ambient air pollutants (PM2.5, PM10, and O3) and birch pollen concentrations were continuously monitored in Kraków. Basophil activation tests (BAT) were performed using commercial birch pollen extracts, Bet v1 allergen, and natural pollen collected from highly and less polluted areas. Basophil activation was quantified by CD63 expression using flow cytometry. RESULTS:Asthmatic symptoms showed significant positive correlations with both birch pollen and PM concentrations (p < 0.05), especially in 2023. Pollen collected from polluted sites induced significantly stronger basophil activation compared with pollen from less polluted areas (p < 0.0001). The magnitude of basophil activation correlated with serum IgE levels to birch and Bet v 1, as well as with clinical symptom scores. CONCLUSIONS:Air pollution enhances the allergenic potency of birch pollen, resulting in heightened basophil activation and more severe allergic symptoms. These findings highlight the importance of integrating air pollution monitoring alongside pollen surveillance when assessing allergic disease burden and evaluating the effectiveness of allergen immunotherapy.
BACKGROUND:Due to the shared underlying pathophysiological mechanism, chronic rhinosinusitis with nasal polyps (CRSwNP) is frequently associated with comorbid systemic type 2 diseases. Rare, complex cases treated simultaneously with two biologics due to inadequate disease control have been reported. The aim of this study was to assess current use of dual biologic therapy in patients with CRSwNP. METHODS:This retrospective, multicentric study included adult patients with a diagnosis of severe uncontrolled CRSwNP and simultaneous dual type-2 biologic therapy, one of which had to be approved for the treatment of CRSwNP. Indication for dual therapy was made on an individual basis after interdisciplinary consultation. RESULTS:Thirty-four patients diagnosed with CRSwNP from six study centers in Germany, the Netherlands, and Italy were included (mean age 49.1, 55.9% female). Most patients showed complex medical histories with type 2 comorbidities and several futile treatment attempts. The combination therapy consisted of dupilumab/mepolizumab (n = 14), mepolizumab/tezepelumab (n = 2), or benralizumab/dupilumab (n = 14), dupilumab/omalizumab (n = 3), or dupilumab/tezepelumab (n = 1), with a median follow-up time of 25 months (IQR = 6-34). Most frequent comorbidities were asthma (n = 32), eosinophilic granulomatous polyangiitis (n = 13), and hypereosinophilic syndrome (n = 5). CRSwNP disease outcomes significantly improved under dual therapy at 6 months compared to baseline under single biologic therapy (SNOT22: -32.8, p < 0.0001; NPS: -3.2, p < 0.0001; Smell: +3.4, p = 0.003; VAS overall disease severity: -4.3, p = 0.054). Cessation of dual therapy was attempted in four patients, but reintroduced again due to loss of disease control. Five adverse reactions were reported in 4 (11.8%) patients: urticaria, erythema, gastrointestinal symptoms, weight gain, and arthralgia (each n = 1). CONCLUSIONS:In rare cases, dual biologic therapy can be indicated to control CRSwNP and comorbid type 2 diseases. The long-term efficacy and safety of this approach remain unknown and should be reserved for carefully selected cases only, considering the off-label use in some European countries and high associated costs.
BACKGROUND:Ferroptosis is a non-apoptotic form of cell death driven by lipid peroxidation. Although elevated lipid peroxidation has been linked to respiratory epithelial injury, its role in allergic rhinitis (AR) remains unclear. Therefore, in this study, we aimed to assess the role of ferroptosis in AR pathogenesis and elucidate its molecular mechanism. METHODS:Human nasal epithelial cells (HNEpC and RPMI-2650) and Balb/c mice were used to evaluate house dust mite (HDM)-induced ferroptosis related responses and nasal epithelial barrier disruption. Clinical nasal mucosal samples were collected to validate key experimental findings. N6-methyladenosine (m6A) methylation levels were assessed by m6A assays and dot blot analysis, predicted m6A sites were identified using SRAMP, and RIP-qPCR and MeRIP-qPCR were performed to examine RNA-protein interactions and site-specific m6A enrichment, respectively. RESULTS:HDM exposure induced lipid peroxidation-driven ferroptosis-related epithelial barrier disruption. Glutathione peroxidase 4 (GPX4) acted as a protective regulator, as ferroptosis inhibition or GPX4 overexpression alleviated epithelial damage. Growth arrest-specific 1 (GAS1) promoted ferroptosis by suppressing GPX4 expression, a finding further supported by in vivo validation in GAS1-knockdown mice. Mechanistically, this GAS1-GPX4 regulatory relationship was linked to METTL3-mediated m6A modification of GPX4 mRNA at the site 625. CONCLUSIONS:These findings suggest a novel mechanism whereby HDM exposure promotes ferroptosis-related nasal epithelial barrier impairment through GAS1-METTL3-mediated regulation of GPX4 m6A methylation, thereby contributing to AR pathogenesis.
