Annals of Allergy Asthma & Immunology最新文献

Background: Epithelial dysfunction is a central driver of type 2 inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP). Although epigenetic mechanisms are known to regulate mucosal immunity, the specific role of histone deacetylase 7 (HDAC7) in modulating the magnitude of epithelial type 2 responses remains unclear. We hypothesized that HDAC7 functions as an inducible checkpoint to restrain excessive inflammation.

Objective: To explore the role of epithelial HDAC7 in restraining excessive inflammation in CRSwNP.

Methods: Primary human nasal epithelial cells were exposed to inflammatory stimuli to identify HDAC7 inducers. Epithelial HDAC7 expression in patient tissues was correlated with inflammatory markers and remodeling indices. Mechanistic roles were assessed using lentiviral knockdown, transcriptome sequencing, and eosinophil chemotaxis assays.

Results: Interleukin (IL)-13 selectively induced epithelial HDAC7 expression. In clinical tissues, lower HDAC7 expression within the CRSwNP cohort correlated with severe type 2 inflammation and mucosal remodeling. Transcriptomic analysis revealed that HDAC7-low tissues demonstrated enriched type 2 pathways, whereas high expression aligned with T_H1/T_H17 signatures. In vitro, silencing HDAC7 amplified the broader IL-13-induced transcriptional program and specifically enhanced C-C motif chemokine ligand 26 (CCL26) production, promoting C-C chemokine receptor type 3-dependent eosinophil migration. Notably, this effect appeared specific to HDAC7 loss, as broad-spectrum HDAC inhibition with trichostatin A suppressed CCL26 and did not recapitulate the knockdown phenotype.

Conclusion: HDAC7 appears to function as an inducible negative regulator in the nasal epithelium, attenuating IL-13-driven CCL26 production. Disruption of this feedback loop may contribute to exacerbated type 2 inflammation, suggesting epithelial HDAC7 as a potential biomarker and therapeutic target for CRSwNP.

Background: Cow's milk allergy (CMA) is one of the most common food allergies in children and may persist into later childhood. Oral immunotherapy (OIT) is an effective treatment option; however, the optimal timing of initiation and the mechanisms underlying age-related differences in safety remain uncertain.

Objective: To evaluate the safety and efficacy of cow's milk OIT initiated at different ages and to explore the relationship between age, baseline immunologic markers, and adverse reactions in a real-world pediatric cohort.

Methods: We retrospectively analyzed 145 children with IgE-mediated CMA who completed OIT between 2009 and 2024. Patients were grouped by age at OIT initiation (<24 months, 24-48 months, and >48 months). Baseline clinical and laboratory characteristics and OIT-related adverse events (AEs) were compared. Multivariable logistic regression analyses were performed adjusting for relevant clinical covariates to assess the independent effects of age and cow's milk-specific IgE (CM-spIgE) on AEs.

Results: Older children (>48 months) had significantly higher baseline total IgE and CM-spIgE levels and more frequent pre-OIT anaphylaxis and respiratory symptoms. The use of omalizumab and epinephrine was more common in older patients. In multivariable analyses, age and CM-spIgE were each associated with adverse reactions. Early OIT (<24 months) was associated with fewer severe reactions and no anaphylaxis during the maintenance phase.

Conclusion: Earlier initiation of cow's milk OIT seems to be associated with a more favorable safety profile, highly correlated with the baseline immunologic profile. These findings support personalized decision-making that includes age and immunologic markers when determining OIT timing.

Background: Skin barrier dysfunction and inflammation characterize both lesional and nonlesional skin in moderate-to-severe atopic dermatitis (AD) and are associated with relapses and atopic march progression.

Objective: To assess the effects of dupilumab treatment on skin barrier function and integrity using noninvasive methods in children aged 6 to 11 years with moderate-to-severe AD compared with matched healthy volunteers.

Methods: Patients received dupilumab for 16 weeks. Transepidermal water loss (TEWL) before (basal) and after skin tape stripping and epidermal thickness (T_E), measured by optical coherence tomography, were assessed to week 28.

Results: The PEdiatric skin barrier function and LIpidomics STudy in patients with Atopic Dermatitis (PELISTAD) enrolled 23 patients and 18 healthy volunteers. Mean ± SD basal TEWL was significantly higher in AD lesional/nonlesional skin at baseline (55.1 ± 5.5/28.0 ± 3.1 g × m^-2 × h^-1) than in healthy skin (14.0 ± 1.6) and decreased to 30.3 ± 3.1/22.0 ± 2.6 at week 16 and to 29.7 ± 4.3/18.3 ± 2.1 at week 28; TEWL after 5 of 20 skin tape stripping improved similarly. Baseline mean ± SD T_E in lesional/nonlesional skin (251.1 ± 25.8/166.1 ± 15.2 µm) was significantly higher than in healthy skin (118.2 ± 5.1) and decreased to 196.8 ± 18.4/141.9 ± 11.9 at week 16 and to 160.4 ± 12.9/142.7 ± 15.6 at week 28. At weeks 16 and 28, there was no significant difference between TEWL and epidermal thickness in AD lesional and nonlesional skin vs healthy skin.

Conclusion: Using noninvasive techniques to monitor epithelial function, dupilumab treatment restored skin barrier function in children with AD. Improvements achieved at week 16 were sustained to week 28.

Trial registration: ClinicalTrials.gov Identifier: PELISTAD (NCT04718870).

Background: Biologic therapies significantly affect clinical outcomes in patients with chronic rhinosinusitis with nasal polyps (CRSwNPs), including those with comorbid asthma. Tezepelumab and dupilumab act on upstream and downstream type 2 cytokine pathways, respectively.

Objective: To indirectly compare the relative efficacy of dupilumab with tezepelumab based on phase 3 randomized controlled trials in CRSwNP, including those with comorbid asthma.

Methods: A Bucher indirect head-to-head comparison of studies evaluating dupilumab and tezepelumab for relevant outcomes was performed.

Results: Dupilumab and tezepelumab demonstrated comparable significant improvements in endoscopic-, radiologic-, olfactory-, and symptom-based outcomes in CRSwNP. Relative differences in hazard ratios for use of oral corticosteroids and/or surgery favored tezepelumab. However, no differences were observed when considering absolute values. Dupilumab demonstrated superiority in patients with comorbid asthma for symptom control.

Conclusion: Indirect treatment comparison revealed comparable overall clinical benefits of dupilumab and tezepelumab in CRSwNP. However, a prospective head-to-head randomized controlled trial would be needed to confirm their relative efficacy.