Allergy最新文献

Background: Atopic dermatitis (AD) is a common, relapsing inflammatory skin disease driven by an immune imbalance, microbial dysbiosis, and skin barrier impairment, culminating in (neurogenic) inflammation and itch. We hypothesized that the neuropeptide and pruritogen endothelin-1 (ET-1) contributes to AD pathology by impeding skin barrier formation via its cognate receptor ETAR and TRPA1, a cation channel involved in neurogenic inflammation, pain, and itch.

Methods: We utilized differentiated human keratinocytes and ex vivo human skin organ cultures in vitro to evaluate the impact of ET-1 on human skin barrier function. ET-1 effects were assessed at the RNA level by RT-qPCR and at the protein level by quantitative immunofluorescence microscopy. Barrier integrity was monitored using real-time cell analysis and transwell permeability assays.

Results: ET-1 markedly reduced cell resistance in differentiated keratinocytes, an effect abrogated by the ETAR antagonist bosentan. ET-1 significantly decreased expression of skin differentiation markers filaggrin and loricrin, and tight junction proteins occludin, claudin-1, and claudin-4, at mRNA and protein levels. ETAR-specific siRNA in combination with ET-1, rescued ET-1-mediated downregulation of filaggrin. Furthermore, TRPA1 antagonist HC-030031 abrogated the impairing effect of ET-1 on the skin barrier. We observed increased inflammatory responses of ET-1-stimulated keratinocytes, suggesting that the ET-1-initiated barrier disruption could be mediated by IL-6 and IL-1β and induced by TNF-α.

Conclusion: Our findings suggest that a neurogenic inflammation axis ET-1/ETAR/TRPA1 contributes to skin barrier impairment in AD by repressing differentiation markers and tight junction proteins. Additionally, we demonstrate ETAR-blockage as a rational therapeutic modality for patients with AD.

Background: The nasal allergen challenge (NAC) is the gold standard to diagnose allergic rhinitis (AR) and local allergic rhinitis (LAR), but its clinical use remains limited. We investigated whether volatile organic compounds (VOC) in exhaled breath could identify allergic individuals among patients with chronic rhinitis.

Methods: Exhaled breath samples were collected before and 24 h after NAC in participants with AR, LAR, non-allergic rhinitis (NAR), and healthy control (HC). Samples were analyzed using gas chromatography-mass spectrometry, focusing on saturated hydrocarbons. Associations with fractional exhaled nitric oxide (FeNO) and blood eosinophils were also assessed.

Results: We included 28 AR, 31 LAR, 29 NAR, and 14 HC individuals, divided into training and validation sets. A predictive model based on two VOCs (decane and nonadecane) discriminated allergic (AR + LAR) from non-allergic (NAR + HC) subjects (AUC 0.721, 95% CI: 0.506-0.936; permutation test p = 0.009), with moderate performance in the validation set (AUC 0.760, 95% CI: 0.585-0.935; 76.5% sensitivity, 69.2% specificity). Similarly, these two VOCs moderately differentiated LAR and NAR patients (AUC 0.737, 95% CI: 0.545-0.929; permutation test p = 0.011). At baseline, decane levels were higher in LAR than HC subjects (p = 0.007), nonadecane levels were higher in LAR than NAR individuals (p = 0.026), and decane, styrene, and nonanal levels were higher in patients with FeNO ≥ 25 ppb (all p ≤ 0.016). No associations were observed between VOCs and blood eosinophils. NAC induced a significant reduction in nonadecane in allergic patients (p = 0.012), but not in non-allergic subjects.

Conclusion: Exhaled decane and nonadecane might serve as non-invasive biomarkers of allergic inflammation in rhinitis patients, potentially supporting NAC indication. Elevated exhaled nonanal, decane, and styrene may reflect T2 airway inflammation. These exploratory findings require validation in larger, multicenter cohorts with accuracy-improving potential.

Background: Autosomal Dominant-Hyper-IgE Syndrome (AD-HIES) is caused by dominant-negative (DN) STAT3 mutations and characterized by high IgE levels, a lack of Th17-cells, and recurrent infections with extracellular pathogens. We previously identified an enigmatic population of IL-10 producing CCR6⁺B-helper T-cells and investigated here their relationship to Th17-cells and STAT3 signaling requirements.

Methods: Human blood lymphocytes were analyzed by multiparametric flow cytometry in healthy donors and AD-HIES patients. Analysis was performed by conventional gating or with bioinformatic tools. FACS-purified T-cell subsets were activated in vitro and Th17 differentiation assessed. T-cell antigen specificities were assessed by activation with heat-killed pathogens or antigenic peptide pools. B helper capacities were determined according to antibody secretion in B-T co-cultures by ELISA.

Results: CCR6⁺Th-cells that lacked subset-defining differentiation markers ("CCR6^SP") were mostly non-polarized central memory T-cells (T_CM) that produced IL-10 and expressed RORγt. They were pre-committed to a Th17 fate, since TCR stimulation in the absence of polarizing cytokines induced efficient Th17 differentiation. The latter was promoted by an autocrine loop of STAT3-activating cytokines. CCR6⁺Th-cells were reduced in patients with DN-STAT3 mutations but contained activated CCR6^SPT-cells that produced IL-10 and responded vigorously to AD-HIES-associated pathogens. These residual CCR6⁺Th-cells provided B-cell help for IgG and IgE production.

Conclusions: Th17 differentiation in AD-HIES patients was not completely impaired but arrested at an intermediate stage of IL-10-producing "pre-Th17"-cells. Surprisingly, DN-STAT3 mutations did not inhibit IL-10 production by CD4⁺T-cells. Pre-Th17-cells were activated by AD-HIES-associated pathogens and possessed B-helper functions, suggesting that they are not protective but may promote aberrant IgE production.

Background: Allergen immunotherapy is the only disease-modifying treatment for IgE-mediated diseases for patients 5 years and over. The question is often asked why children receive the same doses as adults. There is not a single dose-finding study including children and/or adolescents. Moreover, randomized controlled trials that include all age groups but report effects separately are rare.

Method: This randomized trial investigated the safety and tolerability of an accelerated dose escalation schedule (One-Strength group) compared to the standard regimen (Standard group) when using a birch pollen SCIT allergoid in patients aged 5-65 years.

Results: Overall, 201 patients were randomized to the two regimens: 87 adults, 52 adolescents, 62 children. Three hundred eighty-two treatment-related adverse drug reactions (ADRs) occurred in 81 patients (40.5%). A higher proportion of patients in the One-Strength group (48.5%) experienced at least one ADR compared to those in the Standard group (32.0%). The majority of ADRs were local (93.3%), and the majority were of mild intensity (95.8%). 3 patients in the One-Strength and 1 patient in the Standard group developed a total of 9 systemic ADRs, which all were classified as WAO grade 1 or 2 and most of mild intensity. No event of WAO grade 3 or higher was reported. No serious ADR occurred. Overall, tolerability was assessed as "very good" or "good" by more than 96% of investigators and patients. Safety and tolerability were comparable in the three age groups.

Conclusion: Birch pollen SCIT was safe and well-tolerated when administered using a One-Strength dose-escalation regimen in patients aged 5-65 years.

Background: The Prevention of Allergy via Cutaneous Intervention (PACI) randomized controlled trial (RCT) demonstrated that early enhanced topical corticosteroid (TCS) therapy modestly reduced food allergy (FA) at 28 weeks of age. The present prospective follow-up study (PACI-ON) evaluated whether these effects persisted to age 3 years.

Methods: Participants were randomized in infancy to early enhanced (proactive) or early conventional (reactive) TCS treatment (1:1) for atopic dermatitis (AD) until 28 weeks. A total of 590 (91%) children who completed the PACI RCT were followed to age 3 years. During follow-up, no protocolized interventions were given; all participants received usual care. Main outcomes included physician-diagnosed FA, AD severity (EASI, POEM), sensitization profiles, allergic comorbidities, and growth parameters as safety outcomes.

Results: At age 3 years, the prevalence of any FA remained lower in the early enhanced group than in the conventional group (47.4% vs. 58.8%, p = 0.006), mainly driven by a reduced prevalence of raw egg allergy (30.4% vs. 40.5%, p = 0.013). No between-group differences were observed for wheeze, asthma, or rhinitis. Japanese cedar sensitization at age 2 was lower in the enhanced group (6.1% vs. 12.2%, p = 0.02 6) but not at age 3. AD control and quality of life were well maintained and similar across groups, with > 90% achieving mild or less disease. Early growth suppression at 1 year resolved by age 3.

Conclusion: Early enhanced AD intervention was associated with a sustained modest reduction in its planned primary follow-up outcome of FA and safety (growth) up to age 3. Although most differences were small and may reflect early diagnosis and good overall management in both groups, the findings support early AD treatment as a potential strategy to modify allergic disease trajectories.