Journal of Allergy and Clinical Immunology最新文献

Background: Neuronal dysfunction is implicated in the pathophysiology of asthma and functional dyspepsia (FD). However, the relationship between these diseases remains unclear.

Objective: This study aimed to clarify the clinical implications of comorbid FD in asthma and to explore the unified pathway between asthma and FD by focusing on airway neuronal dysfunction.

Methods: Clinical indices and biomarkers, including capsaicin cough sensitivity (C-CS), were compared between patients with asthma with and without FD. C-CS was determined on the basis of capsaicin concentration that induced at least 2 coughs (C2) or 5 coughs (C5). Additionally, the associations of airway inflammation with airway innervation and gastrointestinal motility were evaluated in mouse models of type 2 airway inflammation.

Results: Patients with asthma with FD had worse asthma control and cough severity and lower C2 and C5 thresholds than those without FD. The severity of FD symptoms was negatively correlated with C2 and C5 thresholds. FD and poor asthma control were predictors of heightened C-CS (defined as C5 ≤ 2.44 μmol) in asthma. A mouse model of papain-induced airway inflammation developed airway hyperinnervation and gastrointestinal dysmotility, and both pathologies were ameliorated by an anti-IL-33 antibody. Moreover, papain-induced gastrointestinal dysmotility was mitigated by silencing the airway sensory neurons using QX-314, a sodium channel blocker. Furthermore, sputum IL-33 levels were significantly elevated in patients with asthma with FD or heightened C-CS compared to their counterparts.

Conclusion: FD is significantly associated with airway neuronal dysfunction in asthma. IL-33-mediated airway neuronal dysfunction may contribute to the interaction between asthma and FD.

Background: In the United States, dupilumab is approved for moderate-to-severe eosinophilic or oral corticosteroid-dependent asthma, and omalizumab is approved for managing moderate-to-severe allergic asthma uncontrolled by inhaled corticosteroids. However, limited comparative effectiveness data exist for these biologics due to differing patient characteristics and treatment histories.

Objective: This study assessed the real-world effectiveness of dupilumab and omalizumab for asthma in patients in the United States.

Methods: In this retrospective observational study, TriNetX Dataworks electronic medical record data were used to identify patients with asthma age ≥12 years who initiated (index) dupilumab or omalizumab between November 2018 and September 2020 and who had at least 12 months of pre- and post-index clinical information. Inverse probability of treatment weighting was applied to balance potential confounding in treatment groups. Asthma exacerbation rates and systemic corticosteroid (SCS) prescriptions were compared using a doubly robust negative binomial regression model, adjusting for baseline exacerbation/SCS rates and patient characteristics with ≥10% standardized differences after inverse probability of treatment weighting.

Results: All inclusion and exclusion criteria were met by 2138 dupilumab patients and 1313 omalizumab patients. After weighting, the majority of baseline characteristics were balanced (standard difference <10%) between the 2 groups. Dupilumab was associated with a 44% lower asthma exacerbation rate (P < .0001) versus omalizumab. Additionally, dupilumab treatment significantly (P < .05) reduced SCS prescriptions by 28% during the follow-up period compared with omalizumab treatment.

Conclusions: The US ADVANTAGE real-world study demonstrated a significant reduction in severe asthma exacerbations and SCS prescriptions for patients prescribed dupilumab compared with patients prescribed omalizumab during 12 months of follow-up.

Background: The role of air pollution in eczema and food allergy development remains understudied.

Objective: We aimed to assess whether exposure to air pollution is associated with eczema and food allergies in the first 10 years of life.

Methods: HealthNuts recruited a population-based sample of 1-year-old infants who were followed up at ages 4, 6, and 10 years. Annual average fine particulate matter (particulate matter with diameter of 2.5 μm or less, or PM_2.5) and nitrogen dioxide (NO₂) exposures were assigned to geocoded residential addresses. Eczema was defined by parent report. Oral food challenges to peanut, egg, and sesame were used to measure food allergy. Multilevel logistic regression models were fitted, and estimates were reported as adjusted odds ratios.

Results: Those exposed to high concentration of NO₂ (<10 ppb) at age 1 year had higher peanut allergy prevalence at ages 1 (adjusted odds ratio [95% confidence interval], 2.21 [1.40-3.48]) and 4 (2.29 [1.28-4.11]) years. High exposure to NO₂ at 6 years old were associated with higher peanut allergy prevalence at age 6 (1.34 [1.00-1.82] per 2.7 ppb NO₂ increase) years. Similarly, increased PM_2.5 at age 1 year was associated with peanut allergy at ages 4, 6, and 10 years (respectively, 1.27 [1.01-1.60], 1.27 [1.01-1.56], and 1.46 [1.05-2.04] per 1.2 μg/m PM_2.5 increase) years. We found that increased concentrations of NO₂ or PM_2.5 at age 1 year were associated with persistent peanut allergy at later ages. Little evidence of associations was observed with eczema or with egg allergy.

Conclusions: Early-life exposure to PM_2.5 and NO₂ was associated with peanut allergy prevalence and persistence. Policies aiming at reducing air pollution could potentially reduce presence and persistence of peanut allergy.

Background: Investigating the contributory role that epithelial cell metabolism plays in allergic inflammation is a key factor to understanding what influences dysfunction and the pathogenesis of the allergic disease eosinophilic esophagitis (EoE). We previously highlighted that the absence of hypoxia signaling through hypoxia-inducible factor (HIF)-1α in EoE contributes to esophageal epithelial dysfunction. However, metabolic regulation by HIF-1α has not been explored in esophageal allergy.

Objectives: We sought to define the role of HIF-1α-mediated metabolic dysfunction in esophageal epithelial differentiation processes and barrier function in EoE.

Methods: In RNA sequencing of EoE patient biopsy samples, we observed the expression pattern of key genes involved in mitochondrial metabolism/oxidative phosphorylation (OXPHOS) and glycolysis. Seahorse bioenergetics analysis was performed on EPC2-hTERT cells to decipher the metabolic processes involved in epithelial differentiation processes. In addition, air-liquid interface cultures were used to delineate metabolic dependency mechanisms required for epithelial differentiation.

Results: Transcriptomic analysis identified an increase in genes associated with OXPHOS in patients with EoE. Epithelial origin of this signature was confirmed by complex V immunofluorescence of patient biopsy samples. Bioenergetic analysis in vitro revealed that differentiated epithelium was less reliant on OXPHOS compared with undifferentiated epithelium. Increased OXPHOS potential and reduced glycolytic capacity was mirrored in HIF1A-knockdown EPC2-hTERT cells that exhibited a significant absence of terminal markers of epithelial differentiation, including involucrin. Pharmacologic glucose transport inhibition phenocopied this, while rescue of the HIF-1α-deficient phenotype using the pan-prolyl hydroxylase inhibitor dimethyloxalylglycine resulted in restored expression of epithelial differentiation markers.

Conclusions: An OXPHOS-dominated metabolic pattern in EoE patients, brought about largely by the absence of HIF-1α-mediated glycolysis, is linked with the deficit in esophageal epithelial differentiation.

Background: Atopic dermatitis is characterized by scratching and a T_H2-dominated local and systemic response to cutaneously encountered antigens. Dendritic cells (DCs) capture antigens in the skin and rapidly migrate to draining lymph nodes (dLNs) where they drive the differentiation of antigen-specific naive T cells.

Objective: We sought to determine whether non-T-cell-derived IL-4 acts on skin-derived DCs to promote the T_H2 response to cutaneously encountered antigen and allergic skin inflammation.

Methods: DCs from dLNs of ovalbumin (OVA)-exposed skin were analyzed by flow cytometry and for their ability to polarize OVA-specific naive CD4⁺ T cells. Skin inflammation following epicutaneous sensitization of tape-stripped skin was assessed by flow cytometry of skin cells and real-time quantitative PCR of cytokines. Cytokine secretion and antibody levels were evaluated by ELISA.

Results: Scratching upregulated IL4 expression in human skin. Similarly, tape stripping caused rapid basophil-dependent upregulation of cutaneous Il4 expression in mouse skin. In vitro treatment of DCs from skin dLNs with IL-4 promoted their capacity to drive T_H2 differentiation. DCs from dLNs of OVA-sensitized skin of Il4^-/- mice and CD11c-CreIl4r^flox/- mice, which lack IL-4Rα expression in DCs (DC^Δ/Δll4ra mice), were impaired in their capacity to drive T_H2 polarization compared with DCs from controls. Importantly, OVA-sensitized DC^Δ/Δll4ra mice demonstrated impaired allergic skin inflammation and OVA-specific systemic T_H2 response evidenced by reduced T_H2 cytokine secretion by OVA-stimulated splenocytes and lower levels of OVA-specific IgE and IgG1 antibodies, compared with controls.

Conclusions: Mechanical skin injury causes basophil-dependent upregulation of cutaneous IL-4. IL-4 acts on skin DCs that capture antigen and migrate to dLNs to promote their capacity for T_H2 polarization and drive allergic skin inflammation.

Background: Certain environmental allergen exposures are more common in disadvantaged communities and may contribute to differences in susceptibility to upper respiratory infections (URIs).

Objectives: We examined associations between indoor allergens and: (1) URI; (2) URI + cold symptoms; (3) URI + cold symptoms + pulmonary eosinophilic inflammation (fraction of exhaled nitric oxide ≥20 ppb); and (4) URI + cold symptoms + reduced lung function (percent predicted forced expiratory volume in 1 second of <80%).

Methods: We used data from the Environmental Control as Add-on Therapy for Childhood Asthma (ECATCh) study. Allergen concentrations were measured in air (mouse) and settled dust (mouse, cockroach, dog, and cat). URI was determined by testing nasal mucus for upper respiratory viruses. We evaluated associations between allergen concentrations and URI-associated outcomes accounting for age, sex, study month, season, health insurance, and household size.

Results: Ninety participants (92% Black, 92% public insurance) with 192 observations were included; 52 (27%) of observations were positive for URI. A doubling in cockroach allergen concentration increased the odds of a URI with cold symptoms by 18% (odds ratio [OR] = 1.18, 95% confidence interval [CI], 0.99-1.40), the odds of a URI + cold symptoms + pulmonary eosinophilic inflammation by 31% (OR = 1.31, 95% CI, 1.10-1.57), and the odds of a URI + cold symptoms + reduced lung function by 45% (OR = 1.45, 95% CI, 1.13-1.85). Mouse allergen concentrations were positively associated with all outcomes. Associations were suggestively stronger among children sensitized to pest allergens.

Conclusions: Cockroach and mouse, but not dog or cat, allergen exposure may predispose children with asthma to URIs with colds and lower respiratory outcomes.

Background: Inborn errors of immunity (IEIs) are more than 500 different rare congenital disorders of the immune system characterized by susceptibility to infections and immune dysregulation. The significant overlap of the clinical features among the different forms may lead to diagnostic delay. High throughput sequencing techniques may allow a timely genetic definition. Guidelines for the use and the interpretation of genetic testing produced by the American College of Medical Genetics and Genomics (ACMG) and the European Society of Human Genetics (ESHG) do not cover specificities for the application to IEIs.

Objective: The aim of this consensus study is to define the best approach to genetic testing for IEIs.

Methods: A panel of experts in the context of the Italian Primary Immunodeficiency Network (IPINet) composed a list of statements that were evaluated using Delphi method.

Results: The experts recommend that genetic testing for IEIs should be offered to selected patients with warning signs for IEIs and highlight the crucial role of thorough phenotyping and functional tests for the conclusive diagnosis of IEI. Comprehensive educational programs targeted to health care professionals and the public should be developed to increase IEIs awareness and reduce the diagnostic delay. Ethical issues should be pondered over the diagnostic advantages of genetic tests requested for diagnostic purposes.

Conclusion: Adherence to the guidelines on the use and interpretation of genetic testing for the diagnosis of IEIs should help limiting the inappropriate use of these techniques and reduce the risk of misdiagnosis and apprehension for inconclusive genetic results.