Journal of Allergy and Clinical Immunology最新文献

{"title":"The normal, the abnormal, and the at risk: How can old and new birth cohort studies help?","authors":"Yukiko Kunitomo, Meredith C McCormack, Andrew Bush","doi":"10.1016/j.jaci.2025.03.004","DOIUrl":"10.1016/j.jaci.2025.03.004","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cigarette smoke-induced epithelial cell ferroptosis promotes neutrophilic inflammation in patients with nasal polyps.","authors":"Li Pan, Ze Yu, Wen-Xuan Xiang, Shi-Ran Sun, Jing-Xian Li, Yi-Ke Deng, Meng-Chen Wang, Ji-Xin Zhong, Kun Huang, Pei-Song Gao, Li-Ping Zhu, Yin Yao, Zheng Liu","doi":"10.1016/j.jaci.2025.02.034","DOIUrl":"https://doi.org/10.1016/j.jaci.2025.02.034","url":null,"abstract":"<p><strong>Background: </strong>Regulation of epithelial cell death has emerged as a key mechanism maintaining immune homeostasis in the airway. However, the mechanisms governing epithelial cell survival in nasal polyps (NPs) remains poorly understood.</p><p><strong>Objective: </strong>To investigate the ferroptosis of nasal epithelial cell and its implications in the pathogenesis of NPs.</p><p><strong>Methods: </strong>The cell death, lipid peroxidation, and ferrous iron levels in nasal epithelial cells were determined by flow cytometry. Biomarkers and signaling pathways associated with ferroptosis were evaluated by quantitative RT-PCR, single-cell and bulk RNA-sequencing, immunofluorescence staining, and western blotting. Human nasal epithelial cells (HNECs) and 16HBE cells were stimulated with different agents. Mitochondrial ultrastructure in HNECs were visualized by transmission electron microscopy. Cytokine levels were quantified using ELISA. A cigarette smoke extract (CSE)-induced mouse model was established and treated with deferoxamine.</p><p><strong>Results: </strong>Nasal epithelial cells from both eosinophilic and noneosinophilic NPs showed intensified lipid peroxidation and altered mitochondrial morphology, resembling the features of ferroptosis. Ferroptosis triggered C-X-C motif ligand (CXCL)8 production in 16HBE cells and HNECs through the activation of mitogen-activated protein kinase pathway. CSE exposure elevated ferrous iron levels by upregulating transferrin receptor 1, led to ferroptosis and subsequent CXCL8 production in HNECs. Deferoxamine treatment inhibited nasal epithelial cell ferroptosis, CXCL8 levels, and neutrophilic numbers in a CSE-induced mice model. Smoking burden was correlated with CXCL8 levels and neutrophil infiltration in patients with NPs. An analysis of 494,176 UK Biobank participants revealed smoking as a risk factor for NPs (Odds Ratio: 1.346, 95% Confidence Interval: 1.245-1.456, P < 0.001).</p><p><strong>Conclusion: </strong>Smoking-induced ferroptosis promotes CXCL8 production in nasal epithelial cells and thus potentially exacerbates neutrophilic inflammation in NPs.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Observational birth cohorts for causal and predictive inference: The example of childhood asthma and allergic diseases.","authors":"Brittney M Snyder, Ewoud Schuit, Bryan S Blette, William D Dupont, Christian Rosas-Salazar, Karel K G Moons, Tebeb Gebretsadik","doi":"10.1016/j.jaci.2025.03.005","DOIUrl":"10.1016/j.jaci.2025.03.005","url":null,"abstract":"<p><p>Prospective birth cohort studies have identified important factors associated with the development and occurrence of early life conditions and facilitated exploration of causal mechanisms. We discuss the strengths, importance, and biases of birth cohort data for causal inference and predictive modeling, using childhood asthma and allergic disease research as an illustrative example. State-of-the-art study design and statistical methodologies are considered and recommended to mitigate bias and infer causality, as well as using cohort assembly for increased power, sample size, and generalizability. These include effective control for confounding, limiting loss to follow-up, and leveraging risk factors for precision. While logistical and methodologic challenges exist for establishing, maintaining, and analyzing birth cohorts and their respective data, this prospective study design offers numerous benefits for inferring causality over other observational designs, and it is often the only alternative for assessing critical research questions. With long-term follow-up and extensive data collection, birth cohort studies represent powerful tools for studying disease etiology and have been integral to developing effective treatment and prevention strategies.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of Daily Steps Over Time with Adult Asthma Incidence.","authors":"Joshua C Halevi, Jeffrey Annis, Hiral Master, Basil M Kahwash, Evan L Brittain, Katherine N Cahill","doi":"10.1016/j.jaci.2025.02.033","DOIUrl":"https://doi.org/10.1016/j.jaci.2025.02.033","url":null,"abstract":"<p><strong>Background: </strong>Higher daily step counts is associated with reduced risk of many chronic diseases. Increased physical activity improves asthma outcomes. There are no known prevention strategies for adult incident asthma.</p><p><strong>Objective: </strong>To determine whether objective physical activity impacts adult asthma incidence.</p><p><strong>Methods: </strong>Participants in the All of Us Research Program retrospective cohort aged ≥ 18 years with linked personal activity tracker and electronic health record data met inclusion. Asthma was defined as two ICD-9/10 codes and ≥ 1 medication. Participants with an asthma diagnosis date before/within six months of activity monitor initiation were assigned prevalent asthma; participants diagnosed after six months of activity monitoring were assigned incident asthma.</p><p><strong>Results: </strong>8,360 participants met inclusion. Median average steps/day were higher among asthma-free participants [7,795 (5,879-9,921, 95% CI), n = 7,700] than participants with prevalent [6,968 (5,036-9,014, 95% CI), n = 450] or incident asthma [6,953 (5,215-8,261), n = 210] (p < 0.0001). Significant time by incident asthma interaction was observed with a greater decline in steps/day over time in the incident asthma cohort (p = 0.018). An inverse relationship was observed between average steps/day and asthma incidence after adjusting for age, sex, race, body mass index, major depressive disorder, sleep apnea, and chronic obstructive lung disease [adjusted hazard ratio 0.93 (0.88-0.98, 95% CI) per 1,000 average daily step increase].</p><p><strong>Conclusions: </strong>Objectively measured daily steps are lower in adults who develop incident asthma and may represent a modifiable risk factor to reduce asthma incidence. Future studies should objectively monitor physical activity among adults at risk for and with asthma.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel dominant-negative variant of IRF8 in a mother and son: Clinical, phenotypic and biological characteristics.","authors":"Hyoungjun Ham, Crescent R Isham, Elizabeth H Ristagno, Cristina Correia, Scott M Ennis, Richard K Kandasamy, Kishore Garapati, Cheng Zhang, Mindy C Kohlhagen, Elham Sadighi Akha, Maria F Rodriguez-Quevedo, Destiny F Schultz, Baoyu Chen, Thomas G Boyce, Seth W Gregory, Mira A Kohorst, Surendra Dasari, David L Murray, Kevin C Halling, Benjamin R Kipp, Attila Kumánovics, Hu Li, Akhilesh Pandey, Daniel D Billadeau, Amir A Sadighi Akha","doi":"10.1016/j.jaci.2024.11.041","DOIUrl":"https://doi.org/10.1016/j.jaci.2024.11.041","url":null,"abstract":"<p><strong>Background: </strong>The few reported patients with pathogenic IRF8 variants have manifested 2 distinct phenotypes: (1) an autosomal recessive severe immunodeficiency with significant neutrophilia and absence of or significant decrease in monocytes and dendritic cells and (2) a dominant-negative form with only a decrease in conventional type 2 dendritic cells (cDC2s) and susceptibility to mycobacterial disease.</p><p><strong>Objectives: </strong>Genetic testing of a child with persistent EBV viremia identified a novel IRF8 variant: c.1279dupT (p.∗427Leuext∗42). The variant was also found in his mother, who was subsequently diagnosed with a human papillomavirus-positive tumor. We sought to examine the pathogenicity of the identified IRF8 variant and its phenotypic and functional characteristics.</p><p><strong>Methods: </strong>Immunophenotypic and functional flow cytometry, natural killer cell cytotoxicity, matrix-assisted laser desorption/ionization-time of flight mass spectrometry, T-cell receptor Vβ spectratyping, Sanger sequencing, RNA-sequencing, Olink proteomics, immunoblotting, molecular cloning, dual-luciferase reporter assay, immunofluorescence microscopy, and image analysis.</p><p><strong>Results: </strong>The 42 amino acid C-terminal extension of the mutant IRF8 (∼4 kDa heavier than wild type) impaired IRF8 nuclear localization in a dominant-negative manner and inhibited IRF1/IRF8-mediated transcriptional activities. Both patients had a decrease in plasmacytoid dendritic cells (pDCs) and in cDC1s, a mild neutrophilia and a mild monocytosis. Their existing pDCs had impaired IFN-α production. On TLR engagement, the production of IL-1β, IL-6, IL-10, and IL-12 by their monocytes and of IL-12 by their myeloid DCs were within normal limits. Natural killer cell development and cytolytic activity were essentially normal. RNA-sequencing and proteomic approaches bolstered the phenotypic and functional findings.</p><p><strong>Conclusions: </strong>This study defines the pathogenic nature of the c.1279dupT (p.∗427Leuext∗42) IRF8 variant, determines its dominant-negative mechanism of action, and broadens the existing phenotype of human IRF8 immunodeficiency.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A predictive model for identification of pediatric individuals with common variable immunodeficiency through electronic medical records.","authors":"Nouf Alsaati, Chris Penney, Ingo Helbig, Kathleen E Sullivan","doi":"10.1016/j.jaci.2025.02.032","DOIUrl":"10.1016/j.jaci.2025.02.032","url":null,"abstract":"<p><strong>Introduction: </strong>Common variable immunodeficiency (CVID) is characterized by recurrent sinopulmonary infections. However, in the pediatric population, recurrent sinopulmonary infections early in life are common, which can render key clinical features of CVID less distinctive. Accordingly, the diagnosis of CVID is often delayed owing to the heterogeneous nature of the presentation and the broad range of ages of onset. A 10-year lag in diagnosis has been found for CVID, and there is a critical need for improved time to diagnosis.</p><p><strong>Objective: </strong>Our aim was to utilize machine learning techniques to identify a clinical signature of CVID in a pediatric population.</p><p><strong>Methods: </strong>Our selected cohort included 112 individuals with CVID and 627 controls. The controls were restricted from having other medical conditions associated with infection. A machine learning data set was constructed by summing patient-level counts of clinical metrics. A total of 3 supervised machine learning classifiers were trained, tuned, and performance-tested. We validated our findings using a distinct control cohort with high medical complexity and tested a logistic regression approach.</p><p><strong>Results: </strong>Key features associated with CVID were chest radiograph count, number of antibiotic prescriptions, and number of common infections. Our Extreme Gradient Boosting (XGBoost) model best predicted eventual CVID diagnosis, with an F1 score of 0.77, a total of 21 of 29 CVID diagnoses classified correctly (8 false-negative results), and 179 of 183 patients without CVID correctly classified (4 false-positive results) up to 10 years before the eventual clinical diagnosis. Key features with a robust association with pediatric CVID were the frequency of common infections and antibiotic prescriptions.</p><p><strong>Conclusion: </strong>In spite of a high frequency of infections in the comparator population, the clinical signature of pediatric CVID was sufficiently distinctive to enable early identification.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Network analysis reveals protein modules associated with childhood respiratory diseases.","authors":"Nicole Prince, Sofina Begum, Kevin M Mendez, Lourdes G Ramirez, Yulu Chen, Qingwen Chen, Su H Chu, Priyadarshini Kachroo, Ofer Levy, Joann Diray-Arce, Paolo Palma, Augusto A Litonjua, Scott T Weiss, Rachel S Kelly, Jessica A Lasky-Su","doi":"10.1016/j.jaci.2025.02.030","DOIUrl":"10.1016/j.jaci.2025.02.030","url":null,"abstract":"<p><strong>Background: </strong>The first year of life represents a dynamic immune development period that impacts the risk of developing respiratory-related diseases, including asthma, recurrent infections, and eczema. However, the role of immune-mediating proteins in childhood respiratory diseases is not well characterized in early life.</p><p><strong>Objective: </strong>The objective of this study was to investigate relationships between protein profiles at age 1 year and respiratory-related diseases by age 6 years, including asthma, recurrent wheeze, respiratory infections, and eczema.</p><p><strong>Methods: </strong>We applied weighted gene correlation network analysis to derive modules of highly correlated proteins during early life immune development using plasma samples collected from children at age 1 year (n = 294) in the Vitamin D Antenatal Asthma Reduction Trial. Using regression analysis, we evaluated relationships between protein modules at age 1 and respiratory-related diseases by age 6. We integrated protein modules with additional omics and social, demographic, and environmental data for further characterization.</p><p><strong>Results: </strong>Our analysis identified 4 protein modules at age 1 year associated with incidence of childhood asthma and/or recurrent wheeze (adjusted Ps = .02 to .03), respiratory infections (adjusted Ps = 6.3 × 10^-9 to 2.9 × 10^-6), and eczema (adjusted P = .01) by age 6 years; associations between modules and clinical outcomes were temporally sensitive and were not recapitulated using protein profiles at age 6 years. Age 1 modules were associated with environmental factors (adjusted Ps = 2.8 × 10^-10 to .03) and alterations in metabolomic pathways (adjusted Ps = 2.8 × 10^-6 to .04). No genome-wide single nucleotide polymorphisms were identified for any protein module.</p><p><strong>Conclusion: </strong>These findings suggested that protein profiles at age 1 year predicted development of respiratory-related diseases by age 6. Applying network approaches to study protein profiles may represent a new strategy to identify children susceptible to respiratory-related diseases in the first year of life.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tezepelumab inhibits highly functional truncated thymic stromal lymphopoietin in chronic rhinosinusitis.","authors":"Aiko Oka, Aiko I Klingler, Masanori Kidoguchi, Julie A Poposki, Lydia A Suh, Junqin Bai, Whitney W Stevens, Anju T Peters, Leslie C Grammer, Kevin C Welch, Stephanie S Smith, David B Conley, Robert P Schleimer, Robert C Kern, Bruce K Tan, Shigeharu Fujieda, Mitsuhiro Okano, Atsushi Kato","doi":"10.1016/j.jaci.2025.02.031","DOIUrl":"10.1016/j.jaci.2025.02.031","url":null,"abstract":"<p><strong>Background: </strong>Thymic stromal lymphopoietin (TSLP) and its functional cleavage products are elevated in nasal polyps (NPs) and play important roles in type 2 (T2) inflammation in chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) by activating myeloid dendritic cells (mDCs) and group 2 innate lymphoid cells (ILC2s). However, whether tezepelumab, a human mAb against TSLP, inhibits functional cleaved TSLP and also the role of TSLP in CRS without nasal polyps (CRSsNP) have not yet been studied.</p><p><strong>Objective: </strong>We sought to investigate the effects of tezepelumab on cleaved TSLP in CRS.</p><p><strong>Methods: </strong>The mRNA expression levels for TSLP and T2 markers in ethmoid tissues (ETs) from 31 controls and 118 patients with CRSsNP and in NPs from 53 patients with CRSwNP were measured by quantitative RT-PCR. Cleaved TSLP was prepared from full-length recombinant TSLP by incubation with tissue extracts of NPs and CRSsNP ETs. The effects of tezepelumab on cleaved TSLP-induced inflammation were evaluated using PBMCs by monitoring the production of chemokines (CCL17 and CCL22 for mDCs) and cytokines (IL-5 and IL-13 for ILC2s).</p><p><strong>Results: </strong>The mRNA expression level of TSLP was elevated not only in NPs but also in ETs from T2 CRSsNP compared with non-T2 CRSsNP and controls, and was positively correlated with T2 markers in CRSsNP (P < .001). CRSsNP ET also truncated and created highly active TSLP products. The activation of mDCs and ILC2s by full-length TSLP and cleaved TSLP created by ET and NP extracts was dose-dependently inhibited by tezepelumab.</p><p><strong>Conclusions: </strong>TSLP plays a role in T2 inflammation in CRSsNP and CRSwNP. Treatment with tezepelumab may benefit patients with T2 CRS by inhibiting active forms of TSLP.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First description of familial hypertryptasemia.","authors":"Ignacio Dávila, Laura Hernández-Hernández, Felix Lorente-Toledano, Catalina Sanz, María Isidoro-García","doi":"10.1016/j.jaci.2025.01.041","DOIUrl":"https://doi.org/10.1016/j.jaci.2025.01.041","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reply.","authors":"Harvinder Singh Gill","doi":"10.1016/j.jaci.2025.01.039","DOIUrl":"https://doi.org/10.1016/j.jaci.2025.01.039","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}