Journal of Allergy and Clinical Immunology最新文献

{"title":"The diagnostic pitfall of sIL-2R in hemophagocytic lymphohistiocytosis: A key marker lost in analytic translation.","authors":"Josia Fauser,Werner Klotz,Manuel Trebo,Andreas Pircher,Sieghart Sopper,Dominik Wolf,Günter Weiss,David Haschka","doi":"10.1016/j.jaci.2025.09.005","DOIUrl":"https://doi.org/10.1016/j.jaci.2025.09.005","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"45 1","pages":""},"PeriodicalIF":14.2,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215834","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":"Lifestyle-associated metabolite signatures and the risk of late-onset asthma.","authors":"Qinyu Chang,Lu Chen,Yiqun Zhu,Ben Liu,Xin Zhou,Huaying Liang,Fengyu Lin,Dianwu Li,Zhuanxing Zhu,Zhaojun Pan,Xiang Chen,Hong Liu,Dianjianyi Sun,Jun Lv,Liming Li,Pinhua Pan,Canqing Yu,Yan Zhang, ","doi":"10.1016/j.jaci.2025.09.020","DOIUrl":"https://doi.org/10.1016/j.jaci.2025.09.020","url":null,"abstract":"BACKGROUNDUnhealthy lifestyle behaviors, leading to systemic metabolic disturbances, are significantly linked to the risk of late-onset asthma. However, the underlying metabolism-related mechanisms remain unclear.OBJECTIVEThis study aims to identify lifestyle-related metabolites and assess their predictive value for incident asthma.METHODSUsing NMR metabolomics data from the UK Biobank population (aged 40-69), plasma metabolites associated with healthy lifestyle scores were identified through multiple linear regression. Cox proportional hazards regression was used to further screen metabolites linked to late-onset asthma risk. Elastic net regularization selected critical metabolites for developing an asthma risk prediction model, incorporating conventional clinical characteristics and lifestyle factors. A metabolic score based on non-zero regularization coefficients was derived, and its association with asthma risk was evaluated through survival analysis. Models and metabolic score performance were validated in unused internal UK Biobank participants and an external China Kadoorie Biobank cohort.RESULTSAmong 198,607 participants (mean age 56.4 years), 159 plasma metabolites were significantly related to healthy lifestyle scores, 103 of which were associated with incident asthma risk. Nine metabolites were selected and incorporated into the asthma risk prediction model, significantly improving its predictive performance (Area under the curve: 0.812 vs. 0.758). Individuals with an unfavorable metabolic signature exhibited a 77.0% increased risk (hazard ratio [HR] 1.770, 95% confidence interval [CI] 1.634-1.918) of developing asthma compared to those with a favorable metabolic signature, with a stronger effect observed in females (HR 1.914, 95% CI 1.729-2.118). The results for the predictive model and metabolic score were confirmed in both internal and external validations.CONCLUSIONMultiple lifestyle-related metabolites are associated with late-onset asthma risk and can help stratify asthma risk, particularly among females.","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"27 1","pages":""},"PeriodicalIF":14.2,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229222","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":"Analysis of airway inflammation demonstrates a mechanism for T2-biologic failure in asthma","authors":"P. Jane McDowell PhD ,&nbsp;Adnan Azim PhD ,&nbsp;John Busby PhD ,&nbsp;Sarah Diver PhD ,&nbsp;Freda Yang MD ,&nbsp;Catherine Borg MSc ,&nbsp;Vanessa Brown PhD ,&nbsp;Rahul Shrimanker PhD ,&nbsp;Koirobi Haldar PhD ,&nbsp;Rekha Chaudhuri MD ,&nbsp;Christopher E. Brightling FMedSci ,&nbsp;Ian D. Pavord FMedSci ,&nbsp;Peter Howarth MD ,&nbsp;James D. Chalmers PhD ,&nbsp;Liam G. Heaney MD ,&nbsp;Medical Research Council UK Refractory Asthma Stratification Programme (RASP-UK Consortium)","doi":"10.1016/j.jaci.2025.05.031","DOIUrl":"10.1016/j.jaci.2025.05.031","url":null,"abstract":"<div><h3>Background</h3><div>Targeted type 2 (T2) biologics have transformed asthma care, but the clinical response to biologic therapy varies between patients.</div></div><div><h3>Objective</h3><div>We sought to assess airways inflammation in T2-high asthmatic patients treated with anti–IL-5 biologics to investigate whether differential mechanism of airway inflammation explains varied response to biologics.</div></div><div><h3>Methods</h3><div>Proteomic analysis (Olink, 1463 protein panel) and high-sensitivity cytokine analysis (ELISAs) were performed on induced sputum from T2-high severe asthmatic patients in the UK multicenter Mepolizumab EXacerbation study. Samples included were pre-mepolizumab (n = 28), stable on mepolizumab (n = 43), and at first exacerbation (n = 26).</div></div><div><h3>Results</h3><div>Clustering of sputum proteins while stable on mepolizumab identified 2 clusters. Cluster 1 had increased differentially expressed sputum proteins pre-mepolizumab, stable on mepolizumab, and at exacerbation. Patients in cluster 1 were younger at diagnosis, had a longer duration of asthma, lower FEV₁%, and higher 5-Question Asthma Control Questionnaire score on mepolizumab. Cluster 1 had increased expression of proinflammatory cytokines (IL-1β, IL-6, and soluble IL-6R), epithelial alarmins (thymic stromal lymphopoietin [TSLP] and IL-33), and neutrophil activation (myeloperoxidase [MPO], neutrophil elastase [NE], and neutrophil extracellular trap concentration [NET]). All patients were T2-high with no difference in fractional exhaled nitric oxide, eosinophil number, or activity (eosinophil-derived neurotoxin, EDN) across the 2 clusters.</div></div><div><h3>Conclusions</h3><div>In a cohort of T2-high severe asthmatic patients, a subgroup of patients with long duration of disease had worse clinical parameters, increased sputum proteins with increased markers of neutrophil activity, proinflammatory cytokines, and epithelial alarmins even when stable on mepolizumab. This suggests the presence of biology not treated by targeted T2 biologics, which may contribute to poorer outcomes on biologics and could be a treatable airways trait in severe asthma.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"156 4","pages":"Pages 911-922"},"PeriodicalIF":11.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533353","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":"Type 2 cytokines pleiotropically modulate sensory nerve architecture and neuroimmune interactions to mediate itch","authors":"Mithilesh Kumar Jha PhD ,&nbsp;Yingnan Han PhD ,&nbsp;Zhipeng Liu PhD ,&nbsp;Yannis Hara PhD ,&nbsp;Ingeborg M. Langohr PhD ,&nbsp;Caroline Morel PhD ,&nbsp;Colleen L. Maloney BS ,&nbsp;Peter Piepenhagen PhD ,&nbsp;Heming Xing PhD ,&nbsp;Corneliu A. Bodea PhD ,&nbsp;Dinesh S. Bangari PhD ,&nbsp;Hamid Mattoo PhD ,&nbsp;Alexandra Hicks PhD","doi":"10.1016/j.jaci.2025.05.011","DOIUrl":"10.1016/j.jaci.2025.05.011","url":null,"abstract":"<div><h3>Background</h3><div>Anti–type 2 cytokine therapies represent promising interventions for chronic itch; however, their precise mechanisms in restoring nerve architecture and mitigating inflammation and pruritus remain incompletely understood.</div></div><div><h3>Objectives</h3><div>This study aimed to elucidate the mechanistic roles of IL-4, IL-13, and IL-31 in the pathophysiology of itch associated with type 2 inflammatory skin diseases.</div></div><div><h3>Methods</h3><div>The effect of IL-4, IL-13, and/or IL-31 on neurite outgrowth and/or transcriptomic changes was analyzed in human and mouse dorsal root ganglion (DRG) neuronal cultures. Mouse ear pinnae were processed for histologic, transcriptomic, and proteomic analyses 4 days after intradermal injection of IL-4, IL-13, and/or IL-31. To evaluate functional correlations with neuronal responses, mice were subcutaneously challenged with IL-4, IL-13, and/or IL-31, and scratching behavior was monitored. Association between IL-4/IL-13–IL-4Rα axis and severity of atopic dermatitis was evaluated through correlative analyses of human DRG transcriptomic changes and atopic dermatitis transcriptomic datasets (GSE130588 and BioMaP-Consortium).</div></div><div><h3>Results</h3><div>IL-4 and IL-13 promote mouse and human DRG sensory neuron growth, with effects similar to or greater than IL-31. In mice, intradermal IL-4, IL-13, and IL-31 increased epidermal nerve growth; however, only IL-4 and IL-13 induced hyperplasia and immune cell recruitment. Multiomic analyses revealed that IL-4 and IL-13 have a broader impact on neuroimmune interactions than IL-31. In a murine DRG neuron–eosinophil coculture, IL-4Rα blockade reduced neurite growth. IL-13 and IL-31 elicited acute scratching, demonstrating their roles as direct pruritogens; IL-4 synergistically enhanced IL-13–induced itch, resulting in greater pruritic responses than IL-31. Additionally, a set of itch-associated genes upregulated by IL-4 and IL-13 and downregulated by dupilumab-mediated IL-4Rα blockade in human DRG neuronal cultures showed positive correlation with atopic dermatitis severity.</div></div><div><h3>Conclusions</h3><div>These findings establish the IL-4/IL-13–IL-4Rα axis as a key regulator of inflammatory skin nerve innervation, neuroimmune interactions, barrier integrity, and itch response, highlighting its mechanistic role in modulating sensory neuronal function and shaping the inflammatory microenvironment that drives itch pathophysiology.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"156 4","pages":"Pages 1066-1081.e12"},"PeriodicalIF":11.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144173847","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":"Small proline-rich protein 2A drives epithelial remodeling in eosinophilic chronic rhinosinusitis with nasal polyps via SAA2 upregulation","authors":"Shaobing Xie MD, PhD ,&nbsp;Sijie Jiang BS ,&nbsp;Xuan Yuan BS ,&nbsp;Liyuan Liu BS ,&nbsp;Maonan Wu BS ,&nbsp;Wenjing Gu MD, PhD ,&nbsp;Hua Zhang MD, PhD ,&nbsp;Zhihai Xie MD, PhD ,&nbsp;Weihong Jiang MD, PhD ,&nbsp;Peisong Gao MD, PhD","doi":"10.1016/j.jaci.2025.05.012","DOIUrl":"10.1016/j.jaci.2025.05.012","url":null,"abstract":"<div><h3>Background</h3><div><span><span>Eosinophilic </span>chronic rhinosinusitis with </span>nasal polyps<span> (eCRSwNP) is a severe subtype of chronic rhinosinusitis<span> characterized by eosinophilic inflammation, type 2 immune responses, and tissue remodeling in the sinonasal mucosa.</span></span></div></div><div><h3>Objective</h3><div>We sought to identify genes contributing to eCRSwNP pathogenesis and elucidate their roles in epithelial dysfunction and tissue remodeling.</div></div><div><h3>Methods</h3><div><span><span>Transcriptome sequencing was conducted on </span>nasal tissues from patients with eCRSwNP, noneosinophilic CRSwNP (neCRSwNP), and healthy controls and from a CRSwNP mouse model with small proline-rich protein 2A knockout (</span><em>Sprr2a</em>^{<em>−/−</em>}) mice. Epithelial-mesenchymal transition (EMT) was examined in the CRSwNP mouse model and air-liquid interface culture system with nasal epithelial cells.</div></div><div><h3>Results</h3><div><span>Transcriptomic analysis<span> revealed that SPRR2A expression was significantly elevated in eCRSwNP nasal tissues<span> compared with neCRSwNP and healthy controls. High SPRR2A expression correlated with increased eosinophil infiltration, epithelial thickness, and IL-13 levels. In the CRSwNP mouse model, </span></span></span><em>Sprr2a</em>^{<em>−/−</em>}<span> mice displayed reduced epithelial thickness, fewer nasal polyps, lower IL-4 and IL-13 levels, and attenuated EMT. </span><em>In vitro</em>, nasal epithelial cells from <em>Sprr2a</em>^{<em>−/−</em>} mice demonstrated reduced EMT markers and preserved barrier integrity. Further transcriptomic analysis identified serum amyloid A3 (Saa3) as a downstream mediator of SPRR2A. Saa3 expression was reduced in <em>Sprr2a</em>^{<em>−/−</em>}<span> mice, whereas serum amyloid A2 (SAA2 [human]) was upregulated in eCRSwNP compared with neCRSwNP and healthy controls and positively correlated with SPRR2A levels. In air-liquid interface cultures, Saa3 induced EMT and barrier dysfunction and increased IL-6, thymic stromal lymphopoietin, IL-33, and TGF-β1 production.</span></div></div><div><h3>Conclusions</h3><div>These findings suggest that SPRR2A promotes eosinophilic inflammation and tissue remodeling via SAA2, highlighting the SPRR2A-SAA2 axis as a potential therapeutic target in eCRSwNP.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"156 4","pages":"Pages 1038-1052.e5"},"PeriodicalIF":11.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187046","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":"Autoantibodies in patients with 22q11.2 deletion syndrome and psychosis","authors":"Samantha Y. Starkey MD ,&nbsp;Kelly Maurer BS ,&nbsp;Anne Bassett CM, MD, FRCPC ,&nbsp;Donna M. McDonald McGinn MS, CGC ,&nbsp;Kathleen E. Sullivan MD, PhD","doi":"10.1016/j.jaci.2025.07.013","DOIUrl":"10.1016/j.jaci.2025.07.013","url":null,"abstract":"<div><h3>Background</h3><div>The 22q11.2 deletion syndrome occurs in roughly 1 in 2000 live births. It is one of the most common chromosomal conditions worldwide. It has a frequency of psychosis in adulthood of 25%, making it the most common known etiology for psychosis. The mechanisms of disease for psychosis are poorly understood; however, there are data supporting a role for inflammation. Given the altered immune system in 22q11.2 deletion syndrome, this study examined autoantibodies associated with psychosis.</div></div><div><h3>Objective</h3><div>The underlying hypothesis that we tested was whether patients with psychosis have an immune landscape different from that of patients without psychosis. In this study, we tested whether increased autoantibody levels were seen in patients with psychosis.</div></div><div><h3>Methods</h3><div>We utilized the University of Texas Southwestern autoantibody array to measure levels of autoantibodies in patients and controls. The analyses were performed using a 2-tailed Student <em>t</em> test with Benjamini-Hochberg correction for false discovery rate.</div></div><div><h3>Results</h3><div>In general, both child and adult patients had lower levels of autoantibodies than the controls. The adult patients with psychosis, however, had significantly higher autoantibody levels than the adult patients without psychosis. Of the 10 patients with psychosis, 8 had levels of autoantibodies to single-stranded DNA that were more than 2 SDs higher than in the controls. This was not accompanied by clear clinical autoimmunity.</div></div><div><h3>Conclusion</h3><div>Patients with 22q11.2 deletion syndrome and psychosis appear to have immunologic characteristics different from those of patients who carry the deletion but do not have psychosis. Overall, autoantibody levels were significantly higher in patients with psychosis. This finding may define a high-risk group within the population with 22q11.2 deletion syndrome.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"156 4","pages":"Pages 1103-1110"},"PeriodicalIF":11.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144747841","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":"Neuroimmune interactions: TH2 cytokines reversibly drive neuronal architecture and peripheral sensitization in atopic skin to mediate itch","authors":"Laurent Misery MD, PhD ,&nbsp;Matthieu Talagas MD, PhD","doi":"10.1016/j.jaci.2025.08.003","DOIUrl":"10.1016/j.jaci.2025.08.003","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"156 4","pages":"Pages 909-910"},"PeriodicalIF":11.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955010","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":"News & Notes-AAAAI","authors":"","doi":"10.1016/S0091-6749(25)00907-8","DOIUrl":"10.1016/S0091-6749(25)00907-8","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"156 4","pages":"Pages A20-A21"},"PeriodicalIF":11.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204511","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":"Informed clinical decisions by outfoxing human FOXN1 variants","authors":"Christian A. Wysocki MD, PhD ,&nbsp;Nicolai S.C. van Oers PhD","doi":"10.1016/j.jaci.2025.05.025","DOIUrl":"10.1016/j.jaci.2025.05.025","url":null,"abstract":"<div><div>Thymic T-cell development is orchestrated by thymic epithelial cells. The master transcriptional regulator of these cells is forkhead box N1 (FOXN1), which controls their differentiation, expansion, and function. Biallelic founder mutations in <em>FOXN1</em><span><span> caused a nude/severe combined immunodeficiency phenotype due to congenital thymic aplasia and </span>alopecia universalis<span>. This established the critical role of FOXN1 in thymic epithelial cells and epithelial cells in the skin and nails. The emergence of newborn screening<span> for severe T-cell deficiency via the T-cell receptor excision circle assay, along with exome and genome sequencing, has led to dramatic increases in the number of </span></span></span><em>FOXN1</em> variants identified. The consequent impact of the <em>FOXN1</em> variants ranges from pathogenic to benign, yet most <em>FOXN1</em> mutations are listed as variants of unknown significance. Among monoallelic <em>FOXN1</em><span> variants are some that act as dominant negative, resulting in a transient T-cell lymphopenia. In this review, the clinical impacts of diverse </span><em>FOXN1</em> variants are categorized by mutation type and location. Knowing how these <em>FOXN1</em> mutations affect protein function informs clinical care as well as laboratory monitoring, prophylactic measures, and allogeneic thymic implant decisions. This review provides key functional insights into <em>FOXN1,</em> enabling better clinical care.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"156 4","pages":"Pages 845-853"},"PeriodicalIF":11.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247993","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":"The Editors’ Choice","authors":"","doi":"10.1016/j.jaci.2025.08.007","DOIUrl":"10.1016/j.jaci.2025.08.007","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"156 4","pages":"Pages 899-903"},"PeriodicalIF":11.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204513","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}