{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T07:03:41Z","timestamp":1789542221867,"version":"build-2803163510"},"reference-count":44,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pediatric Allergy Immunology"],"published-print":{"date-parts":[[2026,8]]},"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n Childhood asthma and wheezing disorders are heterogeneous conditions that may be reflected by distinct immune response patterns. In this study, we investigated whether CD3\/CD28\u2010stimulated cytokine responses differ between children with asthma, preschool wheeze, and healthy controls.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n Baseline samples from 511 children in the All Age Asthma cohort (ALLIANCE; 196 children with asthma, 181 with preschool wheeze, and 134 healthy controls) were analyzed. Whole blood was stimulated with anti\u2010CD3\/CD28 antibodies for 48\u2009h, and 37 cytokines were quantified using multiplex immunoassays. Cytokine co\u2010variation patterns were assessed using principal component analysis (PCA). Co\u2010regulated cytokine modules were identified using CytoMod, and associations with clinical characteristics were examined using linear and logistic regression models.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Two cytokines, sCD30 and sCD163, showed significant age\u2010related decreases (\n \u03b2<\/jats:italic>\n \u2009=\u2009\u2212.07 (95% CI \u22120.09 to \u22120.06),\n p<\/jats:italic>\n adj\u2009=\u20091.2e\u201014; and\n \u03b2<\/jats:italic>\n \u2009=\u2009\u2212.03 (95% CI \u22120.04 to \u22120.01),\n p<\/jats:italic>\n adj\u2009=\u2009.018, respectively). After correction for multiple testing, no individual cytokine differed significantly between children with asthma, preschool wheeze, or healthy controls. PCA demonstrated highly conserved cytokine co\u2010variation patterns across groups (Spearman's rho >.9 for the first principal component loadings). Modular analysis identified six distinct co\u2010regulatory modules after adjustment for background cytokine levels. Associations between module expression and clinical characteristics were generally modest. Module 1, comprising cytokines associated with tissue remodeling and IL\u20106 signaling, was inversely associated with asthma in children aged \u22656\u2009years (OR\u2009=\u20090.63 (95% CI 0.46\u20130.85),\n p<\/jats:italic>\n adj\u2009=\u2009.017). However, this association attenuated in age\u2010matched sensitivity analyses (OR\u2009=\u20090.72 (95% CI 0.51\u20130.99),\n p<\/jats:italic>\n adj\u2009=\u2009.281), suggesting residual age\u2010related confounding.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n CD3\/CD28\u2010stimulated cytokine responses show highly conserved T\u2010cell activation networks across pediatric asthma, preschool wheeze, and health, with limited ability to distinguish between clinical groups at the single\u2010cytokine level. Nevertheless, modular network analyses identify coordinated immune patterns associated with clinical features, highlighting the potential value of immune profiling in refining biological phenotyping and advancing the understanding of immune heterogeneity in pediatric airway disease.<\/jats:p>\n \n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/pai.70455","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T06:08:36Z","timestamp":1787033316000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Whole\u2010blood\n CD3<\/scp>\n \/\n CD28<\/scp>\n \u2010stimulated cytokine responses in children with preschool wheeze, asthma, and healthy controls"],"prefix":"10.1111","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7188-5227","authenticated-orcid":false,"given":"Lennart","family":"Riemann","sequence":"first","affiliation":[{"name":"Department of Pediatric Pneumology, Allergology, and Neonatology Hannover Medical School Hannover Germany"},{"name":"Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH) German Center for Lung Research (DZL) Hannover Germany"},{"name":"Cluster of Excellence RESIST (EXC 2155) Hannover Medical School Hannover Germany"},{"name":"Institute of Immunology, Hannover Medical School Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8084-104X","authenticated-orcid":false,"given":"Ruth","family":"Grychtol","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pneumology, Allergology, and Neonatology Hannover Medical School Hannover Germany"},{"name":"Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH) German Center for Lung Research (DZL) Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pneumology, Allergology, and Neonatology Hannover Medical School Hannover Germany"},{"name":"Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH) German Center for Lung Research (DZL) Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"DeLuca","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pneumology, Allergology, and Neonatology Hannover Medical School Hannover Germany"},{"name":"Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH) German Center for Lung Research (DZL) Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1652-8873","authenticated-orcid":false,"given":"Bianca","family":"Schaub","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Allergy Dr. von Hauner Children's Hospital, LMU University Hospital, Ludwig\u2010Maximilians\u2010University (LMU) Munich Germany"},{"name":"German Center for Lung Research (DZL), Comprehensive Pneumology Center (CPC\u2010M), LMU Munich Germany"},{"name":"German Center for Child and Adolescent Health\u2010DZKJ, LMU Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Maison","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Allergy Dr. von Hauner Children's Hospital, LMU University Hospital, Ludwig\u2010Maximilians\u2010University (LMU) Munich Germany"},{"name":"German Center for Lung Research (DZL), Comprehensive Pneumology Center (CPC\u2010M), LMU Munich Germany"},{"name":"Institute of Asthma and Allergy Prevention (IAP), Helmholtz Munich \u2013 German Research Center for Environmental Health (GmbH) Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5342-979X","authenticated-orcid":false,"given":"Markus","family":"Weckmann","sequence":"additional","affiliation":[{"name":"German Center for Lung Research (DZL), Airway Research Center North (ARCN) Borstel Germany"},{"name":"Department of Pediatric Pneumology & Allergology University Hospital Schleswig\u2010Holstein (UKSH) L\u00fcbeck Germany"},{"name":"Division of Epigenetics of Chronic Lung Diseases, Priority Area Chronic Lung Diseases Research Center Borstel \u2013 Leibniz Lung Center Borstel Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Folke","family":"Brinkmann","sequence":"additional","affiliation":[{"name":"German Center for Lung Research (DZL), Airway Research Center North (ARCN) Borstel 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Center for Lung Research (DZL), Airway Research Center North (ARCN) Borstel Germany"},{"name":"Department of Pediatric Respiratory Medicine, Inselspital University Children's Hospital of Bern, University of Bern Bern Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8893-4515","authenticated-orcid":false,"given":"Erika","family":"von Mutius","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Allergy Dr. von Hauner Children's Hospital, LMU University Hospital, Ludwig\u2010Maximilians\u2010University (LMU) Munich Germany"},{"name":"German Center for Lung Research (DZL), Comprehensive Pneumology Center (CPC\u2010M), LMU Munich Germany"},{"name":"Institute of Asthma and Allergy Prevention (IAP), Helmholtz Munich \u2013 German Research Center for Environmental Health (GmbH) Munich Germany"},{"name":"Member of the German Centre for Lung Research (DZL) Giessen 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