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Publications

Journal Article Ppublish

PubMed: 42608997 DOI: 10.1111/pai.70455

Whole-blood CD3/CD28-stimulated cytokine responses in children with preschool wheeze, asthma, and healthy controls.

Pediatr Allergy Immunol 37(8):e70455

Authors: Lennart Riemann, Ruth Grychtol, Bin Liu, David DeLuca, Bianca Schaub, Nicole Maison, Markus Weckmann, Folke Brinkmann, Thomas Bahmer, Klaus F Rabe, Matthias V Kopp, Erika von Mutius, Anna-Maria Dittrich, Chrysanthi Skevaki, Gesine Hansen, Christine Happle

Affiliations

  • Department of Pediatric Pneumology, Allergology, and Neonatology, Hannover Medical School, Hannover, Germany.
  • Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany.
  • Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.
  • Institute of Immunology, Hannover Medical School, Hannover, Germany.
  • Department of Pediatric Pneumology, Allergology, and Neonatology, Hannover Medical School, Hannover, Germany. Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany.
  • Department of Pulmonary and Allergy, Dr. von Hauner Children's Hospital, LMU University Hospital, Ludwig-Maximilians-University (LMU), Munich, Germany.
  • German Center for Lung Research (DZL), Comprehensive Pneumology Center (CPC-M), LMU, Munich, Germany.
  • German Center for Child and Adolescent Health-DZKJ, LMU, Munich, Germany.
  • Institute of Asthma and Allergy Prevention (IAP), Helmholtz Munich - German Research Center for Environmental Health (GmbH), Munich, Germany.
  • German Center for Lung Research (DZL), Airway Research Center North (ARCN), Borstel, Germany.
  • Department of Pediatric Pneumology & Allergology, University Hospital Schleswig-Holstein (UKSH), Lübeck, Germany.
  • Division of Epigenetics of Chronic Lung Diseases, Priority Area Chronic Lung Diseases, Research Center Borstel - Leibniz Lung Center, Borstel, Germany.
  • Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany.
  • Department of Medicine, Christian Albrechts University, Kiel, Germany.
  • Department of Pediatric Respiratory Medicine, Inselspital, University Children's Hospital of Bern, University of Bern, Bern, Switzerland.
  • Member of the German Centre for Lung Research (DZL), Giessen, Germany.
  • Institute of Clinical Chemistry and Laboratory Medicine, Johannes Gutenberg University Mainz, Mainz, Germany.
  • Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps-University Marburg, University of Giessen Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Marburg, Germany.
  • German Center for Lung Research - Deutsches Zentrum für Lungenforschung (DZL), The Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany.
  • Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
  • Center for Research and Education in Public Health (CEPHRE), Academy of Athens, Athens, Greece.

Abstract

BACKGROUND

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-stimulated cytokine responses differ between children with asthma, preschool wheeze, and healthy controls.

METHODS

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-CD3/CD28 antibodies for 48 h, and 37 cytokines were quantified using multiplex immunoassays. Cytokine co-variation patterns were assessed using principal component analysis (PCA). Co-regulated cytokine modules were identified using CytoMod, and associations with clinical characteristics were examined using linear and logistic regression models.

RESULTS

Two cytokines, sCD30 and sCD163, showed significant age-related decreases (β = -.07 (95% CI -0.09 to -0.06), padj = 1.2e-14; and β = -.03 (95% CI -0.04 to -0.01), padj = .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-variation patterns across groups (Spearman's rho >.9 for the first principal component loadings). Modular analysis identified six distinct co-regulatory 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-6 signaling, was inversely associated with asthma in children aged ≥6 years (OR = 0.63 (95% CI 0.46-0.85), padj = .017). However, this association attenuated in age-matched sensitivity analyses (OR = 0.72 (95% CI 0.51-0.99), padj = .281), suggesting residual age-related confounding.

CONCLUSIONS

CD3/CD28-stimulated cytokine responses show highly conserved T-cell activation networks across pediatric asthma, preschool wheeze, and health, with limited ability to distinguish between clinical groups at the single-cytokine 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.

MeSH

Cytokines, Blood, Hypersensitivity, Immune System Diseases, Asthma, Child