ArticleFrontiers in immunology2026
Integrative multi-omics reveals that downregulation of HLA-DPA1/DPB1 drives macrophage immune-metabolic dysregulation in pediatric asthma.
Article in Frontiers in immunology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Pediatric asthma (PA) is a prevalent chronic respiratory disease. Emerging evidence suggests that dysregulated macrophage heterogeneity and immune-metabolic crosstalk contribute to disease pathogenesis, yet specific molecular nodes linking innate immune dysfunction to PA remain unidentified. This study aimed to identify and characterize immune checkpoint-related candidate key genes in PA. Methods: Bulk RNA-sequencing data from airway epithelium of PA patients (training set GSE152004) were analyzed for differential expression, followed by intersection with immune checkpoint-related genes. Four machine learning algorithms (SVM-RFE, Boruta, LASSO, and XGBoost) were applied to screen candidate key genes, which were further validated in an independent dataset (GSE65204). A nomogram was constructed to evaluate diagnostic value. Functional enrichment, immune infiltration, and regulatory network analyses were performed. Results: HLA-DPA1 and HLA-DPB1 were identified as candidate key genes by consensus of all four algorithms. Both were significantly downregulated in PA and showed high diagnostic value (nomogram). Downregulation of HLA-DPA1/DPB1 correlated with attenuated antigen presentation and enhanced metabolic dysfunction. IL-13-treated bronchial epithelial cells and patient samples confirmed reduced mRNA and protein expression. Exploratory single-cell analysis revealed that HLA-DPA1/DPB1 were enriched in macrophages, specifically a Macro2 subset characterized by metabolic and stress-related functions-highlighting macrophage heterogeneity in innate immune regulation. Pseudotime trajectory suggested a shift from immune-activated toward metabolically stressed states. Cell-cell communication analysis identified epithelial cells as primary signal senders, with macrophages and dendritic cells as central receivers, and the MIF signaling axis as a key intercellular bridge. Conclusion: This multi-level integrated transcriptomic analysis identified HLA-DPA1 and HLA-DPB1 as candidate key genes in childhood asthma, and reveals their potential role in immune-metabolic dysregulation centered on macrophage functional heterogeneity. Our data are consistent with a potential role for these genes in immune-metabolic dysregulation centered on macrophage functional heterogeneity, although direct functional validation is required to establish causality. These findings provide new insights into innate immune circuits in childhood asthma and lay a foundation for potential molecular targets for future precision therapeutic strategies.
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