HLA-DPA1 and HLA-DPB1 expression is downregulated in pediatric asthma with high diagnostic value

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. 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. In vitro IL-13 stimulation of bronchial epithelial cells and patient peripheral blood mononuclear cell samples were used for experimental validation. Single-cell RNA-seq data (GSE254127) were analyzed for cell typing, macrophage subclustering, pseudotime trajectory, and cell−cell communication. 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. 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.