Background Pediatric infectious mononucleosis (IM) is a systemic inflammatory syndrome typically triggered by primary Epstein–Barr virus (EBV) infection. The disease is characterized by a profound disruption of immune homeostasis, which can be characterized by the balance between pro-inflammatory Th17 cells and suppressive Treg cells. While hypoxia-inducible factor-1α (HIF-1α) is known to direct T-cell behavior in various inflammatory conditions, its specific role in the immunopathology of IM remains largely uncharacterized. This study aims to investigate the systemic expression of HIF-1α in pediatric IM and evaluate its correlation with the Th17/Treg homeostatic axis. Methods In this prospective case-control study, we enrolled pediatric patients with acute IM and healthy, age- and sex-frequency-matched controls. Peripheral blood CD4+ T-cell subsets (Th17: CD3+CD4+IL-17A+; Treg: CD3+CD4+CD25+CD127low) were quantified via multi-color flow cytometry. Systemic levels of HIF-1α, IL-17A, and TGF-β1 were determined by enzyme-linked immunosorbent assay (ELISA). The relationship between metabolic stabilization and immune phenotype was evaluated using Spearman correlation analysis. Results The final analysis included 40 IM patients and 37 healthy controls. Compared to the controls, IM patients exhibited a significant systemic accumulation of HIF-1α (p < 0.001) and IL-17A concentrations (p = 0.008), alongside a marked expansion of Th17 cells (p < 0.001) and a significant increase in the Th17/Treg ratio (p < 0.001). Conversely, the IM cohort experienced significantly depletions in Treg frequencies (p < 0.001) and TGF-β1 levels (p = 0.005). Correlation analysis revealed that serum HIF-1α was correlated significantly positively with Th17 frequency, the Th17/Treg ratio, and IL-17A levels and significantly negatively with Treg frequency and TGF-β1 levels. Conclusions Our findings reveal a significant systemic stabilization of HIF-1α in pediatric IM patients, which reflects an immunometabolic signature associated with the acute viral response. The significant correlation between HIF-1α and the shift in T-cell subsets suggests that HIF-1α may be seen as systemic sensor of disease severity in EBV infection. The results provide a theoretical foundation for targeting metabolic pathways to restore immune homeostasis in hyper-inflammatory viral diseases.

The HIF-1α–Th17/Treg axis in pediatric infectious mononucleosis: a clinical investigation of metabolic-immune dysregulation

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2026年6月25日

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Pengli Yang,
Huiping Ni,
Lingfang Du,
Meiling Wang,
Gaofeng Pang

摘要

Background

Pediatric infectious mononucleosis (IM) is a systemic inflammatory syndrome typically triggered by primary Epstein–Barr virus (EBV) infection. The disease is characterized by a profound disruption of immune homeostasis, which can be characterized by the balance between pro-inflammatory Th17 cells and suppressive Treg cells. While hypoxia-inducible factor-1α (HIF-1α) is known to direct T-cell behavior in various inflammatory conditions, its specific role in the immunopathology of IM remains largely uncharacterized. This study aims to investigate the systemic expression of HIF-1α in pediatric IM and evaluate its correlation with the Th17/Treg homeostatic axis.

Methods

In this prospective case-control study, we enrolled pediatric patients with acute IM and healthy, age- and sex-frequency-matched controls. Peripheral blood CD4⁺ T-cell subsets (Th17: CD3⁺CD4⁺IL-17A⁺; Treg: CD3⁺CD4⁺CD25⁺CD127^low) were quantified via multi-color flow cytometry. Systemic levels of HIF-1α, IL-17A, and TGF-β1 were determined by enzyme-linked immunosorbent assay (ELISA). The relationship between metabolic stabilization and immune phenotype was evaluated using Spearman correlation analysis.

Results

The final analysis included 40 IM patients and 37 healthy controls. Compared to the controls, IM patients exhibited a significant systemic accumulation of HIF-1α (p < 0.001) and IL-17A concentrations (p = 0.008), alongside a marked expansion of Th17 cells (p < 0.001) and a significant increase in the Th17/Treg ratio (p < 0.001). Conversely, the IM cohort experienced significantly depletions in Treg frequencies (p < 0.001) and TGF-β1 levels (p = 0.005). Correlation analysis revealed that serum HIF-1α was correlated significantly positively with Th17 frequency, the Th17/Treg ratio, and IL-17A levels and significantly negatively with Treg frequency and TGF-β1 levels.

Conclusions

Our findings reveal a significant systemic stabilization of HIF-1α in pediatric IM patients, which reflects an immunometabolic signature associated with the acute viral response. The significant correlation between HIF-1α and the shift in T-cell subsets suggests that HIF-1α may be seen as systemic sensor of disease severity in EBV infection. The results provide a theoretical foundation for targeting metabolic pathways to restore immune homeostasis in hyper-inflammatory viral diseases.