Distinct immune cell profiles associated with high-altitude hypoxia and severe acute mountain sickness

High-altitude hypobaric hypoxia is associated with immune dysregulation, potentially linked to the progression of altitude illnesses such as acute mountain sickness (AMS) in unacclimatized individuals. However, the immune signatures associated with AMS severity remain poorly understood. This study investigated immune dynamics under high-altitude exposure and identified immune signatures associated with AMS severity. In this longitudinal study, 205 lowlanders travelled from Chongqing (∼200 m) to Xizang (∼3600 m) by air. Immune status was comprehensively assessed using multi-parametric flow cytometry, alongside monitoring of clinical features at baseline, 1 day after arrival (acute phase) and after 90 days at high altitude (chronic phase). Results demonstrated that high-altitude exposure induced systemic, sustained immune cell perturbations. Using the high-altitude immune score (HI score), derived from immune cell composition, we revealed immune status was associated with hypoxic conditions and changed concurrently with haematopoietic and liver function. Cross-sectional analysis revealed immune cell alterations associated with AMS severity, including reduced frequencies of eosinophils, basophils, plasmacytoid dendritic cells and CD4⁺ T cells, which was more evident in severe AMS patients. Among these immune alterations, the reduction in eosinophils mediates the relationship between hypoxia and AMS severity. In vitro experiments further suggested hypoxia-induced eosinophil apoptosis may account for the eosinophil reduction. Through network analysis, we identified two immune features as potential biomarkers for predicting and classifying severe AMS cases. This study provides detailed immune dynamics under high-altitude hypoxia exposure and unveils key immune features associated with AMS severity, offering valuable insights for disease prediction and stratification. KEY POINTS: High-altitude exposure induces systemic perturbations in the immune system. Immune status correlates with haematopoietic and liver function under hypoxia. Immune cell alterations are associated with the severity of acute mountain sickness (AMS). The reduction in eosinophils is likely driven by hypoxia-induced apoptosis. Immune biomarkers can predict and diagnose severe AMS cases.