Immunoprofiling Reveals Disease-Associated Alterations of Eosinophils in Acute Mountain Sickness: A Cross-Sectional and Longitudinal Cohort Study

Abstract

Background: High-altitude exposure disrupts biological homeostasis, particularly affecting lowlanders ascending to high altitudes who frequently develop acute mountain sickness (AMS), the most common altitude-related illness. Harsh environmental conditions are thought to impair adaptive mechanisms, potentially weakening immune functions, increasing susceptibility to infections, and elevating cancer risks among lowland populations. Given these associations between high-altitude environments and immune function, this study characterized the overall changes in the immune cell landscape during prolonged high-altitude exposure and AMS-associated immune signatures.

Methods: This was a cross-sectional and longitudinal study involving 205 lowlanders assessed at sea level, as well as following acute (24 hours) and chronic (90 days) high-altitude exposure. A longitudinal analysis using mixed models was conducted to evaluate changes in immunophenotypes across three time points. High-Altitude Immune Score (HAIS) was developed to quantify immune status, derived from the non-metric multidimensional scaling (NMDS) matrix through principal curve analysis. Participants were classified into subgroups based on their Lake Louise Scores (LLS), a validated scoring system for AMS assessment. We investigated differences in immunophenotypes across subgroups. Additionally, network-based analyses were conducted to identify potential biomarkers for classifying AMS severity.

Findings: High-altitude exposure induces systemic changes in both innate and adaptive immune compartments.Longitudinal assessment of immune status by the HAIS uncovers a immune trajectory characterized by changes in eosinophils (rho = -0.68, padj = 3.19e-93) and natural killer cells (rho = 0.50, padj = 6.51e-48). These changes captured by the HAIS correlate with the decreased peripheral capillary oxygen saturation (SpO2) levels (rho = -0.24, p = 8.36e-09) under high-altitude exposure demonstrating the hypoxia-related nature of this immune trajectory. Furthermore, AMS group (n = 88) unveiled a significant decrease in frequencies (padj = 0.000378) and eosinophil counts (padj = 0.000063) from baseline to acute phase and a increase from acute to chronic phase, along with altered correlations in immune structure. Mediation analysis revealed a potential bidirectional mediation effect between the frequency changes in eosinophils and AMS (eosinophils → AMS: proportion = 11%, p = 0.032; AMS → eosinophils: proportion = 14%, p = 0.028). Additionally, network-based analysis identified two immunophenotypes as biomarkers for classifying AMS severity.

Interpretation: These findings highlight the pivotal role of eosinophils in the immune response to high-altitude exposure and the development of AMS. Further investigations into the mechanisms underlying the observed eosinophil dynamics and their functional implications could provide valuable insights into potential therapeutic targets for mitigating altitude illnesses.

Funding: This research has been supported by the National Key R&D Program of China (2023YFA1801200), National Natural Science Foundation of China (32288101, U23A20475, 32200536), Shanghai Municipal Science and Technology Major Project (2023SHZDZX02, 2017SHZDZX01), CAMS Innovation Fund for Medical Science (2019-I2M-5-066) and the 111 Project (B13016).

Declaration of Interest: All authors declare no competing interests.

Ethical Approval: The study was approved by the Human Ethics Committee of Fudan University with approval numbers: FE22228I. All animal procedures were approved by the Institutional Ethics Committee of Fudan University, China. The Institutional Ethics Committee of Fudan University is authorized to provide animal ethics approval for the research conducted in our submitted manuscript.

Keywords: High-Altitude, Acute Mountain Sickness, Immunophenotype, Eosinophils, Immune Structure