Innate Immune Phenotypes During Acute High-Altitude Exposure.

Vargas, Abel, Veronica Penuelas, Karapet G Mkrtchyan, Kathy Pham, Shyleen Frost, Esteban A Moya, James J Yu, Tatum S Simonson, and Erica C Heinrich. Innate immune phenotypes during acute high-altitude exposure. High Alt Med Biol. 00:00-00, 2025. Introduction: High altitude is a physiologically stressful environment due to limited oxygen availability. Decades of study reveal the complex plasticity in many physiological systems that manifests at high altitude to maintain oxygen delivery. However, there are gaps in our knowledge regarding how high-altitude exposure influences immune function. Since tissue and cellular hypoxia occur during injury and infection, we hypothesized that sustained hypoxemia during high-altitude travel may impact inflammatory and immune phenotypes due to crosstalk between hypoxia and inflammatory response pathways. Methods: We recruited 17 healthy participants and examined their immune phenotypes at sea level and during 3 days at 3,800 m elevation. Specific attention was paid to neutrophil phenotypes because changes in these cells have not been reported at high altitude. Results: We found several impacts of high altitude on immune cell populations, including shifts in monocytes from classical to intermediate (p = 0.004 after 1 night at high altitude [HA1], and p < 0.001 after 2 nights at high altitude [HA2]) and nonclassical subsets (p = 0.013 on HA2), and increases in total B cells (p = 0.001 on HA2, p = 0.004 [HA3]). An effect of altitude was found for neutrophil CD15 expression (p < 0.001), with a trend toward increased expression over time at high altitude. Higher Acute Mountain Sickness (AMS) scores on the second day at high altitude were associated with more pronounced shifts to nonclassical monocyte populations (R² = 0.79, p = 0.001). These data indicate that acute high-altitude travel results in a pro-inflammatory immune response, which may contribute to AMS. This response appears to blunt with acclimatization, although elevation in B cells remain by HA3.