Beyond Altitude Sickness: How Low Oxygen Can Rewire Your Immune System
Low-oxygen exposure at high altitude reprograms immune cells, weakening bacterial defences for months after descent.
In the thin air above 3000m, climbers battle fatigue, cold and altitude sickness, but what if the damage outlasts the expedition?
A team at the University of Edinburgh has shown that even a brief spell of low oxygen can reprogram key immune cells at the bone-marrow level. Their work suggests that hypoxia leaves a “memory” in the immune system, weakening bacterial defense for months after descent.
Mountaineering, hypoxia and the immune knowledge gap
High-altitude mountaineering places individuals in an environment of reduced oxygen availability and increased physical stress, raising questions about how the immune system copes.
At elevations where oxygen levels drop significantly, climbers experience headaches, decreased performance and altitude sickness, yet less is known about the longer-term effects on immune defense. Some work has shown alterations in immune cell numbers during short-term hypoxia: for example, breathing hypoxic gas equivalent to ~4000m led to a rise in neutrophil counts and a drop in lymphocytes. However, whether such exposures leave a lasting impact on immune cells once climbers return to sea level remains unclear. For people who repeatedly ascend to altitude, such as mountaineers, guides or workers, this gap could represent a hidden health risk.
The new study from the University of Edinburgh set out to determine whether low-oxygen exposure can leave a durable imprint on one of the body’s front-line immune cells: the neutrophil.
“Neutrophils are key first responder cells to infection. Without them, people are unable to defend themselves against bacteria,” corresponding author Dr. Sarah Walmsley, professor and chair of respiratory medicine at the University of Edinburgh, told Technology Networks.
The team aimed to find out if hypoxia leaves a “memory effect” that persists beyond the exposure itself.
How hypoxia reprograms neutrophils
Walmsley and colleagues analyzed neutrophils from two groups: survivors of acute respiratory distress syndrome (ARDS) (a severe low-oxygen illness) and healthy volunteers who had been exposed to high-altitude hypoxia. They looked at mature circulating neutrophils in peripheral blood and bone-marrow precursor cells – the progenitors that give rise to new neutrophils.
“In individuals who are exposed to low oxygen levels either during critical illness (ARDS) or altitude, the bone marrow makes defective neutrophils that are less able to fight infection even once the oxygen levels are restored,” said Walmsley.
Hypoxia triggered a molecular process called histone clipping in neutrophils and in their progenitors. Histones are proteins that help package DNA and control which genes are active. Clipping removes a chemical tag that normally “switches on” genes involved in fighting bacteria.
As a result, neutrophils show persistent changes in gene expression and behavior, essentially becoming less effective at mounting antimicrobial defenses.
The same epigenetic modifications were also seen in bone-marrow progenitor cells – meaning that new neutrophils generated after recovery may already carry the “memory” of hypoxia.
In altitude volunteers, neutrophils isolated months later were slower to engulf bacteria and released fewer infection-fighting enzymes.
“These immune responses persist for at least six to nine months after return to normal oxygen levels,” Walmsley added.
“Changes in bone marrow progenitor cells provide the mechanism by which this altered behavior continues long after the exposure has been removed,” she said.
In animal models, Bacillus Calmette-Guérin (BCG) vaccination partially reversed neutrophil defects.
Mountaineering and immune risk
The study offers the first evidence that hypoxia can reprogram immune defenses for the long term. Climbing at elevation may carry a hidden immune cost beyond the immediate physical risks.
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“For people who are otherwise healthy, a defect in neutrophil responses alone may not be sufficient to increase their risk of infection, as the body has other mechanisms of defense that can compensate. However, if exposed to an infection, neutrophils are not as effective at killing bacteria after one week of altitude exposure,” said Walmsley.
“Our work would suggest that upon return from altitude, their immune resilience is diminished for many months,” she said. “Our neutrophil behaviors are shaped by past exposures, and we are currently working to understand whether this effect is additive.”
However, the study has limitations: it is laboratory-based with relatively small volunteer groups and findings still need real-world validation in large cohorts of altitude-exposed individuals. It is not yet known exactly how long the immune vulnerability lasts or how strong it is in healthy high-altitude climbers without severe illness.
The team is also pursuing the question of reversibility: “In our work, when we use an animal model, we see partial recovery with BCG vaccination, suggesting that some of these damaging responses can be reversed. This opens exciting new avenues to treat dysfunctional neutrophil inflammation and improve infection responses,” said Walmsley.
Future work is needed to understand whether staged ascents or tailored acclimatization regimes minimize immune reprogramming.
For mountaineers, the risk lies not only in the mountains, but potentially in the months that follow their descent.
Reference: Sanchez-Garcia MA, Sadiku P, Ortmann BM, et al. Hypoxia induces histone clipping and H3K4me3 loss in neutrophil progenitors resulting in long-term impairment of neutrophil immunity. Nat Immunol. 2025. doi: 10.1038/s41590-025-02301-9
About the interviewee:
Dr. Sarah Walmsley is a professor of respiratory medicine at the University of Edinburgh, an honorary consultant physician at NHS Lothian and dean of research and a director of the Edinburgh Clinical Academic Training Scheme. Walmsley undertook her medical training at the University of Edinburgh graduating in 1997, and an MRC training fellowship at the University of Cambridge with award of her PhD in 2004.
Her specialist training in Respiratory Medicine was in Sheffield, where she also held a Wellcome Intermediate Fellowship, prior to her move to Edinburgh as a Wellcome Senior Clinical Fellow. During this time, Walmsley had two periods of maternity leave. She is currently based in the Centre for Inflammation Research in the Institute for Regeneration and Repair in Edinburgh. Her work is focused on understanding how local oxygen and nutrient availability in the inflamed environment can reprogram neutrophil behaviour in both acute and chronic inflammatory lung disease states.
