Hypoxia Rewires Immunity Months After High-Altitude Publicity

In the skinny air above 3000m, climbers battle fatigue, chilly and altitude illness, however what if the harm outlasts the expedition?

A workforce on the University of Edinburgh has proven that even a short spell of low oxygen can reprogram key immune cells on the bone-marrow stage. Their work means that hypoxia leaves a “memory” within the immune system, weakening bacterial protection for months after descent.

Mountaineering, hypoxia and the immune information hole

High-altitude mountaineering locations people in an surroundings of diminished oxygen availability and elevated bodily stress, elevating questions on how the immune system copes.

At elevations the place oxygen ranges drop considerably, climbers expertise headaches, decreased performance and altitude sickness, but much less is understood concerning the longer-term results on immune protection. Some work has proven alterations in immune cell numbers throughout short-term hypoxia: for instance, respiration hypoxic gasoline equal to ~4000m led to a rise in neutrophil counts and a drop in lymphocytes. However, whether or not such exposures go away a long-lasting influence on immune cells as soon as climbers return to sea stage stays unclear. For individuals who repeatedly ascend to altitude, corresponding to mountaineers, guides or employees, this hole may characterize a hidden well being threat.

The new examine from the University of Edinburgh got down to decide whether or not low-oxygen publicity can go away a sturdy imprint on one of many physique’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 writer Dr. Sarah Walmsley, professor and chair of respiratory drugs on the University of Edinburgh, instructed Technology Networks.

The workforce aimed to seek out out if hypoxia leaves a “memory effect” that persists past the publicity itself.

How hypoxia reprograms neutrophils

Walmsley and colleagues analyzed neutrophils from two teams: survivors of acute respiratory misery syndrome (ARDS) (a extreme low-oxygen sickness) and wholesome volunteers who had been uncovered to high-altitude hypoxia. They checked out 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,” stated Walmsley.

Hypoxia triggered a molecular course of known as histone clipping in neutrophils and of their progenitors. Histones are proteins that assist package deal DNA and management which genes are energetic. Clipping removes a chemical tag that usually “switches on” genes concerned in preventing micro organism.

As a end result, neutrophils present persistent adjustments in gene expression and habits, basically turning into much less efficient at mounting antimicrobial defenses.

The similar epigenetic modifications had been additionally seen in bone-marrow progenitor cells – which means that new neutrophils generated after restoration could already carry the “memory” of hypoxia.

In altitude volunteers, neutrophils remoted months later had been slower to engulf micro organism and launched 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 stated.

In animal fashions, Bacillus Calmette-Guérin (BCG) vaccination partially reversed neutrophil defects.

Mountaineering and immune threat

The examine gives the primary proof that hypoxia can reprogram immune defenses for the long run. Climbing at elevation could carry a hidden immune value past the quick bodily dangers.

“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,” stated Walmsley.

“Our work would suggest that upon return from altitude, their immune resilience is diminished for many months,” she stated. “Our neutrophil behaviors are shaped by past exposures, and we are currently working to understand whether this effect is additive.”

However, the examine has limitations: it’s laboratory-based with comparatively small volunteer teams and findings nonetheless want real-world validation in massive cohorts of altitude-exposed people. It isn’t but recognized precisely how lengthy the immune vulnerability lasts or how sturdy it’s in wholesome high-altitude climbers with out extreme sickness.

The workforce can also be pursuing the query 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,” stated Walmsley.

Future work is required to know whether or not staged ascents or tailor-made acclimatization regimes decrease immune reprogramming.

For mountaineers, the chance lies not solely within the mountains, however probably within the months that comply with their descent.

Reference: Sanchez-Garcia MA, Sadiku P, Ortmann BM, et al. Hypoxia induces histone clipping and H3K4me3 loss in neutrophil progenitors leading to 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 drugs on the University of Edinburgh, an honorary guide doctor at NHS Lothian and dean of analysis and a director of the Edinburgh Clinical Academic Training Scheme. Walmsley undertook her medical coaching on the University of Edinburgh graduating in 1997, and an MRC coaching fellowship on the University of Cambridge with award of her PhD in 2004.  

Her specialist coaching in Respiratory Medicine was in Sheffield, the place she additionally held a Wellcome Intermediate Fellowship, previous to her transfer to Edinburgh as a Wellcome Senior Clinical Fellow.  During this time, Walmsley had two intervals of maternity go away.  She is presently primarily based in the Centre for Inflammation Research within the Institute for Regeneration and Repair in Edinburgh.  Her work is targeted on understanding how native oxygen and nutrient availability within the infected surroundings can reprogram neutrophil behaviour in each acute and persistent inflammatory lung illness states.