Integrated cytokine and immune cell profiling reveals that HAPE patients exhibit a pro-inflammatory, vascular injury signature with elevated inflammatory interleukins and myeloid/chemotactic factors, accompanied by expansion of classical monocytes, implicating a myeloid vascular program associated with HAPE.
Key Findings
Results
Healthy high-altitude sojourners displayed an anti-inflammatory immune profile marked by suppression of CXCR3 axis chemokines compared to low-altitude controls.
The anti-inflammatory profile was characterized by suppression of CXC chemokine receptor 3 (CXCR3) axis chemokines
This pattern was interpreted as representing adaptive acclimatization to hypobaric hypoxia
Peripheral blood was collected along with clinical details for all groups
Results
HAPE patients exhibited a distinct pro-inflammatory, vascular injury immune signature compared to both healthy high-altitude sojourners and low-altitude controls.
HAPE patients numbered 90 participants, the largest of the three study groups
The HAPE signature included elevated levels of inflammatory interleukins
Elevated myeloid and chemotactic factors were also observed in HAPE patients
The signature was characterized as a 'pro-inflammatory, vascular injury signature'
Plasma proteomic markers were quantified using a targeted panel
Results
Classical monocyte populations were expanded in HAPE patients, implicating a myeloid vascular program in the pathogenesis of HAPE.
Monocyte and dendritic cell subsets in peripheral blood mononuclear cells (PBMCs) were immunophenotyped by multicolor flow cytometry
Expansion was specifically observed in the classical monocyte subset
The authors interpret this as implicating 'a myeloid vascular program associated with HAPE'
Both monocyte and dendritic cell subsets were assessed as part of the immune cell profiling
Background
Innate immune dysregulation was identified as a critical and largely unexplored determinant of HAPE, alongside established hemodynamic drivers.
Elevated pulmonary arterial pressure and capillary stress failure are recognized as central hemodynamic drivers of HAPE
The study characterizes innate immune dysregulation as 'an equally critical, largely unexplored determinant of HAPE'
The study aimed to 'systematically delineate the immune and molecular programs that distinguish pathological responses to hypobaric hypoxia from acclimatization'
An integrated approach combining plasma proteomic markers and multicolor flow cytometry immunophenotyping was used
Methods
The study design enabled direct comparison of immune profiles across three distinct altitude-related physiological states: low-altitude controls, adapted high-altitude sojourners, and HAPE patients.
Three groups were studied: LA-Cntrl (n = 19), HA-Cntrl (n = 47), and HAPE patients (n = 90), totaling 156 participants
Peripheral blood was collected along with clinical details from all participants
Both plasma proteomics (targeted panel) and cellular immunophenotyping (multicolor flow cytometry) were employed
This design allowed distinction between pathological hypoxic responses and normal acclimatization responses
What This Means
This research suggests that high-altitude pulmonary edema (HAPE) — a dangerous condition where fluid builds up in the lungs in otherwise healthy people who travel to high altitudes — is associated with a specific pattern of immune system activation. The researchers compared blood samples from 90 HAPE patients, 47 healthy people who had successfully adjusted to high altitude, and 19 people living at low altitude. They measured proteins involved in inflammation and mapped out specific immune cell populations using advanced laboratory techniques. They found that people who successfully adapted to high altitude showed a dampened, anti-inflammatory immune response, while HAPE patients showed the opposite: a highly activated, pro-inflammatory state with elevated levels of signaling molecules that promote inflammation and vascular damage, along with an increased number of a specific type of immune cell called classical monocytes.
This research suggests that the immune system plays a much larger role in HAPE than previously appreciated. While it has been known that high blood pressure in the lung's blood vessels is important in HAPE, these findings point to immune system dysfunction as an 'equally critical' contributing factor. The expansion of classical monocytes — a type of white blood cell involved in inflammation and vascular responses — in HAPE patients suggests that an overactive innate (first-line) immune response may contribute to the harmful fluid leakage into the lungs that defines this condition.
Practically, these findings open potential new avenues for understanding why some people develop HAPE while others safely acclimatize. The identification of a distinct immune 'signature' in HAPE patients could, in future research, lead to ways of identifying individuals at higher risk or to the exploration of immune-targeted approaches in the management of this life-threatening condition. However, further research would be needed to determine whether these immune changes are a cause or consequence of HAPE.
Singh K, Ali M, G K, Palmo T, Kumari S, Thinlas T, et al.. (2026). Integrated Cytokine and Immune Cell Profiling Reveals a Distinct Immune Signature Associated with High-Altitude Pulmonary Edema.. International journal of molecular sciences. https://doi.org/10.3390/ijms27177787