Cardiovascular

Longitudinal immune profiling demonstrates persistent MAIT cell reduction and temporal cytokine alterations after aneurysmal subarachnoid hemorrhage.

TL;DR

aSAH is associated with sustained systemic inflammatory activation and selective alterations of MAIT-cell populations, with cytokine associations with functional outcome attenuated after adjustment for WFNS score and age, suggesting they primarily reflect disease severity rather than independent prognostic effects.

Key Findings

Patients with aSAH demonstrated persistently elevated IL-6, IL-18, and IL-15 levels across all three examined time points (days 1, 5, and 9 after ictus).

  • Cytokine measurements were taken longitudinally on days 1, 5, and 9 after ictus in 48 aSAH patients
  • Serum concentrations were measured using multiplex immunoassay
  • IL-6, IL-18, and IL-15 remained elevated throughout the entire observation period compared to healthy controls
  • These elevations were present from the earliest time point (day 1) through the subacute phase (day 9)

IL-7, IL-12p40, IP-10, and CXCL-9 showed delayed increases during the subacute phase following aSAH.

  • Unlike IL-6, IL-18, and IL-15, these cytokines did not show early elevation on day 1
  • The increases appeared during the subacute phase, suggesting a temporally distinct immune response pattern
  • Ten cytokines total were measured: IL-6, IL-7, IL-12p40, IL-12p70, IL-15, IL-17A, IL-18, IL-22, IP-10, and CXCL-9
  • The temporal pattern distinguishes early acute inflammatory mediators from delayed subacute responders

IL-6 and IL-15 concentrations were significantly higher in patients with unfavorable 3-month functional outcome, while IL-22 levels were increased in patients with favorable recovery.

  • Functional outcome was assessed at 3 months post-aSAH
  • The associations between these cytokines and outcome were identified in univariate analyses
  • These associations were not independent of disease severity after adjustment for WFNS score and age
  • After multivariable adjustment, the cytokine-outcome relationships were attenuated, suggesting they primarily reflect disease severity rather than independent prognostic effects
  • IL-22 was uniquely associated with favorable recovery, distinguishing it from the pro-inflammatory cytokines

Flow cytometry revealed a persistent reduction in circulating MAIT-cell frequencies following aSAH, while other innate-like lymphocyte populations remained largely unchanged.

  • Flow cytometric immunophenotyping was performed in a subgroup of 16 patients
  • Populations evaluated included MAIT cells, NK cells, γδ T cells, iNKT cells, and NKT-like cells
  • MAIT cell reduction was persistent across the observation period
  • NK cells, γδ T cells, iNKT cells, and NKT-like cells were largely unaffected, indicating selective rather than global innate-like lymphocyte dysregulation

DN (double negative) MAIT-cell frequencies demonstrated significant negative correlations with circulating IL-18 levels across all examined time points.

  • The correlation between DN MAIT cells and IL-18 was observed on days 1, 5, and 9
  • The negative correlation indicates that higher IL-18 levels were associated with lower DN MAIT-cell frequencies
  • IL-18 was one of the persistently elevated cytokines throughout the post-aSAH period
  • This relationship provides evidence of a mechanistic link between IL-18-associated inflammation and MAIT-cell dysregulation

This was a prospective observational study enrolling 48 aSAH patients with longitudinal immune profiling compared against healthy controls.

  • Peripheral blood cytokine profiles were analyzed longitudinally at three time points: days 1, 5, and 9 after ictus
  • A subgroup of 16 patients underwent flow cytometric immunophenotyping for innate-like lymphocyte populations
  • Disease severity was assessed using the WFNS score
  • Three-month functional outcome was used as the clinical endpoint for association analyses
  • Multiplex immunoassay was used for serum cytokine quantification

What This Means

This research followed 48 patients who experienced bleeding around the brain caused by a ruptured aneurysm (called aneurysmal subarachnoid hemorrhage, or aSAH) and tracked how their immune systems responded over the first nine days. The researchers measured ten different immune signaling proteins (cytokines) in the blood and, in a smaller group of 16 patients, analyzed specific immune cell populations. They found that the immune response was not uniform: some inflammatory proteins (IL-6, IL-18, and IL-15) were elevated immediately and stayed high throughout the observation period, while others (IL-7, IL-12p40, IP-10, and CXCL-9) only rose later in the recovery process. Patients who had worse outcomes at three months tended to have higher levels of IL-6 and IL-15, while those who recovered better had higher levels of IL-22. However, when accounting for how severe the initial hemorrhage was, these cytokine differences no longer independently predicted outcomes, suggesting the cytokine levels largely mirror how sick the patients were to begin with rather than being separate predictors of recovery. The study also found a notable and persistent reduction in a specialized type of immune cell called MAIT (mucosal-associated invariant T) cells in the bloodstream of aSAH patients, while other similar immune cell types were relatively unaffected. MAIT cells are part of the innate-like immune system and play roles in responding to infection and regulating inflammation. The reduction in a specific subtype of MAIT cells (double-negative MAIT cells) was consistently linked to higher levels of the inflammatory protein IL-18, suggesting these two immune changes may be connected. This research suggests that aSAH triggers a complex, time-dependent immune response that selectively depletes certain immune cell populations. The persistent loss of MAIT cells and their relationship with IL-18 may offer new avenues for understanding the immune-related brain injury that occurs after aneurysm rupture. While cytokine levels were associated with patient outcomes, their link to disease severity means they may serve more as markers of how serious the hemorrhage is rather than as independent targets or predictors—an important distinction for future research aiming to develop immune-based therapies for this serious condition.

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Citation

Merei A, Balazs N, Chayeen B, Engelmann P, Berki T, Erdő-Bonyár S, et al.. (2026). Longitudinal immune profiling demonstrates persistent MAIT cell reduction and temporal cytokine alterations after aneurysmal subarachnoid hemorrhage.. Frontiers in neurology. https://doi.org/10.3389/fneur.2026.1900084