Immune Checkpoint Dysregulation in Aneurysmal Subarachnoid Hemorrhage: A Prospective Study of sCTLA-4 and sPD-L1 as Biomarkers of Symptomatic Vasospasm

Várnai, Réka and Szebeni, Gábor and Gémes, Nikolett and Schwarcz, Attila and Molnár, Tihamér and Olah, Csaba and Csécsei, Péter (2025) Immune Checkpoint Dysregulation in Aneurysmal Subarachnoid Hemorrhage: A Prospective Study of sCTLA-4 and sPD-L1 as Biomarkers of Symptomatic Vasospasm. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 26 (17). No.-8228. ISSN 1661-6596

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Abstract

Aneurysmal subarachnoid hemorrhage (aSAH) is a severe stroke subtype often complicated by symptomatic cerebral vasospasm (sVP), contributing to delayed cerebral ischemia and poor outcomes. Immune dysregulation, particularly T-cell imbalances and pro-inflammatory cytokines, is implicated in vasospasm development. Soluble immune checkpoint proteins—CTLA-4 (sCTLA-4) and PD-L1 (sPD-L1)—regulate immune homeostasis and may serve as biomarkers or modulators of inflammation in aSAH. This prospective cohort study included 179 aSAH patients, divided into sVP+ (n = 48) and sVP− (n = 131), plus 50 healthy controls. Serum sCTLA-4 and sPD-L1 levels were measured on days 1, 5, and 9 post-ictus using Luminex xMAP. Associations with clinical outcomes were analyzed using non-parametric statistics and hierarchical clustering. Both sCTLA-4 and sPD-L1 were significantly elevated in sVP+ patients versus sVP− and controls, increasing over time. sCTLA-4 was significantly higher in sVP+ on days 5 (p = 0.001) and 9 (p < 0.001), and sPD-L1 on days 5 and 9 (both p < 0.001). Clustering revealed distinct expression patterns between sVP+ and sVP− groups. Elevated sCTLA-4 and sPD-L1 levels are associated with sVP after aSAH and may serve as biomarkers for early immune dysfunction, offering insights into potential therapeutic targets.

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