Ujas T A, Anderson K L, Lutshumba J, Hart S N, Turchan-Cholewo J, Hatton K W, Bachstetter A D, Nikolajczyk B S, Stowe A M
Department of Neuroscience, University of Kentucky, Lexington, USA.
Department of Pharmacology and Nutritional Sciences, University of Kentucky Lexington, Kentucky, USA.
medRxiv. 2024 Aug 19:2024.08.16.24312086. doi: 10.1101/2024.08.16.24312086.
Delayed cerebral ischemia (DCI) is a significant complication of aneurysmal subarachnoid hemorrhage (aSAH). This study profiled immune responses after aSAH and evaluated their association with DCI onset.
Twelve aSAH patients were enrolled. Leukocyte populations and cytokine levels were analyzed in cerebrospinal fluid (CSF) and peripheral blood (PB) on days 3, 5, 7, 10, and 14 post-aSAH. Peripheral blood mononuclear cells (PBMCs) were collected and their cytokine production quantified following stimulation.
Mixed-effects models revealed distinct immune cell dynamics in CSF compared to blood. Natural killer T cell frequency increased over time in CSF only, while monocyte/macrophage numbers increased in both CSF and PBMCs. CD4+ HLA II+ T cells increased in circulation. Unstimulated PBMCs showed increased IL-1β, IL-6, and TNFα production, peaking at 7 days post-aSAH, coinciding with typical DCI onset. Ex vivo stimulation of PBMCs showed that only IL-6 significantly changed over time. In CSF, cytokines peaked 5 days post-injury, preceding immune cell profile alterations.
Our findings reveal a time-dependent immune response following aSAH, with distinct within-patient patterns in CSF and PB. The early CSF cytokine peak preceding immune cell changes suggests a potential mechanistic link and identifies the cytokine response as a promising therapeutic target. This cytokine surge may drive immune cell expansion and prime PBMCs for increased inflammatory activity, potentially contributing to DCI risk. Future studies should explore the importance and sources of specific cytokines in driving immune activation. These insights may inform the development of targeted immunomodulatory strategies for preventing or managing DCI in aSAH patients.
迟发性脑缺血（DCI）是动脉瘤性蛛网膜下腔出血（aSAH）的一种严重并发症。本研究描绘了aSAH后的免疫反应，并评估了它们与DCI发生的关联。
招募了12例aSAH患者。在aSAH后的第3、5、7、10和14天，分析脑脊液（CSF）和外周血（PB）中的白细胞群体和细胞因子水平。收集外周血单个核细胞（PBMC），并在刺激后对其细胞因子产生进行定量分析。
混合效应模型显示，与血液相比，CSF中的免疫细胞动态明显不同。仅CSF中的自然杀伤T细胞频率随时间增加，而CSF和PBMC中的单核细胞/巨噬细胞数量均增加。循环中的CD4 + HLA II + T细胞增加。未刺激的PBMC显示IL-1β、IL-6和TNFα产生增加，在aSAH后7天达到峰值，这与典型的DCI发作时间一致。PBMC的体外刺激显示，只有IL-6随时间有显著变化。在CSF中，细胞因子在损伤后5天达到峰值，早于免疫细胞谱改变。
我们的研究结果揭示了aSAH后随时间变化的免疫反应，CSF和PB中存在患者体内的不同模式。免疫细胞变化之前CSF中细胞因子的早期峰值表明存在潜在的机制联系，并将细胞因子反应确定为一个有前景的治疗靶点。这种细胞因子激增可能会驱动免疫细胞扩增，并使PBMC对增加的炎症活动产生预激作用，可能导致DCI风险增加。未来的研究应探讨特定细胞因子在驱动免疫激活中的重要性和来源。这些见解可能为开发针对性的免疫调节策略提供依据，以预防或管理aSAH患者的DCI。
