Mark Julian R, Titus Ann M, Staley Hannah A, Alvarez Stephan, Mahn Savanna, McFarland Nikolaus R, Wallings Rebecca L, Tansey Malú Gámez
Department of Neuroscience, University of Florida, College of Medicine, Gainesville, FL 32610, USA.
Center for Translational Research in Neurodegenerative Disease, University of Florida, College of Medicine, Gainesville, FL 32610, USA.
bioRxiv. 2024 Dec 7:2024.12.05.625499. doi: 10.1101/2024.12.05.625499.
The motor stage of idiopathic Parkinson's disease (iPD) can be preceded for years by a prodromal stage characterized by non-motor symptoms like REM sleep behavior disorder (RBD). Here, we show that multiple stages of iPD, including the pre-motor prodromal stage, can be stratified according to the inflammatory and immunometabolic responses to stimulation of peripheral blood mononuclear cells . We identified increased stimulation-dependent secretion of TNF, IL-1β, and IL-8 in monocytes from RBD patients and showed diminished proinflammatory cytokine secretion in monocytes and T cells in early and moderate stages of PD. Mechanistically, immune activation revealed deficits in CD8 T-cell mitochondrial health in moderate PD, and relative mitochondrial health in CD8 T cells was positively correlated with stimulation-dependent T-cell cytokine secretion across the PD spectrum. Dysregulated immunometabolism may drive peripheral inflammation and PD progression, and stimulation-based assays have potential to reveal novel biomarkers for patient stratification and progression with immune endophenotypes.
特发性帕金森病（iPD）的运动阶段可能在数年前就有一个前驱阶段，其特征为出现如快速眼动睡眠行为障碍（RBD）等非运动症状。在此，我们表明，iPD的多个阶段，包括运动前前驱阶段，可根据对外周血单核细胞刺激的炎症和免疫代谢反应进行分层。我们发现RBD患者单核细胞中肿瘤坏死因子（TNF）、白细胞介素-1β（IL-1β）和白细胞介素-8（IL-8）的刺激依赖性分泌增加，并表明在PD早期和中期，单核细胞和T细胞中的促炎细胞因子分泌减少。从机制上讲，免疫激活显示中度PD患者CD8 T细胞线粒体健康存在缺陷，并且CD8 T细胞中的相对线粒体健康与整个PD谱系中刺激依赖性T细胞细胞因子分泌呈正相关。免疫代谢失调可能会驱动外周炎症和PD进展，基于刺激的检测方法有潜力揭示用于患者分层和免疫内表型进展的新型生物标志物。
