Mapping the complexity of ME/CFS: Evidence for abnormal energy metabolism, altered immune profile and vascular dysfunction

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder with undefined mechanisms, no diagnostic tools and treatments. To investigate concurrent system dysfunctions, we recruited age- and sex-matched ME/CFS patients and healthy controls for a multi-modal analysis of energy metabolism, immune profiles and plasma proteomics. Immune cells from ME/CFS patients show elevated adenosine monophosphate (AMP) and adenosine diphosphate (ADP) with a reduced ATP/ADP ratio, indicating decreased ATP generation and cellular energy stress. Immune profiling reveals skewing towards less mature effector subsets of CD4+, CD8+ and gd T cells, with reduced CD1c+CD141- conventional DC type 2 and CD56lowCD16+ terminal natural killer cells. Elevated levels of plasma proteins associated with thrombus formation and vascular reactivity may contribute to the endothelial dysfunction observed in ME/CFS patients. Classification and Regression Tree modelling identifies variables with strong predictive potential for ME/CFS. Together, this study provides insights into the somatic symptoms and underlying biology of ME/CFS.肌痛性脑脊髓炎/慢性疲劳综合征（Myalgic encephalomyelitis/chronic fatigue syndrome, ME/CFS）是一种发病机制未明、缺乏诊断工具与治疗手段的复杂疾病。为探究其多系统并发功能异常，本研究招募了年龄与性别匹配的ME/CFS患者与健康对照，开展了能量代谢、免疫谱及血浆蛋白质组学的多模态分析。研究发现，ME/CFS患者的免疫细胞中，一磷酸腺苷（adenosine monophosphate, AMP）与二磷酸腺苷（adenosine diphosphate, ADP）水平升高，同时三磷酸腺苷/二磷酸腺苷（ATP/ADP）比值降低，提示ATP生成减少及细胞能量应激。免疫谱分析显示，CD4+、CD8+及γδ T细胞的效应亚群偏向未成熟表型，同时CD1c+CD141- 2型常规树突状细胞（conventional DC type 2, cDC2）以及CD56lowCD16+ 终末自然杀伤细胞水平显著降低。与血栓形成及血管反应性相关的血浆蛋白水平升高，可能参与ME/CFS患者中已被观察到的内皮功能障碍的发生发展。分类回归树建模筛选出了对ME/CFS具有较强预测潜力的变量。综上，本研究为阐明ME/CFS的躯体症状及潜在生物学机制提供了新的见解。