Wang Xinxia, Gao Yao, Wang Dan, Du Xinzhe, Liu Sha
Department of Psychiatry, First Hospital/First Clinical Medical College of Shanxi Medical University, Taiyuan, Shanxi, People's Republic of China.
Shanxi Key Laboratory of Artificial Intelligence Assisted Diagnosis and Treatment for Mental Disorder, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, People's Republic of China.
Neuropsychiatr Dis Treat. 2024 Nov 28;20:2347-2361. doi: 10.2147/NDT.S490717. eCollection 2024.
Late-onset depression (LOD) is often associated with more severe cognitive impairment and a higher risk of disability and suicide. Emerging evidence suggests that immune system problems may be involved. This study aims to systematically characterize the genetic signature of LOD based on the immune landscape.
The expression profile of GSE76826 was obtained from the Gene Expression Omnibus (GEO) database to gather gene expression data for 10 LOD patients and 12 healthy controls (HC). Various analyses, such as Single-Sample Gene Set Enrichment Analysis (ssGSEA) and Weighted Gene Co-expression Network Analysis (WGCNA), were used to mine key genes closely related to LOD. ImmuCellAI helped us understand differences in the immune environment between LOD patients and controls, and we used an LOD animal model to validate the relevant immune characteristics.
We found enriched immune pathways linked to LOD and adaptive immune responses. Using advanced bioinformatics techniques, we identified two key genes: and , which have good diagnostic efficacy (AUC=0.925, 95% CI=1.00-0.83) for LOD. Neutrophil infiltration increased significantly in LOD, while CD8+ T lymphocytes (CD8_T) decreased. We finally constructed an animal model of LOD, validated two key genes and microglia marker genes in blood and hippocampus, and detected elevated pro-inflammatory factors such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α).
We identified and validated the presence of aberrant expression of and in LOD and described a possible immune mechanism involving increased release of IL-6 and TNF-α, leading to decreased CD8_T infiltration and increased neutrophil infiltration. Meanwhile, peripheral inflammation across the blood-brain barrier further promotes microglia activation, leading to neuronal damage.
迟发性抑郁症（LOD）通常与更严重的认知障碍以及更高的残疾和自杀风险相关。新出现的证据表明，免疫系统问题可能与之有关。本研究旨在基于免疫格局系统地表征LOD的基因特征。
从基因表达综合数据库（GEO）中获取GSE76826的表达谱，以收集10例LOD患者和12名健康对照（HC）的基因表达数据。使用了各种分析方法，如单样本基因集富集分析（ssGSEA）和加权基因共表达网络分析（WGCNA），来挖掘与LOD密切相关的关键基因。免疫细胞人工智能（ImmuCellAI）帮助我们了解LOD患者和对照之间免疫环境的差异，并且我们使用LOD动物模型来验证相关的免疫特征。
我们发现了与LOD和适应性免疫反应相关的富集免疫途径。使用先进的生物信息学技术，我们鉴定出两个关键基因： 和 ，它们对LOD具有良好的诊断效能（AUC = 0.925，95% CI = 1.00 - 0.83）。LOD患者中性粒细胞浸润显著增加，而CD8 + T淋巴细胞（CD8_T）减少。我们最终构建了LOD动物模型，在血液和海马中验证了两个关键基因和小胶质细胞标记基因，并检测到促炎因子如白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）升高。
我们鉴定并验证了LOD中 和 异常表达的存在，并描述了一种可能的免疫机制，涉及IL-6和TNF-α释放增加，导致CD8_T浸润减少和中性粒细胞浸润增加。同时，外周炎症穿过血脑屏障进一步促进小胶质细胞活化，导致神经元损伤。
