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单细胞转录组鉴定阿尔茨海默病外周血生物标志物GZMK+ CD8+ T细胞
Identification of Peripheral Blood GZMK+ CD8+ T Cells As Biomarkers of Alzheimer's Disease Based on Single-Cell Transcriptome
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摘要:目的 基于单细胞RNA测序（single cell RNA sequencing, scRNA-seq）挖掘阿尔茨海默病（Alzheimer's disease, AD）外周血免疫特征作为生物标志物，系统性探索AD外周血免疫细胞亚型丰度、基因表达特征和细胞通讯异常。方法 从GEO数据库中下载AD外周血免疫细胞scRNA-seq数据集GSE168522，于RAD-Blood网页服务器（）中分析AD患者血液细胞组成成分变化，利用CellChat分析AD患者血液中异常的细胞间通讯作用。结果 AD患者和健康人血液中有两种CD8+ T细胞，其中一类高表达颗粒酶K（granzyme K, GZMK）〔伪发现率（false discovery rate, FDR）<0.05〕，另一类高表达GZMA、GZMB和GZMH（FDR<0.05）。GZMK+ CD8+ T细胞在AD患者血液中含量升高32.9%（P=5.15E-21），与其他细胞类型的交互作用增加，并可能通过主要组织相容性复合体Ⅰ类（major histocompatibility complex class Ⅰ, MHC-Ⅰ）信号转导异常与AD关联，红细胞为GZMK+ CD8+ T细胞MHC-Ⅰ信号通路异常提供了主要配体，即人类白细胞抗原（human leukocyte antigen, HLA）Ⅰ类分子（HLA-A、HLA-B、HLA-C和HLA-E）。血液RESISTIN信号通路仅富集于AD患者血液中，其可能是AD血液特异性信号通路。结论 外周血GZMK+ CD8+ T细胞含量升高、GZMK+ CD8+ T细胞与红细胞的交互作用增加、RESISTIN通路增强是潜在的AD标志物。Abstract:Objective Based on single-cell RNA sequencing (scRNA-seq) to explore immune characteristics in the peripheral blood of patients with Alzheimer's disease (AD) as biomarkers.Methods GSE168522, the scRNA-seq dataset of AD peripheral blood immune cells, was downloaded from the Gene Expression Omnibus (GEO) database and was analyzed in the RAD-Blood web server (). The changes in blood cell composition in AD patients were analyzed. The abnormal communications between different types of cells in AD patients were investigated by the CellChat R package.Results There were two kinds of CD8+ T cells in the blood of AD patients and healthy individuals, one of which highly expressed granzyme K (GZMK) (false discovery rate FDR<0.05), and the other highly expressed GZMA, GZMB, and GZMH (FDR<0.05). In the blood of AD patients, the content of GZMK+ CD8+ T cells was increased by 32.9% (P=5.15E-21), their interactions with other cell types were increased, and they might be associated with AD through the abnormal signal transduction of major histocompatibility complex class Ⅰ (MHC-Ⅰ). Erythrocyte provided the main ligands, that are, human leukocyte antigen (HLA) class Ⅰ molecules, including HLA-A, HLA-B, HLA-C, and HLA-E, for the abnormal MHC-Ⅰ signaling pathway of GZMK+ CD8+ T cells. The RESISTIN signaling pathway was specifically enriched in the blood of AD patients.Conclusion The increased content of peripheral blood GZMK+ CD8+ T cells, the increased interaction between GZMK+ CD8+ T cells and erythrocytes, and the enhanced RESISTIN pathway are potential blood biomarkers of AD.
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