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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

    摘要
  • 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（http://www.bioinform.cn/RAD-Blood/）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 (http://www.bioinform.cn/RAD-Blood/). 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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