Although many researchers of Parkinson’s disease (PD) have shifted their focus from the central nervous system (CNS) to the peripheral blood, a significant knowledge gap remains between PD severity and the peripheral immune response. In the current study, we aimed to map the peripheral immunity atlas in peripheral blood mononuclear cells (PBMCs) from PD patients and healthy controls using single-cell RNA sequencing (scRNA-seq). Our study employed scRNA-seq analysis to map the peripheral immunity atlas in PD by profiling PBMCs from PD-Early, PD-Late patients and matched controls. By enlarging the blood sample size, we validated the roles of NK cells in numerous immune-related biological processes. We also detected the infiltration of NK cells into the cerebral motor cortex as the disease progressed, using human brain sections, and elucidated the communication between the periphery and CNS and its implications for PD. As a result, cell subpopulation atlases in PBMCs from PD patients and healthy controls along with differentially expressed genes in NK cells were identified by scRNA-seq analysis, representing 6 major immune cell subsets among which NK cells declined in the progression of PD. We further validated NK cell reduction in increasing samples and found that they participated in numerous immune-related biological processes and infiltration into the cerebral motor cortex as the disease proceeded, evidencingd the close communication between the peripheral immune response and CNS. Strikingly, XCL2 positively correlated with PD severity, with good predictive performance of PD and specific expression in subclusters C2 and C5 of NK cells. All these findings delineated the critical role of peripheral immune response mediated by NK cells in the pathogenesis of PD. NK cell-specific XCL2 could be used as a diagnostic marker for treating PD. The indispensable function of NK cells and NK cell-specific molecular biomarkers highlighted the implication of the peripheral immune response in PD progression. Trial registration: ChiCTR, ChiCTR1900023975. Registered 20 June 2019 - Retrospectively registered, https://www.chictr.org.cn/showproj.html?proj=31035.

尽管许多帕金森病 (PD) 的研究人员已将重点从中枢神经系统 (CNS) 转移到外周血液，但帕金森病的严重程度和外周免疫反应之间仍然存在显着的知识差距。在当前的研究中，我们的目标是使用单细胞 RNA 测序 (scRNA-seq) 绘制 PD 患者和健康对照的外周血单核细胞 (PBMC) 的外周免疫图谱。我们的研究采用 scRNA-seq 分析，通过对 PD 早期、PD 晚期患者和匹配对照的 PBMC 进行分析，绘制 PD 外周免疫图谱。通过扩大血液样本量，我们验证了 NK 细胞在许多免疫相关生物过程中的作用。我们还使用人脑切片检测到随着疾病进展 NK 细胞向大脑运动皮层的浸润，并阐明了外周和中枢神经系统之间的通讯及其对 PD 的影响。结果，通过 scRNA-seq 分析鉴定了 PD 患者和健康对照的 PBMC 中的细胞亚群图谱以及 NK 细胞中的差异表达基因，代表了 6 个主要的免疫细胞亚群，其中 NK 细胞在 PD 的进展中下降。我们进一步验证了越来越多的样本中NK细胞的减少，发现它们参与了许多与免疫相关的生物过程，并随着疾病的进展而渗透到大脑运动皮层，证明了外周免疫反应与中枢神经系统之间的密切联系。引人注目的是，XCL2 与 PD 严重程度呈正相关，对 PD 具有良好的预测性能，并且在 NK 细胞亚群 C2 和 C5 中特异性表达。所有这些发现都阐明了 NK 细胞介导的外周免疫反应在 PD 发病机制中的关键作用。 NK 细胞特异性 XCL2 可用作治疗 PD 的诊断标志物。 NK 细胞和 NK 细胞特异性分子生物标志物不可或缺的功能凸显了外周免疫反应在 PD 进展中的意义。试用注册：ChiCTR，ChiCTR1900023975。 2019 年 6 月 20 日注册 - 追溯注册，https://www.chictr.org.cn/showproj.html?proj=31035。