Parkinson’s disease (PD) is marked by a loss of dopamine neurons, decreased dopamine transporter (DAT) and tyrosine hydroxylase (TH) expression. However, this validation approach cannot be used for diagnostic, drug effectiveness or investigational purposes in human patients because midbrain tissue is accessible postmortem. PD pathology affects both the central nervous and peripheral immune systems. Therefore, we immunophenotyped blood samples of PD patients for the presence of myeloid derived suppressor cells (MDSCs) and discovered that DAT⁺/TH⁺ monocytic MDSCs, but not granulocytic MDSCs are increased, suggesting a targeted immune response to PD. Because in peripheral immune cells DAT activity underlies an immune suppressive mechanism, we investigated whether expression levels of DAT and TH in the peripheral immune cells marks PD. We found drug naïve PD patients exhibit differential DAT⁺/TH⁺ expression in peripheral blood mononuclear cells (PBMCs) compared to aged/sex matched healthy subjects. While total PBMCs are not different between the groups, the percentage of DAT⁺/TH⁺ PBMCs was significantly higher in drug naïve PD patients compared to healthy controls irrespective of age, gender, disease duration, disease severity or treatment type. Importantly, treatment for PD negatively modulates DAT⁺/TH⁺ expressing PBMCs. Neither total nor the percentage of DAT⁺/TH⁺ PBMCs were altered in the Alzheimer’s disease cohort. The mechanistic underpinning of this discovery in human PD was revealed when these findings were recapitulated in animal models of PD. The reverse translational experimental strategy revealed that alterations in dopaminergic markers in peripheral immune cells are due to the disease associated changes in the CNS. Our study demonstrates that the dopaminergic machinery on peripheral immune cells displays an association with human PD, with exciting implications in facilitating diagnosis and investigation of human PD pathophysiology.

帕金森病 (PD) 的特点是多巴胺神经元丧失、多巴胺转运蛋白 (DAT) 和酪氨酸羟化酶 (TH) 表达减少。然而，这种验证方法不能用于人类患者的诊断、药物有效性或研究目的，因为中脑组织在死后是可获取的。 PD 病理影响中枢神经和外周免疫系统。因此，我们对 PD 患者的血液样本进行了免疫表型分析，以确定髓源性抑制细胞 (MDSC) 的存在，并发现 DAT ⁺ /TH ⁺单核细胞 MDSC 增加，但粒细胞 MDSC 没有增加，这表明对 PD 存在靶向免疫反应。由于在外周免疫细胞中 DAT 活性是免疫抑制机制的基础，因此我们研究了外周免疫细胞中 DAT 和 TH 的表达水平是否标志着 PD。我们发现，与年龄/性别匹配的健康受试者相比，未接受药物治疗的 PD 患者外周血单核细胞 (PBMC) 中 DAT ⁺ /TH ⁺表达存在差异。虽然各组之间的总 PBMC 没有差异，但与健康对照相比，无论年龄、性别、病程、疾病严重程度或治疗类型如何，初治 PD 患者的 DAT ⁺ /TH ⁺ PBMC 百分比均显着较高。重要的是，PD 治疗会对表达 DAT ⁺ /TH ⁺的 PBMC 产生负调节。在阿尔茨海默病队列中，DAT ⁺ /TH ⁺ PBMC 总数和百分比均未改变。当这些发现在 PD 动物模型中得到重现时，人类 PD 中这一发现的机制基础就得到了揭示。 逆翻译实验策略表明，外周免疫细胞中多巴胺能标记物的改变是由于中枢神经系统疾病相关的变化所致。我们的研究表明，外周免疫细胞上的多巴胺能机制与人类帕金森病有关，这对于促进人类帕金森病病理生理学的诊断和研究具有令人兴奋的意义。