Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute, Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Catalonia, Spain.
Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, Barcelona, Catalonia, Spain.
Brain. 2020 Dec 1;143(12):3717-3733. doi: 10.1093/brain/awaa269.
There is no consensus on the exact role of the adaptive immune system in Parkinson's disease pathogenesis, although there is increasing evidence that it is somehow involved. Moreover, T cell infiltration in the brain has not been thoroughly studied in Parkinson's disease and no study has assessed the infiltration in incidental Lewy body diseases cases that are considered to be early presymptomatic stages of the disease. In this study, we performed an immunohistochemistry/immunofluorescence quantitative and phenotypic assessment of T cell infiltration in human substantia nigra pars compacta and analysed the correlations with neuronal death and synucleinopathy throughout different stages of the disease. We included two groups of incidental Lewy disease in the study. One of the groups, which is believed to be the earliest stage of the disease, showed α-synuclein aggregates only in the olfactory bulb. The second group also presented α-synuclein aggregates in the substantia nigra. We also assessed the formation of different α-synuclein aggregates throughout the different stages of the unified staging system for Lewy body disorders (I to IV). We found that CD8 T cells were increased in diagnosed Parkinson's disease cases compared to the control group and their density positively correlated with neuronal death. Some of the infiltrating CD8 T cells were indeed contacting dopaminergic neurons. No differences were found regarding CD4 T cells. In the earliest stage of the disease, when substantia nigra α-synuclein aggregation is absent, we found a robust CD8 T cell infiltration and no dopaminergic neuronal death yet. Conversely, in the next stage we found neuronal loss and a milder CD8 T cell infiltration. CD8 T cell infiltration paralleled that of α-synuclein accumulation and neuronal death throughout stages II to IV. We also confirmed that CD8 T cells in charge of immune surveillance and involved in the aetiopathogenesis of the disease are equipped with cytolytic enzymes (granzyme A, B and K) and/or proinflammatory cytokines (interferon gamma), and that phenotypic differences were observed between early and late stages of the disease. We also demonstrate that a high proportion of nigral CD8 T cells are tissue resident memory T cells. Our results show that nigral cytotoxic CD8 T cell infiltration is an earlier pathogenic event than α-synuclein aggregation and neuronal death and that it parallels the progression of neuronal death and synucleinopathy in Parkinson's disease. Overall, our study suggests that CD8 T cell cytotoxic attack may initiate and propagate neuronal death and synucleinopathy in Parkinson's disease.
目前对于适应性免疫系统在帕金森病发病机制中的确切作用尚未达成共识，尽管越来越多的证据表明其可能存在一定程度的参与。此外，在帕金森病中，T 细胞浸润尚未得到深入研究，也没有研究评估偶发性路易体疾病病例中的浸润情况，这些病例被认为是疾病的早期无症状前阶段。在本研究中，我们对人类黑质致密部的 T 细胞浸润进行了免疫组织化学/免疫荧光定量和表型评估，并分析了与不同疾病阶段神经元死亡和突触核蛋白病的相关性。我们纳入了两组偶发性路易体疾病作为研究对象。其中一组被认为是疾病的最早阶段，仅在嗅球中出现α-突触核蛋白聚集。第二组也在黑质中出现了α-突触核蛋白聚集。我们还评估了不同统一路易体疾病分期系统（I 至 IV 期）阶段中不同α-突触核蛋白聚集的形成情况。我们发现，与对照组相比，诊断为帕金森病的病例中 CD8 T 细胞增加，其密度与神经元死亡呈正相关。一些浸润的 CD8 T 细胞实际上与多巴胺能神经元接触。CD4 T 细胞没有差异。在疾病的最早阶段，当黑质中不存在α-突触核蛋白聚集时，我们发现了强烈的 CD8 T 细胞浸润，但尚未出现多巴胺能神经元死亡。相反，在下一个阶段，我们发现了神经元丢失和更轻微的 CD8 T 细胞浸润。CD8 T 细胞浸润与 II 至 IV 期的α-突触核蛋白积累和神经元死亡平行。我们还证实，负责免疫监视并参与疾病发病机制的 CD8 T 细胞具有细胞毒性酶（颗粒酶 A、B 和 K）和/或促炎细胞因子（干扰素 γ），并且在疾病的早期和晚期阶段观察到表型差异。我们还证明，黑质中相当比例的 CD8 T 细胞是组织驻留记忆 T 细胞。我们的结果表明，黑质中细胞毒性 CD8 T 细胞浸润是比α-突触核蛋白聚集和神经元死亡更早的致病事件，并且与帕金森病中神经元死亡和突触核蛋白病的进展平行。总的来说，我们的研究表明，CD8 T 细胞的细胞毒性攻击可能启动并传播帕金森病中的神经元死亡和突触核蛋白病。
