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CD8 T cell nigral infiltration precedes synucleinopathy in early stages of Parkinson's disease.
Brain. 2020 12 01; 143(12):3717-3733.B

Abstract

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.

Authors+Show Affiliations

Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute, Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Catalonia, Spain.Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute, Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Catalonia, Spain.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. Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Catalonia, Spain.Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute, Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Catalonia, Spain.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33118032

Citation

Galiano-Landeira, Jordi, et al. "CD8 T Cell Nigral Infiltration Precedes Synucleinopathy in Early Stages of Parkinson's Disease." Brain : a Journal of Neurology, vol. 143, no. 12, 2020, pp. 3717-3733.
Galiano-Landeira J, Torra A, Vila M, et al. CD8 T cell nigral infiltration precedes synucleinopathy in early stages of Parkinson's disease. Brain. 2020;143(12):3717-3733.
Galiano-Landeira, J., Torra, A., Vila, M., & Bové, J. (2020). CD8 T cell nigral infiltration precedes synucleinopathy in early stages of Parkinson's disease. Brain : a Journal of Neurology, 143(12), 3717-3733. https://doi.org/10.1093/brain/awaa269
Galiano-Landeira J, et al. CD8 T Cell Nigral Infiltration Precedes Synucleinopathy in Early Stages of Parkinson's Disease. Brain. 2020 12 1;143(12):3717-3733. PubMed PMID: 33118032.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CD8 T cell nigral infiltration precedes synucleinopathy in early stages of Parkinson's disease. AU - Galiano-Landeira,Jordi, AU - Torra,Albert, AU - Vila,Miquel, AU - Bové,Jordi, PY - 2019/10/16/received PY - 2020/06/16/revised PY - 2020/07/02/accepted PY - 2020/10/30/pubmed PY - 2021/3/2/medline PY - 2020/10/29/entrez KW - Parkinson’s disease KW - cytotoxic T lymphocyte KW - incidental Lewy body disease KW - tissue resident memory T cells KW - α-synuclein SP - 3717 EP - 3733 JF - Brain : a journal of neurology JO - Brain VL - 143 IS - 12 N2 - 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. SN - 1460-2156 UR - https://www.unboundmedicine.com/medline/citation/33118032/CD8_T_cell_nigral_infiltration_precedes_synucleinopathy_in_early_stages_of_Parkinson's_disease_ L2 - https://academic.oup.com/brain/article-lookup/doi/10.1093/brain/awaa269 DB - PRIME DP - Unbound Medicine ER -