Neurodegeneration by α-synuclein-specific T cells in AAV-A53T-α-synuclein Parkinson's disease mice.

Autor: Karikari AA; Department of Neurology, University Hospital of Würzburg, Würzburg, Germany., McFleder RL; Department of Neurology, University Hospital of Würzburg, Würzburg, Germany., Ribechini E; Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany., Blum R; Institute of Clinical Neurobiology, University Hospital of Würzburg, Würzburg, Germany., Bruttel V; Section for Experimental Tumor Immunology, Department of Obstetrics and Gynecology, University Hospital of Würzburg, Würzburg, Germany., Knorr S; Department of Neurology, University Hospital of Würzburg, Würzburg, Germany., Gehmeyr M; Department of Neurology, University Hospital of Würzburg, Würzburg, Germany., Volkmann J; Department of Neurology, University Hospital of Würzburg, Würzburg, Germany., Brotchie JM; Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada., Ahsan F; Section for Experimental Tumor Immunology, Department of Obstetrics and Gynecology, University Hospital of Würzburg, Würzburg, Germany., Haack B; Section for Experimental Tumor Immunology, Department of Obstetrics and Gynecology, University Hospital of Würzburg, Würzburg, Germany., Monoranu CM; Institute of Pathology, Department of Neuropathology, University of Würzburg, Würzburg, Germany., Keber U; Department of Neuropathology, Philipps University and University Hospital of Marburg, Marburg, Germany., Yeghiazaryan R; Department of Neuropathology, Philipps University and University Hospital of Marburg, Marburg, Germany., Pagenstecher A; Department of Neuropathology, Philipps University and University Hospital of Marburg, Marburg, Germany., Heckel T; Core Unit Systems Medicine, University of Würzburg, Würzburg, Germany., Bischler T; Core Unit Systems Medicine, University of Würzburg, Würzburg, Germany., Wischhusen J; Section for Experimental Tumor Immunology, Department of Obstetrics and Gynecology, University Hospital of Würzburg, Würzburg, Germany., Koprich JB; Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada., Lutz MB; Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany. Electronic address: m.lutz@vim.uni-wuerzburg., Ip CW; Department of Neurology, University Hospital of Würzburg, Würzburg, Germany. Electronic address: ip_c@ukw.de.
Jazyk: angličtina
Zdroj: Brain, behavior, and immunity [Brain Behav Immun] 2022 Mar; Vol. 101, pp. 194-210. Date of Electronic Publication: 2022 Jan 12.
DOI: 10.1016/j.bbi.2022.01.007
Abstrakt: Background: Antigen-specific neuroinflammation and neurodegeneration are characteristic for neuroimmunological diseases. In Parkinson's disease (PD) pathogenesis, α-synuclein is a known culprit. Evidence for α-synuclein-specific T cell responses was recently obtained in PD. Still, a causative link between these α-synuclein responses and dopaminergic neurodegeneration had been lacking. We thus addressed the functional relevance of α-synuclein-specific immune responses in PD in a mouse model.
Methods: We utilized a mouse model of PD in which an Adeno-associated Vector 1/2 serotype (AAV1/2) expressing human mutated A53T-α-Synuclein was stereotactically injected into the substantia nigra (SN) of either wildtype C57BL/6 or Recombination-activating gene 1 (RAG1) -/- mice. Brain, spleen, and lymph node tissues from different time points following injection were then analyzed via FACS, cytokine bead assay, immunohistochemistry and RNA-sequencing to determine the role of T cells and inflammation in this model. Bone marrow transfer from either CD4 + /CD8 - , CD4 - /CD8 + , or CD4 + /CD8 + (JHD -/- ) mice into the RAG-1 -/- mice was also employed. In addition to the in vivo studies, a newly developed A53T-α-synuclein-expressing neuronal cell culture/immune cell assay was utilized.
Results: AAV-based overexpression of pathogenic human A53T-α-synuclein in dopaminergic neurons of the SN stimulated T cell infiltration. RNA-sequencing of immune cells from PD mouse brains confirmed a pro-inflammatory gene profile. T cell responses were directed against A53T-α-synuclein-peptides in the vicinity of position 53 (68-78) and surrounding the pathogenically relevant S129 (120-134). T cells were required for α-synuclein-induced neurodegeneration in vivo and in vitro, while B cell deficiency did not protect from dopaminergic neurodegeneration.
Conclusions: Using T cell and/or B cell deficient mice and a newly developed A53T-α-synuclein-expressing neuronal cell culture/immune cell assay, we confirmed in vivo and in vitro that pathogenic α-synuclein peptide-specific T cell responses can cause dopaminergic neurodegeneration and thereby contribute to PD-like pathology.
(Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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