CD4 T cells mediate brain inflammation and neurodegeneration in a mouse model of Parkinson's disease.
CD4 T cells mediate brain inflammation and neurodegeneration in a mouse model of Parkinson's disease.
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CD4 T细胞在帕金森氏病小鼠模型中介导脑炎症和神经退行性。
DOI：
10.1093/brain/awab103
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发表时间：
2021-08-17
期刊：
影响因子：
--
通讯作者：
Harms AS
中科院分区：
文献类型：
--
作者：
Williams GP;Schonhoff AM;Jurkuvenaite A;Gallups NJ;Standaert DG;Harms AS
α-突触核蛋白是帕金森病的关键病理成分，与先天性和适应性免疫系统的激活有关。这种免疫激活包括小胶质细胞增生、炎性细胞因子增加以及T细胞浸润到中枢神经系统中。最近，来自帕金森病患者的外周循环CD 4和CD 8 T细胞已显示响应于α-突触核蛋白产生Th 1/Th 2细胞因子，表明帕金森病中可能存在慢性记忆T细胞应答。为了了解这些α-syn相关T细胞应答的潜在作用，我们使用了α-突触核蛋白过表达小鼠模型、T细胞缺陷小鼠以及免疫组织化学和流式细胞术的组合。在这项研究中，我们发现小鼠中脑中α-突触核蛋白过表达导致CNS髓样细胞上主要组织相容性复合体II（MHCII）蛋白的上调以及产生IFNγ的CD 4和CD 8 T细胞向CNS的浸润。有趣的是，TCRβ或CD 4的基因缺失以及免疫抑制药物芬戈莫德的使用能够降低CNS骨髓MHCII对α-突触核蛋白的反应。此外，我们观察到，CD 4缺陷小鼠受到保护，免受由于α-syn过表达而观察到的多巴胺能细胞损失。这些结果表明，与α-突触核蛋白病理学相关的T细胞应答可能损害帕金森病中CNS的关键区域，并且靶向这些T细胞应答可能是疾病改善治疗的途径。威廉姆斯等人报道，小鼠中脑中α-突触核蛋白过表达导致CD 4和CD 8 T细胞浸润到CNS中。他们表明，CD 4 T细胞有助于介导α-突触核蛋白诱导的骨髓炎症和神经变性，从而为帕金森病的神经免疫学提供了见解。
α-Synuclein, a key pathological component of Parkinson's disease, has been implicated in the activation of the innate and adaptive immune system. This immune activation includes microgliosis, increased inflammatory cytokines, and the infiltration of T cells into the CNS. More recently, peripherally circulating CD4 and CD8 T cells derived from individuals with Parkinson’s disease have been shown to produce Th1/Th2 cytokines in response to α-synuclein, suggesting there may be a chronic memory T cell response present in Parkinson’s disease. To understand the potential effects of these α-syn associated T cell responses we used an α-synuclein overexpression mouse model, T cell-deficient mice, and a combination of immunohistochemistry and flow cytometry. In this study, we found that α-synuclein overexpression in the midbrain of mice leads to the upregulation of the major histocompatibility complex II (MHCII) protein on CNS myeloid cells as well as the infiltration of IFNγ producing CD4 and CD8 T cells into the CNS. Interestingly, genetic deletion of TCRβ or CD4, as well as the use of the immunosuppressive drug fingolimod, were able to reduce the CNS myeloid MHCII response to α-synuclein. Furthermore, we observed that CD4-deficient mice were protected from the dopaminergic cell loss observed due to α-syn overexpression. These results suggest that T cell responses associated with α-synuclein pathology may be damaging to key areas of the CNS in Parkinson’s disease and that targeting these T cell responses could be an avenue for disease modifying treatments. Williams et al. report that α-synuclein overexpression in the mouse midbrain leads to infiltration of CD4 and CD8 T cells into the CNS. They show that CD4 T cells help mediate α-synuclein-induced myeloid inflammation and neurodegeneration, thereby providing insights into the neuroimmunology of Parkinson’s disease.
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DOI：
10.1084/jem.20122143
发表时间：
2013-09-23
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kreutzfeldt M;Bergthaler A;Fernandez M;Brück W;Steinbach K;Vorm M;Coras R;Blümcke I;Bonilla WV;Fleige A;Forman R;Müller W;Becher B;Misgeld T;Kerschensteiner M;Pinschewer DD;Merkler D
通讯作者：
Merkler D
影响因子：
4.8
作者：
Chandra, Goutam;Rangasamy, Suresh B.;Pahan, Kalipada
通讯作者：
Pahan, Kalipada
影响因子：
15.9
作者：
Brochard, Vanessa;Combadiere, Behazine;Hunot, Stephane
通讯作者：
Hunot, Stephane
影响因子：
4.6
作者：
Kustrimovic N;Rasini E;Legnaro M;Bombelli R;Aleksic I;Blandini F;Comi C;Mauri M;Minafra B;Riboldazzi G;Sanchez-Guajardo V;Marino F;Cosentino M
通讯作者：
Cosentino M
帕金森氏病的患病率在北美。
DOI：
10.1038/s41531-018-0058-0
发表时间：
2018
期刊：
NPJ Parkinson's disease
影响因子：
--
作者：
Marras C;Beck JC;Bower JH;Roberts E;Ritz B;Ross GW;Abbott RD;Savica R;Van Den Eeden SK;Willis AW;Tanner CM;Parkinson’s Foundation P4 Group
通讯作者：
Parkinson’s Foundation P4 Group