T Cell-Mediated Neurodegeneration in Parkinson's Disease

帕金森病中 T 细胞介导的神经变性

• 批准号: 8496144
• 负责人: R Lee Mosley
• 金额: $ 36.2万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8496144
• 关键词: Acute; Address; Adjuvant; Affect; Animal Model; Animals; Antigen-Presenting Cells; Antigens; Area; Biochemical; Biological Assay; CD4 Positive T Lymphocytes; Cell physiology; Cellular Immunity; Cervical lymph node group; Cloning; Cytoplasm; Cytoplasmic Inclusion; Data; Dependovirus; Dose; Effector Cell; Elements; Environment; Epitopes; Experimental Models; Functional disorder; Funding; Genomics; Helper-Inducer T-Lymphocyte; Immune; Immune system; In Vitro; Incidence; Inflammation; Inflammatory; Intoxication; Laboratories; Lead; Lewy Bodies; Link; Lymphoid; Lymphoid Tissue; Maps; Mediating; Microglia; Midbrain structure; Modeling; Molecular; Mus; Mutate; Nerve Degeneration; Neurites; Neurons; Neurotoxins; Nitrates; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Patients; Process; Proteins; Proteomics; Recombinant adeno-associated virus (rAAV); Role; Self Tolerance; Site; Specificity; Substantia nigra structure; Swelling; System; T cell response; T-Cell Proliferation; T-Lymphocyte; Techniques; Testing; Time; Toxin; adaptive immunity; alpha synuclein; base; chemokine; cytokine; cytotoxicity; dopaminergic neuron; in vivo; insight; migration; neuroinflammation; neurotoxic; neurotoxicity; nitration; novel; public health relevance; research study; response

DESCRIPTION (provided by applicant): Increasing evidence suggests that neurotoxic inflammatory activities affect pathogenesis and progression of Parkinson's disease (PD). Neuroinflammatory processes also produce oxidized and modified self-CNS proteins which lead to dysfunction, misfolding, aggregation, and retention of those oxidized products. In PD, nitrated a-synuclein (N-a-syn) is found aggregated within the cytoplasm and Lewy bodies of dopaminergic neurons within the substantia nigra and is released to the extraneuronal environment by dying and damaged neurons. We demonstrated that after 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) intoxication, N-a-syn is readily detected in ventral midbrain and cervical lymph nodes (CLN), but not other secondary lymphoid tissues; activates microglia and antigen presenting cells (APCs); and is recognized by the adaptive immune system whereas unmodified a-synuclein is not recognized. Moreover, N-a-syn-specific T cells exacerbate MPTP-induced microglia-mediated inflammation and subsequent neurodegeneration. We hypothesize that the tempo and progression of PD is accelerated by N-a-syn stimulation of microglia and APCs, recognition by the adaptive immune system of neoantigenic epitopes on N-a-syn, and induction of effector T cells that extravasate to neuroinflammatory sites, exacerbate inflammatory microglia, and augment microglia-mediated neurotoxicity. Thus this proposal seeks to elucidate the induction and role of T cell-mediated immunity in the pathogenesis of Parkinson's disease. To test our hypothesis, 3 proposed aims will determine 1) the N-a-syn epitopes and MHC elements permissive for induction of T helper cells that mediate dopaminergic neurodegeneration, 2) N-a-syn-specific T helper effector subset(s) responsible for exacerbated neurodegeneration, and 3) molecular and biochemical mechanisms by which N-a-syn specific Teff subset(s) modulate neurodegeneration. PUBLIC HEALTH RELEVANCE: While Parkinson's disease (PD) is linked to neuroinflammation and neurodegeneration due to proinflammatory cytokines, chemokines, reactive intermediates, and neurotoxins, we have shown in an experimental model of PD that nitrated a-synuclein, a component commonly found in dopaminergic neurons and Lewy body inclusions in PD patients, elicits both innate and T cell responses which exacerbate inflammation and neurodegeneration. We propose to delineate which antigens and cellular components permit the induction of these antigen- specific effector T cells and which effector T cells are responsible for augmenting neuroinflammation and neurodegeneration. Using state of the art proteomic and genomic techniques and functional blockade assays, we propose to delineate the biochemical and molecular factors by which effector T cells exacerbate inflammation and neurodegeneration, and validate their relevance in two complementary models of PD neurodegeneration.

描述（由申请人提供）：越来越多的证据表明神经毒性炎症活动影响帕金森病（PD）的发病机制和进展。神经炎症过程还会产生氧化和修饰的自身中枢神经系统蛋白，从而导致这些氧化产物的功能障碍、错误折叠、聚集和保留。在 PD 中，硝化 a-突触核蛋白 (N-a-syn) 被发现聚集在黑质内多巴胺能神经元的细胞质和路易体内，并通过死亡和受损的神经元释放到神经元外环境。我们证明，在 1-甲基 4-苯基 1,2,3,6-四氢吡啶 (MPTP) 中毒后，N-a-syn 很容易在腹侧中脑和颈淋巴结 (CLN) 中检测到，但在其他次级淋巴组织中则不然；激活小胶质细胞和抗原呈递细胞 (APC)；并被适应性免疫系统识别，而未修饰的α-突触核蛋白则不被识别。此外，N-a-syn 特异性 T 细胞会加剧 MPTP 诱导的小胶质细胞介导的炎症和随后的神经退行性变。我们假设 N-a-syn 对小胶质细胞和 APC 的刺激、适应性免疫系统对 N-a-syn 上新抗原表位的识别以及诱导效应 T 细胞外渗到神经炎症部位，加剧炎症性小胶质细胞，从而加速 PD 的速度和进展。 ，并增强小胶质细胞介导的神经毒性。因此，该提案旨在阐明 T 细胞介导的免疫在帕金森病发病机制中的诱导和作用。为了检验我们的假设，提出的 3 个目标将确定 1) 允许诱导介导多巴胺能神经变性的 T 辅助细胞的 N-a-syn 表位和 MHC 元件，2) 负责加剧神经变性的 N-a-syn 特异性 T 辅助效应器子集，3) N-a-syn 特异性 Teff 子集调节神经退行性变的分子和生化机制。 公共健康相关性：虽然帕金森病 (PD) 与促炎细胞因子、趋化因子、反应性中间体和神经毒素导致的神经炎症和神经变性有关，但我们在帕金森病实验模型中发现，α-突触核蛋白（多巴胺能神经元中常见的一种成分）被硝化。 PD 患者体内的神经元和路易体内含物会引起先天性和 T 细胞反应，从而加剧炎症和神经变性。我们建议描绘哪些抗原和细胞成分允许诱导这些抗原特异性效应T细胞以及哪些效应T细胞负责增强神经炎症和神经变性。利用最先进的蛋白质组学和基因组技术以及功能阻断测定，我们建议描述效应 T 细胞加剧炎症和神经变性的生化和分子因素，并验证它们在 PD 神经变性的两种互补模型中的相关性。