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: 8073944
• 负责人: R Lee Mosley
• 金额: $ 31.83万
• 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/8073944
• 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，神经毒性炎症活性会影响帕金森氏病（PD）的发病机理和进展。神经炎症过程还产生氧化和改良的自CNS蛋白，从而导致功能障碍，错误折叠，聚集和保留这些氧化产物。在PD中，发现硝化的A-核蛋白（N-A-Syn）在尼格拉底菌中的多巴胺能神经元的细胞质和Lewy体内聚集，并通过垂死和受损的神经元释放到外神经元环境中。我们证明，在1-甲基4-苯基1,2,3,6-四氢吡啶（MPTP）中毒后，在腹中脑和宫颈淋巴结（CLN）中很容易检测到N-A-Syn，但没有其他二级淋巴组织。激活小胶质细胞和抗原呈递细胞（APC）；并被自适应免疫系统认可，而未修饰的A-核蛋白未识别。此外，N-A-A-Syn特异性T细胞加剧了MPTP诱导的小胶质细胞介导的炎症和随后的神经变性。 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氏病发病机理中的诱导和作用。 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子集调节神经变性。 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天生和T细胞反应加剧了炎症和神经退行性。我们建议描述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。使用TAR的蛋白质组学和基因组技术以及功能阻滞测定法，我们建议描述生化和分子因素，通过这些因素，效应T细胞加剧炎症和神经变性，并在PD神经变性的两个互补模型中验证它们的相关性。