Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons.
Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons.
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DOI：
10.1371/journal.pone.0001376
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发表时间：
2008-01-02
期刊：
影响因子：
3.7
通讯作者：
Gendelman HE
中科院分区：
文献类型：
--
作者：
Benner EJ;Banerjee R;Reynolds AD;Sherman S;Pisarev VM;Tsiperson V;Nemachek C;Ciborowski P;Przedborski S;Mosley RL;Gendelman HE
帕金森病（Parkinson 'sdisease，PD）的神经病理包括黑质多巴胺能神经元的缺失、神经元内包涵体或Lewy小体和神经炎症。虽然先天性小胶质细胞炎症活动对疾病的贡献是已知的，但适应性免疫机制如何影响PD病程的证据仍然不清楚。我们推断PD相关的氧化蛋白修饰产生了能够影响黑质纹状体变性的外周适应性T细胞应答的新抗原表位。在1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）中毒小鼠的颈淋巴结（CLN）中可检测到硝基酪氨酸（NT）修饰的α-Syn。CLN内的抗原提呈细胞显示主要组织相容性复合物II类的表面表达增加，启动有效抗原提呈所需的分子机制。MPTP处理的小鼠产生针对天然和硝化α-Syn的抗体。用α-Syn的NT修饰的C-末端尾部片段而不是天然蛋白免疫的小鼠产生仅对修饰的抗原特异性的稳健的T细胞增殖和促炎分泌应答。针对硝化表位产生的T细胞不响应未修饰的蛋白质。缺乏T和B淋巴细胞的小鼠对MPTP诱导的神经退行性变有抵抗力。从用N-α-Syn免疫的小鼠转移T细胞导致强烈的神经炎症反应，伴随加速的多巴胺能细胞损失。这些数据表明，α-Syn内的NT修饰可以绕过或打破免疫耐受并激活引流淋巴组织中的外周白细胞。一种新的疾病机制是α-Syn中的NT修饰诱导适应性免疫应答，加剧PD病理生物学。这些结果对这种致残性神经退行性疾病的发病机制和治疗都有意义。
The neuropathology of Parkinson's disease (PD) includes loss of dopaminergic neurons in the substantia nigra, nitrated α-synuclein (N-α-Syn) enriched intraneuronal inclusions or Lewy bodies and neuroinflammation. While the contribution of innate microglial inflammatory activities to disease are known, evidence for how adaptive immune mechanisms may affect the course of PD remains obscure. We reasoned that PD-associated oxidative protein modifications create novel antigenic epitopes capable of peripheral adaptive T cell responses that could affect nigrostriatal degeneration. Nitrotyrosine (NT)-modified α-Syn was detected readily in cervical lymph nodes (CLN) from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxicated mice. Antigen-presenting cells within the CLN showed increased surface expression of major histocompatibility complex class II, initiating the molecular machinery necessary for efficient antigen presentation. MPTP-treated mice produced antibodies to native and nitrated α-Syn. Mice immunized with the NT-modified C-terminal tail fragment of α-Syn, but not native protein, generated robust T cell proliferative and pro-inflammatory secretory responses specific only for the modified antigen. T cells generated against the nitrated epitope do not respond to the unmodified protein. Mice deficient in T and B lymphocytes were resistant to MPTP-induced neurodegeneration. Transfer of T cells from mice immunized with N-α-Syn led to a robust neuroinflammatory response with accelerated dopaminergic cell loss. These data show that NT modifications within α-Syn, can bypass or break immunological tolerance and activate peripheral leukocytes in draining lymphoid tissue. A novel mechanism for disease is made in that NT modifications in α-Syn induce adaptive immune responses that exacerbate PD pathobiology. These results have implications for both the pathogenesis and treatment of this disabling neurodegenerative disease.
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DOI：
10.1073/pnas.0400569101
发表时间：
2004-06-22
影响因子：
11.1
作者：
Benner, EJ;Mosley, RL;Gendelman, HE
通讯作者：
Gendelman, HE
影响因子：
168.9
作者：
Chartier-Harlin, MC;Kachergus, J;Destée, A
通讯作者：
Destée, A
影响因子：
82.9
作者：
Conway, KA;Harper, JD;Lansbury, PT
通讯作者：
Lansbury, PT
影响因子：
3.5
作者：
El-Agnaf, OMA;Jakes, R;Wallace, A
通讯作者：
Wallace, A
影响因子：
3.4
作者：
Di Monte, DA;Lavasani, M;Manning-Bog, AB
通讯作者：
Manning-Bog, AB