Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198, USA.
J Immunol. 2010 Mar 1;184(5):2261-71. doi: 10.4049/jimmunol.0901852. Epub 2010 Jan 29.
Nitrated alpha-synuclein (N-alpha-syn) immunization elicits adaptive immune responses to novel antigenic epitopes that exacerbate neuroinflammation and nigrostriatal degeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. We show that such neuroimmune degenerative activities, in significant measure, are Th17 cell-mediated, with CD4(+)CD25(+) regulatory T cell (Treg) dysfunction seen among populations of N-alpha-syn-induced T cells. In contrast, purified vasoactive intestinal peptide induced and natural Tregs reversed N-alpha-syn T cell nigrostriatal degeneration. Combinations of adoptively transferred N-alpha-syn and vasoactive intestinal peptide immunocytes or natural Tregs administered to MPTP mice attenuated microglial inflammatory responses and led to robust nigrostriatal protection. Taken together, these results demonstrate Treg control of N-alpha-syn-induced neurodestructive immunity and, as such, provide a sound rationale for future Parkinson's disease immunization strategies.
硝化的α-突触核蛋白（N-α-突触核蛋白）免疫会引发针对新抗原表位的适应性免疫反应，从而加剧 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）帕金森病模型中的神经炎症和黑质纹状体变性。我们表明，这种神经免疫退行性活动在很大程度上是由 Th17 细胞介导的，在 N-α-突触核蛋白诱导的 T 细胞群体中观察到 CD4(+)CD25(+)调节性 T 细胞（Treg）功能障碍。相比之下，纯化的血管活性肠肽诱导的天然 Treg 逆转了 N-α-突触核蛋白 T 细胞黑质纹状体变性。将过继转移的 N-α-突触核蛋白和血管活性肠肽免疫细胞或天然 Treg 组合施用于 MPTP 小鼠，可减轻小胶质细胞的炎症反应，并导致黑质纹状体的显著保护。总之，这些结果表明 Treg 控制 N-α-突触核蛋白诱导的神经破坏性免疫，因此为未来的帕金森病免疫策略提供了合理的依据。
