Mutant Huntingtin Does Not Affect the Intrinsic Phenotype of Human Huntington's Disease T Lymphocytes.
Mutant Huntingtin Does Not Affect the Intrinsic Phenotype of Human Huntington's Disease T Lymphocytes.
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DOI：
10.1371/journal.pone.0141793
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Tabrizi SJ
中科院分区：
文献类型：
--
作者：
Miller JR;Träger U;Andre R;Tabrizi SJ
亨廷顿病是一种致命的神经退行性疾病，由亨廷顿蛋白基因的CAG重复扩增引起。亨廷顿病患者的外周先天免疫系统失调，可能与其发病机制有关。然而，目前还不清楚适应性免疫系统是否也参与其中，或者在多大程度上参与其中。在这里，我们首次对亨廷顿病患者的体外T淋巴细胞进行了全面的研究，重点是一系列T淋巴细胞亚群的频率，以及增殖、细胞因子产生和基因转录的分析。与先天免疫系统相比，T淋巴细胞的内在表型似乎不会受到突变亨廷顿蛋白的存在的影响，亨廷顿病T淋巴细胞与对照细胞相比没有表现出显著的功能差异。T淋巴细胞的转录图谱似乎也没有受到显著影响，这表明亨廷顿病的外周免疫功能障碍可能主要是由先天免疫系统而不是获得性免疫系统介导的。这项研究增加了我们对亨廷顿病对周围组织影响的理解，同时进一步证明了突变蛋白对不同但相关的细胞类型的不同影响。最后，这项研究建议，旨在调节亨廷顿病先天性免疫系统的新疗法的潜在用途不应扩展到包括适应性免疫系统。
Huntington’s disease is a fatal neurodegenerative condition caused by a CAG repeat expansion in the huntingtin gene. The peripheral innate immune system is dysregulated in Huntington’s disease and may contribute to its pathogenesis. However, it is not clear whether or to what extent the adaptive immune system is also involved. Here, we carry out the first comprehensive investigation of human ex vivo T lymphocytes in Huntington’s disease, focusing on the frequency of a range of T lymphocyte subsets, as well as analysis of proliferation, cytokine production and gene transcription. In contrast to the innate immune system, the intrinsic phenotype of T lymphocytes does not appear to be affected by the presence of mutant huntingtin, with Huntington’s disease T lymphocytes exhibiting no significant functional differences compared to control cells. The transcriptional profile of T lymphocytes also does not appear to be significantly affected, suggesting that peripheral immune dysfunction in Huntington’s disease is likely to be mediated primarily by the innate rather than the adaptive immune system. This study increases our understanding of the effects of Huntington’s disease on peripheral tissues, while further demonstrating the differential effects of the mutant protein on different but related cell types. Finally, this study suggests that the potential use of novel therapeutics aimed at modulating the Huntington’s disease innate immune system should not be extended to include the adaptive immune system.