Miller James R C, Träger Ulrike, Andre Ralph, Tabrizi Sarah J
Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom.
PLoS One. 2015 Nov 3;10(11):e0141793. doi: 10.1371/journal.pone.0141793. eCollection 2015.
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.
亨廷顿舞蹈症是一种由亨廷顿基因中CAG重复序列扩增引起的致命性神经退行性疾病。亨廷顿舞蹈症患者的外周固有免疫系统失调，这可能在其发病机制中发挥作用。然而，尚不清楚适应性免疫系统是否也参与其中以及参与的程度如何。在此，我们首次对亨廷顿舞蹈症患者的人离体T淋巴细胞进行了全面研究，重点关注一系列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分析。与固有免疫系统不同，T淋巴细胞的内在表型似乎不受突变型亨廷顿蛋白存在的影响，亨廷顿舞蹈症患者的T淋巴细胞与对照细胞相比未表现出明显的功能差异。T淋巴细胞的转录谱似乎也未受到显著影响，这表明亨廷顿舞蹈症患者的外周免疫功能障碍可能主要由固有免疫系统而非适应性免疫系统介导。这项研究增进了我们对亨廷顿舞蹈症对外周组织影响的理解，同时进一步证明了突变蛋白对不同但相关细胞类型的不同影响。最后，这项研究表明，旨在调节亨廷顿舞蹈症固有免疫系统的新型疗法的潜在应用不应扩展到适应性免疫系统。
