New candidates for CD4 T cell pathogenicity in experimental neuroinflammation and multiple sclerosis
New candidates for CD4 T cell pathogenicity in experimental neuroinflammation and multiple sclerosis
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DOI：
10.1093/brain/awu408
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发表时间：
2015-04-01
期刊：
影响因子：
14.5
通讯作者：
Siffrin, Volker
中科院分区：
文献类型：
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作者：
Hoppmann, Nicola;Graetz, Christiane;Siffrin, Volker
通过分析多发性硬化的实验性自身免疫性脑脊髓炎（EAE）模型中鼠T细胞的转录组学变化，Hoppmann等人鉴定了在CD 4 + T细胞致病性中起作用的候选物。此外，他们表明，一个高度显着比例的多发性硬化症的风险基因差异调节EAE.Multiple硬化症是一种慢性自身免疫性脱髓鞘疾病的中枢神经系统，这被认为是由环境因素在遗传易感个体导致自身反应性T淋巴细胞的激活。大型多中心全基因组关联研究已经确定了多发性硬化症的多个遗传风险位点。在这项研究中，我们研究了多发性硬化症的动物模型实验性自身免疫性脑脊髓炎中T细胞转录组的变化。我们将这些发现与最新免疫芯片分析假设的多发性硬化症风险基因相关联，发现多发性硬化症易感基因在实验性自身免疫性脑脊髓炎中受到显著调节。我们的数据表明，9个与多发性硬化风险相关的不同基因，Bach 2，Il 2 ra，Irf 8，Mertk，Odf 3b，Plek，Rgs 1，Slc 30 a7和Thada，可以证实在致病性CD 4（+）T细胞中受到差异调节。在炎症中枢神经系统内的效应阶段，CD 4（+）T细胞经历全面的转化，我们确定了参与这一过程的关键转录因子和信号网络。这种转化与肝脏X受体/类维生素A X受体信号传导和胆固醇生物合成参与的代谢变化有关，这可能控制中枢神经系统中的T细胞效应器功能。因此，我们的研究证实了多发性硬化症风险基因参与动物模型的病理生理学，并揭示了其他疾病相关的炎症网络。
By analysing transcriptomic changes in murine T cells in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis, Hoppmann et al. identify candidates with a role in CD4+ T cell pathogenicity. Moreover, they show that a highly significant proportion of multiple sclerosis risk genes are differentially regulated in EAE.Multiple sclerosis is a chronic autoimmune demyelinating disease of the central nervous system, which is thought to be triggered by environmental factors in genetically susceptible individuals leading to activation of autoreactive T lymphocytes. Large multi-centre genome-wide association studies have identified multiple genetic risk loci in multiple sclerosis. In this study, we investigated T cell transcriptomic changes in experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis. We correlated these findings with the multiple sclerosis risk genes postulated by the most recent Immunochip analysis and found that multiple sclerosis susceptibility genes were significantly regulated in experimental autoimmune encephalomyelitis. Our data indicate that nine distinct genes associated with multiple sclerosis risk, Bach2, Il2ra, Irf8, Mertk, Odf3b, Plek, Rgs1, Slc30a7 and Thada, can be confirmed to be differentially regulated in pathogenic CD4(+) T cells. During the effector phase within the inflamed CNS, CD4(+) T cells undergo comprehensive transformation and we identified key transcription factors and signalling networks involved in this process. The transformation was linked to metabolic changes with the involvement of liver X receptor/retinoid X receptor signalling and cholesterol biosynthesis, which might control the T cell effector function in the central nervous system. Thus, our study confirms the involvement of multiple sclerosis risk genes in the pathophysiology of the animal model and sheds light on additional disease-relevant inflammatory networks.