Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Cell. 2020 Apr 16;181(2):382-395.e21. doi: 10.1016/j.cell.2020.03.002. Epub 2020 Apr 3.
Multiple sclerosis (MS) is an autoimmune disease characterized by attack on oligodendrocytes within the central nervous system (CNS). Despite widespread use of immunomodulatory therapies, patients may still face progressive disability because of failure of myelin regeneration and loss of neurons, suggesting additional cellular pathologies. Here, we describe a general approach for identifying specific cell types in which a disease allele exerts a pathogenic effect. Applying this approach to MS risk loci, we pinpoint likely pathogenic cell types for 70%. In addition to T cell loci, we unexpectedly identified myeloid- and CNS-specific risk loci, including two sites that dysregulate transcriptional pause release in oligodendrocytes. Functional studies demonstrated inhibition of transcriptional elongation is a dominant pathway blocking oligodendrocyte maturation. Furthermore, pause release factors are frequently dysregulated in MS brain tissue. These data implicate cell-intrinsic aberrations outside of the immune system and suggest new avenues for therapeutic development. VIDEO ABSTRACT.
多发性硬化症 (MS) 是一种自身免疫性疾病，其特征是中枢神经系统 (CNS) 内的少突胶质细胞受到攻击。尽管广泛使用了免疫调节疗法，但由于髓鞘再生和神经元丧失失败，患者仍可能面临进行性残疾，这表明存在其他细胞病理学。在这里，我们描述了一种识别疾病等位基因发挥致病作用的特定细胞类型的一般方法。将这种方法应用于 MS 风险基因座，我们确定了 70%的可能致病细胞类型。除了 T 细胞基因座外，我们还意外地鉴定出了髓系和 CNS 特异性风险基因座，包括两个位点，它们会扰乱少突胶质细胞中的转录暂停释放。功能研究表明，转录延伸的抑制是阻止少突胶质细胞成熟的主要途径。此外，MS 脑组织中的暂停释放因子经常失调。这些数据表明免疫系统外的细胞内在异常，并为治疗开发提供了新途径。视频摘要。
