PDF(Pubmed)
Abstract：
Primary sclerosing cholangitis (PSC) is an immune-mediated liver disease of unknown pathogenesis, with a high risk to develop cirrhosis and malignancies. Functional dysregulation of T cells and association with genetic polymorphisms in T cell-related genes were previously reported for PSC. Here, we genotyped a representative PSC cohort for several disease-associated risk loci and identified rs56258221 (BACH2/MIR4464) to correlate with not only the peripheral blood T cell immunophenotype but also the functional capacities of naive CD4+ T (CD4+ TN) cells in people with PSC. Mechanistically, rs56258221 leads to an increased expression of miR4464, in turn causing attenuated translation of BACH2, a major gatekeeper of T cell quiescence. Thereby, the fate of CD4+ TN is skewed toward polarization into pro-inflammatory subsets. Clinically, people with PSC carrying rs56258221 show signs of accelerated disease progression. The data presented here highlight the importance of assigning functional outcomes to disease-associated genetic polymorphisms as potential drivers of diseases.
摘要：
原发性硬化性胆管炎（PSC）是一种发病机制不明的免疫介导的肝病，患肝硬化和恶性肿瘤的风险很高。先前报道了PSC的T细胞功能失调以及与T细胞相关基因的遗传多态性的关联。这里,我们对一个代表性的PSC队列进行了几个疾病相关风险位点的基因分型,并确定rs56258221(BACH2/MIR4464)不仅与PSC患者外周血T细胞免疫表型相关,而且与初始CD4+T(CD4+TN)细胞的功能能力相关.机械上,rs56258221导致miR4464的表达增加，进而导致T细胞静止的主要看门人BACH2的翻译减弱。因此，CD4+TN的命运偏向极化为促炎性亚群。临床上,携带rs56258221的PSC患者显示出疾病进展加速的迹象。这里提供的数据强调了将功能结果分配给疾病相关的遗传多态性作为潜在的疾病驱动因素的重要性。
