美国西奈山伊坎医学院Dusan Bogunovic团队通过复杂的自身炎症综合症揭示出JAK1激酶转录和生化功能的基本原理。该项研究成果于2020年8月3日在线发表在《免疫》杂志上。

研究人员报道了一个患者，其早期发病的多器官免疫功能异常是由JAK1中的镶嵌、功能获得性突变（S703I）导致的，该突变编码的激酶对超过25种细胞因子的下游信号转导必不可少。通过单细胞RNA测序，研究人员以单细胞分辨率检查了镶嵌性。研究人员发现，JAK1转录主要局限于不同细胞的单个等位基因，从而引入了与基因型不同的突变“转录型”概念。从功能上讲，该突变增加了JAK1活性并激活了与其相??关的催化结构域无关的配对JAK。S703I JAK1不仅对于细胞因子信号传导是超等位的，而且还是新变体，因为它可以实现JAK1非经典介导的信号级联。

鉴于这些结果，该患者接受了JAK抑制剂托法替尼的治疗，从而迅速解决了临床疾病。这些发现为个性化医学提供了一个平台，并同时发现了一些基本生物学原理。

据悉，自身免疫性疾病可由免疫的单基因错误引起。

附：英文原文

Title: Complex Autoinflammatory Syndrome Unveils Fundamental Principles of JAK1 Kinase Transcriptional and Biochemical Function

Author: Conor N. Gruber, Jorg J.A. Calis, Sofija Buta, Gilad Evrony, Jerome C. Martin, Skyler A. Uhl, Rachel Caron, Lauren Jarchin, David Dunkin, Robert Phelps, Bryn D. Webb, Jeffrey M. Saland, Miriam Merad, Jordan S. Orange, Emily M. Mace, Brad R. Rosenberg, Bruce D. Gelb, Dusan Bogunovic

Issue&Volume: 2020-08-03

Abstract: Autoinflammatory disease can result from monogenic errors of immunity. We describe a patient with early-onset multi-organ immune dysregulation resulting from a mosaic, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of >25 cytokines. By custom single-cell RNA sequencing, we examine mosaicism with single-cell resolution. We find that JAK1 transcription was predominantly restricted to a single allele across different cells, introducing the concept of a mutational “transcriptotype” that differs from the genotype. Functionally, the mutation increases JAK1 activity and transactivates partnering JAKs, independent of its catalytic domain. S703I JAK1 is not only hypermorphic for cytokine signaling but also neomorphic, as it enables signaling cascades not canonically mediated by JAK1. Given these results, the patient was treated with tofacitinib, a JAK inhibitor, leading to the rapid resolution of clinical disease. These findings offer a platform for personalized medicine with the concurrent discovery of fundamental biological principles.

DOI: 10.1016/j.immuni.2020.07.006

Source: https://www.cell.com/immunity/fulltext/S1074-7613(20)30313-7