小柯机器人

SYK功能获得变异导致免疫失调和全身性炎症
2021-03-30 16:07

华东师范大学李大力和复旦大学附属儿童医院黄瑛等研究组合作取得一项新成果。他们的研究表明脾酪氨酸激酶(SYK)的功能获得变异导致人类和小鼠的免疫失调和全身性炎症。相关论文发表在2021年3月29日出版的《自然-遗传学》杂志上。

他们在六名患有免疫缺、多器官炎性疾病(例如结肠炎、关节炎和皮炎)以及弥漫性大B细胞淋巴瘤的患者中鉴定了破坏性单等位基因SYK变体。SYK变体增加了磷酸化并增强了下游信号传导,表明功能获得。患者变体(p.Ser550Tyr)的敲入(SYK-Ser544Tyr)小鼠模型概括了人类疾病的各个方面,这些疾病可以用SYK抑制剂部分治疗或从野生型小鼠移植骨髓。

他们的研究表明,SYK功能获得变异会导致潜在的可治疗形式的炎症性疾病。

据了解,SYK是重要的免疫信号分子和治疗靶标。

附:英文原文

Title: Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice

Author: Lin Wang, Dominik Aschenbrenner, Zhiyang Zeng, Xiya Cao, Daniel Mayr, Meera Mehta, Melania Capitani, Neil Warner, Jie Pan, Liren Wang, Qi Li, Tao Zuo, Sarit Cohen-Kedar, Jiawei Lu, Rico Chandra Ardy, Daniel J. Mulder, Dilan Dissanayake, Kaiyue Peng, Zhiheng Huang, Xiaoqin Li, Yuesheng Wang, Xiaobing Wang, Shuchao Li, Samuel Bullers, Ans N. Gammage, Klaus Warnatz, Ana-Iris Schiefer, Gergely Krivan, Vera Goda, Walter H. A. Kahr, Mathieu Lemaire, Chien-Yi Lu, Iram Siddiqui, Michael G. Surette, Daniel Kotlarz, Karin R. Engelhardt, Helen R. Griffin, Robert Rottapel, Hlne Decaluwe, Ronald M. Laxer, Michele Proietti, Sophie Hambleton, Suzanne Elcombe, Cong-Hui Guo, Bodo Grimbacher, Iris Dotan, Siew C. Ng, Spencer A. Freeman, Scott B. Snapper, Christoph Klein, Kaan Boztug, Ying Huang, Dali Li, Holm H. Uhlig, Aleixo M. Muise

Issue&Volume: 2021-03-29

Abstract: Spleen tyrosine kinase (SYK) is a critical immune signaling molecule and therapeutic target. We identified damaging monoallelic SYK variants in six patients with immune deficiency, multi-organ inflammatory disease such as colitis, arthritis and dermatitis, and diffuse large B cell lymphomas. The SYK variants increased phosphorylation and enhanced downstream signaling, indicating gain of function. A knock-in (SYK-Ser544Tyr) mouse model of a patient variant (p.Ser550Tyr) recapitulated aspects of the human disease that could be partially treated with a SYK inhibitor or transplantation of bone marrow from wild-type mice. Our studies demonstrate that SYK gain-of-function variants result in a potentially treatable form of inflammatory disease. Individuals with SYK gain-of-function variants develop immunodeficiency and systemic inflammation, which are recapitulated in a knock-in mouse model. Treatment of these mice with bone marrow transplantation or with a SYK inhibitor ameliorates disease symptoms, highlighting potential therapeutic strategies for patients with SYK mutations.

DOI: 10.1038/s41588-021-00803-4

Source: https://www.nature.com/articles/s41588-021-00803-4

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:41.307
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex


本期文章:《自然—遗传学》:Online/在线发表

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