广州医科大学Seth L. Masters、张玉霞课题组取得一项新突破。他们的最新研究揭示了UNC93B1基因突变易致儿童期全身性红斑狼疮。相关论文于2024年6月3日发表在《自然—免疫学》杂志上。

据了解，已知toll样受体7 (TLR7)的罕见遗传变异会在人类和小鼠中引起红斑狼疮。UNC93B1是一种跨膜蛋白，调节TLR7在核内体中的定位。

在本研究中，课题组人员在一组东亚儿童发病的系统性红斑狼疮患者中发现了两个新的UNC93B1突变(T314A，位于TLR7跨膜结构域的近端，和V117L)。V117L突变与患者血浆和永生化B细胞中I型干扰素和NF-κB依赖性细胞因子的表达增加有关。

表达UNC93B1突变等位基因的THP-1细胞对TLR7/-8的刺激反应增强，但对TLR3或TLR9没有反应，可以通过靶向下游信号分子IRAK1/-4来抑制。表达同源基因Unc93b1^V117L突变的杂合子小鼠患上了一种自发的红斑狼疮样疾病，这种疾病在纯合子小鼠中更为严重，并且再次对TLR7刺激产生过度反应。总之，这项工作正式确定了UNC93B1的遗传突变，该突变可导致儿童期发病的系统性红斑狼疮。

附：英文原文

Title: Genetic variants in UNC93B1 predispose to childhood-onset systemic lupus erythematosus

Author: Al-Azab, Mahmoud, Idiiatullina, Elina, Liu, Ziyang, Lin, Meng, Hrovat-Schaale, Katja, Xian, Huifang, Zhu, Jianheng, Yang, Mandy, Lu, Bingtai, Zhao, Zhiyao, Liu, Yiyi, Chang, Jingjie, Li, Xiaotian, Guo, Caiqin, Liu, Yunfeng, Wu, Qi, Chen, Jiazhang, Lan, Chaoting, Zeng, Ping, Cui, Jun, Gao, Xia, Zhou, Wenhao, Zhang, Yan, Zhang, Yuxia, Masters, Seth L.

Issue&Volume: 2024-06-03

Abstract: Rare genetic variants in toll-like receptor 7 (TLR7) are known to cause lupus in humans and mice. UNC93B1 is a transmembrane protein that regulates TLR7 localization into endosomes. In the present study, we identify two new variants in UNC93B1 (T314A, located proximally to the TLR7 transmembrane domain, and V117L) in a cohort of east Asian patients with childhood-onset systemic lupus erythematosus. The V117L variant was associated with increased expression of type I interferons and NF-κB-dependent cytokines in patient plasma and immortalized B cells. THP-1 cells expressing the variant UNC93B1 alleles exhibited exaggerated responses to stimulation of TLR7/-8, but not TLR3 or TLR9, which could be inhibited by targeting the downstream signaling molecules, IRAK1/-4. Heterozygous mice expressing the orthologous Unc93b1V117L variant developed a spontaneous lupus-like disease that was more severe in homozygotes and again hyperresponsive to TLR7 stimulation. Together, this work formally identifies genetic variants in UNC93B1 that can predispose to childhood-onset systemic lupus erythematosus.

DOI: 10.1038/s41590-024-01846-5

Source: https://www.nature.com/articles/s41590-024-01846-5