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 Unc93b1^V117L 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.

已知 Toll 样受体 7 (TLR7) 的罕见遗传变异会导致人类和小鼠患狼疮。 UNC93B1 是一种跨膜蛋白，调节 TLR7 定位到核内体中。在本研究中，我们在一组东亚儿童期发病的系统性红斑狼疮患者中发现了 UNC93B1 的两个新变体（T314A，位于 TLR7 跨膜结构域附近，以及 V117L）。 V117L 变异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。表达变异 UNC93B1 等位基因的 THP-1 细胞对 TLR7/-8 的刺激表现出过度的反应，但对 TLR3 或 TLR9 的刺激没有反应，可以通过靶向下游信号分子 IRAK1/-4 来抑制这种反应。表达直系同源 Unc93b1 ^V117L变体的杂合子小鼠出现了一种自发性狼疮样疾病，这种疾病在纯合子中更为严重，并且再次对 TLR7 刺激过度反应。总之，这项工作正式鉴定了 UNC93B1 中可能诱发儿童期发病的系统性红斑狼疮的遗传变异。