Our study presents a novel germline c.1715G>T (p.G572V) mutation in the gene encoding Toll-like receptor 8 (TLR8) causing an autoimmune and autoinflammatory disorder in a family with monozygotic male twins, who suffer from severe autoimmune hemolytic anemia worsening with infections, and autoinflammation presenting as fevers, enteritis, arthritis, and CNS vasculitis. The pathogenicity of the mutation was confirmed by in vitro assays on transfected cell lines and primary cells. The p.G572V mutation causes impaired stability of the TLR8 protein, cross-reactivity to TLR7 ligands and reduced ability of TLR8 to attenuate TLR7 signaling. This imbalance toward TLR7-dependent signaling leads to increased pro-inflammatory responses, such as nuclear factor-κB (NF-κB) activation and production of pro-inflammatory cytokines IL-1β, IL-6, and TNFα. This unique TLR8 mutation with partial TLR8 protein loss and hyperinflammatory phenotype mediated by TLR7 ligands represents a novel inborn error of immunity with childhood-onset and a good response to TLR7 inhibition.

中文翻译：

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由于新的 TLR8 突变导致的 TLR8/TLR7 失调导致同卵双胞胎发生严重的自身免疫性溶血性贫血和自身炎症

我们的研究在编码 Toll 样受体 8 ( TLR8) 在一个有同卵双胞胎的家庭中引起自身免疫性和自身炎症性疾病，这些双胞胎患有严重的自身免疫性溶血性贫血并随着感染而恶化，自身炎症表现为发烧、肠炎、关节炎和中枢神经系统血管炎。通过转染细胞系和原代细胞的体外试验证实了突变的致病性。p.G572V 突变导致 TLR8 蛋白的稳定性受损、与 TLR7 配体的交叉反应性以及 TLR8 减弱 TLR7 信号传导的能力降低。这种对 TLR7 依赖性信号传导的不平衡导致促炎反应增加，例如核因子-κB (NF-κB) 激活和促炎细胞因子 IL-1β、IL-6 和 TNFα 的产生。这种独特的TLR8由 TLR7 配体介导的具有部分 TLR8 蛋白丢失和高炎症表型的突变代表了一种新的先天性免疫错误，儿童期发病和对 TLR7 抑制的良好反应。