Interface Gain-of-Function Mutations in TLR7 Cause Systemic and Neuro-inflammatory Disease
Interface Gain-of-Function Mutations in TLR7 Cause Systemic and Neuro-inflammatory Disease
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DOI：
10.1007/s10875-024-01660-6
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发表时间：
2024-02
影响因子：
9.1
通讯作者：
Clémence David;Mihaly Badonyi;Robin Kechiche;Antonella Insalaco;M. Zecca;Fabrizio de Benedetti
中科院分区：
文献类型：
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作者：
Clémence David;Mihaly Badonyi;Robin Kechiche;Antonella Insalaco;M. Zecca;Fabrizio de Benedetti
TLR7识别病原体来源的单链RNA（ssRNA），这是对病毒感染的先天免疫应答不可或缺的功能。值得注意的是，TLR7还可以识别自身衍生的ssRNA，最近发现人类TLR7中的功能获得性突变可导致早发性系统性红斑狼疮（SLE）和视神经肌萎缩症。在这里，我们描述了两个新的TLR7突变，F507S和L528I。虽然L528I替换从头开始，但F507S突变存在于来自同一家族的三个个体中，包括一名严重受影响的男性，特别是考虑到TLR7基因位于X染色体上，并且迄今为止描述的所有其他病例都是女性。在TLR7的残基507和528处的突变的观察表明TLR7二聚化界面在维持免疫稳态中的重要性，其中我们预测改变的同源二聚化增强TLR7信号传导。最后，虽然TLR7突变可导致SLE样疾病，但我们的数据表明与TLR7功能获得相关的更广泛的表型谱，包括显著的神经系统受累。
TLR7 recognizes pathogen-derived single-stranded RNA (ssRNA), a function integral to the innate immune response to viral infection. Notably, TLR7 can also recognize self-derived ssRNA, with gain-of-function mutations in human TLR7 recently identified to cause both early-onset systemic lupus erythematosus (SLE) and neuromyelitis optica. Here, we describe two novel mutations in TLR7, F507S and L528I. While the L528I substitution arose de novo, the F507S mutation was present in three individuals from the same family, including a severely affected male, notably given that the TLR7 gene is situated on the X chromosome and that all other cases so far described have been female. The observation of mutations at residues 507 and 528 of TLR7 indicates the importance of the TLR7 dimerization interface in maintaining immune homeostasis, where we predict that altered homo-dimerization enhances TLR7 signaling. Finally, while mutations in TLR7 can result in SLE-like disease, our data suggest a broader phenotypic spectrum associated with TLR7 gain-of-function, including significant neurological involvement.