TLR7 gain-of-function genetic variation causes human lupus.
TLR7 gain-of-function genetic variation causes human lupus.
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TLR7 功能获得性遗传变异导致人类狼疮
DOI：
10.1038/s41586-022-04642-z
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发表时间：
2022-05
期刊：
影响因子：
64.8
通讯作者：
中科院分区：
文献类型：
--
作者：
尽管间接证据支持增强的Toll样受体7基因(TLR7)信号是人类系统性自身免疫性疾病的一种机制，但缺乏导致狼疮的TLR7基因变异的证据。在这里，我们描述了由TLR7功能获得变异引起的人类系统性红斑狼疮。TLR7是病毒RNA的传感器，并与鸟苷结合。我们在一名严重狼疮儿童中发现了一种从头开始的、以前未描述的错义TLR7Y264H变体，并在其他狼疮患者中发现了其他变体。TLR7Y264H突变体选择性地增加了对鸟苷和2‘，3’-cGMP的感知，当被引入小鼠时足以引起狼疮。我们发现，增强的TLR7信号驱动B细胞受体(BCR)激活的B细胞异常存活，并以细胞内的方式促进CD11c+AGE相关的B细胞和生发中心B细胞的积累。滤泡和滤泡外辅助T细胞也增加，但这些表型是细胞外源性的。MyD88基因的缺失(TLR7下游的一种接头蛋白)挽救了自身免疫、异常的B细胞存活以及所有的细胞和血清学表型。尽管在Tlr7Y264H小鼠中有显著的自发生发中心形成，但生发中心缺陷并不能改善自身免疫，提示致病B细胞起源于卵泡外。我们确定了TLR7和鸟苷自身配体在人类狼疮发病机制中的重要性，为治疗TLR7或MyD88的抑制铺平了道路。错义TLR7Y264H功能获得基因变异导致人类和小鼠的系统性红斑狼疮。
Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease, evidence of lupus-causing TLR7 gene variants is lacking. Here we describe human systemic lupus erythematosus caused by a TLR7 gain-of-function variant. TLR7 is a sensor of viral RNA, and binds to guanosine–. We identified a de novo, previously undescribed missense TLR7Y264H variant in a child with severe lupus and additional variants in other patients with lupus. The TLR7Y264H variant selectively increased sensing of guanosine and 2',3'-cGMP, and was sufficient to cause lupus when introduced into mice. We show that enhanced TLR7 signalling drives aberrant survival of B cell receptor (BCR)-activated B cells, and in a cell-intrinsic manner, accumulation of CD11c+ age-associated B cells and germinal centre B cells. Follicular and extrafollicular helper T cells were also increased but these phenotypes were cell-extrinsic. Deficiency of MyD88 (an adaptor protein downstream of TLR7) rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. Despite prominent spontaneous germinal-centre formation in Tlr7Y264H mice, autoimmunity was not ameliorated by germinal-centre deficiency, suggesting an extrafollicular origin of pathogenic B cells. We establish the importance of TLR7 and guanosine-containing self-ligands for human lupus pathogenesis, which paves the way for therapeutic TLR7 or MyD88 inhibition. The missense TLR7Y264H gain-of-function genetic variation causes systemic lupus erythematosus in humans and mice.
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