小柯机器人

澳大利亚国立大学Carola G. Vinuesa研究组近日取得一项新成果。经过不懈努力，他们发现Toll样受体7(TLR7)功能获得基因变异会导致人类狼疮。2022年4月27日出版的《自然》发表了这项成果。

研究人员发现了由TLR7功能获得变体造成的人类系统性红斑狼疮。TLR7是病毒RNA的感受器，可与鸟苷结合。研究人员在一名患有严重狼疮的儿童中发现了之前未报道的TLR7^Y264H错义变异，并且在其他狼疮患者中发现了TLR7的其他变异。TLR7^Y264H变体选择性地增强了对鸟苷和 2',3'-cGMP的感知，并且该突变可导致小鼠产生狼疮。研究表明，TLR7信号传导增强诱导B细胞受体(BCR)激活的异常B细胞存活，并以细胞内在的方式导致CD11c⁺相关B细胞和生发中心B细胞产生年龄依赖性积累。

滤泡和滤泡外辅助T细胞数目也会增加，但这些都是细胞外源性的。MyD88（TLR7下游的衔接蛋白）的缺失挽救了自身免疫、异常B细胞存活以及所有细胞和血清表型。尽管TLR7^Y264H小鼠形成显著的自发生发中心，但自身免疫并未因生发中心缺乏而得到改善，这表明致病性B细胞起源于滤泡外。研究确定了TLR7和含鸟苷自身配体对人类狼疮发病的重要性，这为治疗性TLR7应用或抑制MyD88铺平了道路。

据悉，尽管间接证据支持TLR7信号传导增强是导致人系统性自身免疫疾病的原因，但缺乏TLR7基因变异诱导狼疮的证据。

附：英文原文

Title: TLR7 gain-of-function genetic variation causes human lupus

Author: Brown, Grant J., Caete, Pablo F., Wang, Hao, Medhavy, Arti, Bones, Josiah, Roco, Jonathan A., He, Yuke, Qin, Yuting, Cappello, Jean, Ellyard, Julia I., Bassett, Katharine, Shen, Qian, Burgio, Gaetan, Zhang, Yaoyuan, Turnbull, Cynthia, Meng, Xiangpeng, Wu, Phil, Cho, Eun, Miosge, Lisa A., Andrews, T. Daniel, Field, Matt A., Tvorogov, Denis, Lopez, Angel F., Babon, Jeffrey J., Lpez, Cristina Aparicio, Gnzalez-Murillo, frica, Garulo, Daniel Clemente, Pascual, Virginia, Levy, Tess, Mallack, Eric J., Calame, Daniel G., Lotze, Timothy, Lupski, James R., Ding, Huihua, Ullah, Tomalika R., Walters, Giles D., Koina, Mark E., Cook, Matthew C., Shen, Nan, de Lucas Collantes, Carmen, Corry, Ben, Gantier, Michael P., Athanasopoulos, Vicki, Vinuesa, Carola G.

Issue&Volume: 2022-04-27

Abstract: Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease1,2,3,4,5,6,7, 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 RNA8,9 and binds to guanosine10,11,–12. 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'-cGMP10,11,12, 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.

DOI: 10.1038/s41586-022-04642-z

Source: https://www.nature.com/articles/s41586-022-04642-z

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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