TLR7 gain-of-function genetic variation causes human lupus
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Brown, Grant J; Fernandez De Canete Nieto, Pablo; Wang, Howard; Medhavy, Arti; Bones, Josiah; Roco, Jonathan; He, Yuke; Qin, Yuting; Cappello, Jean; Ellyard, Julia; Bassett, Katharine; Shen, Qian; Burgio, Gaetan; Zhang, Yaoyuan; Turnbull, Cynthia; MENG, Xiangpeng; Wu, Philip; Cho, Vicky; Miosge, Lisa; Andrews, Daniel; Field, Matthew; Tvorogov, Denis; Lopez, Angel F.; Babon, Jeffrey J; López, Cristina; Gónzalez-Murillo, Africa; Garulo, Daniel Clemente; Pascual, Virginia; Levy, Tess; Cook, Matthew; Corry, Ben; Athanasopoulos, Vicki; Vinuesa, Carola
Description
Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease1-7, 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 guanosine10-12. We identified a de novo, previously undescribed missense TLR7Y264H variant in a child with severe lupus and additional variants in other...[Show more]
dc.contributor.author | Brown, Grant J | |
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dc.contributor.author | Fernandez De Canete Nieto, Pablo | |
dc.contributor.author | Wang, Howard | |
dc.contributor.author | Medhavy, Arti | |
dc.contributor.author | Bones, Josiah | |
dc.contributor.author | Roco, Jonathan | |
dc.contributor.author | He, Yuke | |
dc.contributor.author | Qin, Yuting | |
dc.contributor.author | Cappello, Jean | |
dc.contributor.author | Ellyard, Julia | |
dc.contributor.author | Bassett, Katharine | |
dc.contributor.author | Shen, Qian | |
dc.contributor.author | Burgio, Gaetan | |
dc.contributor.author | Zhang, Yaoyuan | |
dc.contributor.author | Turnbull, Cynthia | |
dc.contributor.author | MENG, Xiangpeng | |
dc.contributor.author | Wu, Philip | |
dc.contributor.author | Cho, Vicky | |
dc.contributor.author | Miosge, Lisa | |
dc.contributor.author | Andrews, Daniel | |
dc.contributor.author | Field, Matthew | |
dc.contributor.author | Tvorogov, Denis | |
dc.contributor.author | Lopez, Angel F. | |
dc.contributor.author | Babon, Jeffrey J | |
dc.contributor.author | López, Cristina | |
dc.contributor.author | Gónzalez-Murillo, Africa | |
dc.contributor.author | Garulo, Daniel Clemente | |
dc.contributor.author | Pascual, Virginia | |
dc.contributor.author | Levy, Tess | |
dc.contributor.author | Cook, Matthew | |
dc.contributor.author | Corry, Ben | |
dc.contributor.author | Athanasopoulos, Vicki | |
dc.contributor.author | Vinuesa, Carola | |
dc.date.accessioned | 2024-03-28T05:23:40Z | |
dc.date.available | 2024-03-28T05:23:40Z | |
dc.identifier.issn | 1476-4687 | |
dc.identifier.uri | http://hdl.handle.net/1885/316395 | |
dc.description.abstract | Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease1-7, 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 guanosine10-12. 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'-cGMP10-12, 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. | |
dc.format.mimetype | application/pdf | |
dc.language.iso | en_AU | |
dc.publisher | Nature Publishing Group | |
dc.rights | © 2022 | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.source | Nature | |
dc.title | TLR7 gain-of-function genetic variation causes human lupus | |
dc.type | Journal article | |
local.description.notes | Imported from ARIES | |
local.identifier.citationvolume | 605 | |
dc.date.issued | 2022 | |
local.identifier.absfor | 320403 - Autoimmunity | |
local.identifier.absfor | 340402 - Biomolecular modelling and design | |
local.identifier.absfor | 310110 - Receptors and membrane biology | |
local.identifier.ariespublication | u5399821xPUB36 | |
local.publisher.url | https://www.nature.com/articles/s41586-022-04642-z | |
local.type.status | Published Version | |
local.contributor.affiliation | Brown, Grant, College of Health and Medicine, ANU | |
local.contributor.affiliation | Fernandez De Canete Nieto, Pablo, College of Health and Medicine, ANU | |
local.contributor.affiliation | Wang, Howard, College of Health and Medicine, ANU | |
local.contributor.affiliation | Medhavy, Arti, College of Health and Medicine, ANU | |
local.contributor.affiliation | Bones, Josiah, College of Science, ANU | |
local.contributor.affiliation | Roco, Jonathan, College of Health and Medicine, ANU | |
local.contributor.affiliation | He, Yuke, Shanghai Jiaotong University | |
local.contributor.affiliation | Qin, Yuting, Shanghai Jiaotong University | |
local.contributor.affiliation | Cappello, Jean, College of Health and Medicine, ANU | |
local.contributor.affiliation | Ellyard, Julia, College of Health and Medicine, ANU | |
local.contributor.affiliation | Bassett, Katharine, College of Health and Medicine, ANU | |
local.contributor.affiliation | Shen, Qian, College of Health and Medicine, ANU | |
local.contributor.affiliation | Burgio, Gaetan, College of Health and Medicine, ANU | |
local.contributor.affiliation | Zhang, Yaoyuan, College of Health and Medicine, ANU | |
local.contributor.affiliation | Turnbull, Cynthia, College of Health and Medicine, ANU | |
local.contributor.affiliation | Meng, Xiangpeng, College of Health and Medicine, ANU | |
local.contributor.affiliation | Wu, Philip, College of Health and Medicine, ANU | |
local.contributor.affiliation | Cho, Vicky, College of Health and Medicine, ANU | |
local.contributor.affiliation | Miosge, Lisa, College of Health and Medicine, ANU | |
local.contributor.affiliation | Andrews, Daniel, College of Health and Medicine, ANU | |
local.contributor.affiliation | Field, Matthew, College of Health and Medicine, ANU | |
local.contributor.affiliation | Tvorogov, Denis, SA Pathology and the University of South Australia | |
local.contributor.affiliation | Lopez, Angel F., SA Pathology | |
local.contributor.affiliation | Babon, Jeffrey J, Walter and Eliza Hall Institute and the University of Melbourne | |
local.contributor.affiliation | López, Cristina, Hospital Infantil Universitario Nino Jesus | |
local.contributor.affiliation | Gónzalez-Murillo, Africa, Hospital Infantil Universitario Nino Jesus | |
local.contributor.affiliation | Garulo, Daniel Clemente, Hospital Infantil Universitario Nino Jesus | |
local.contributor.affiliation | Pascual, Virginia, Weill Cornell Medical College | |
local.contributor.affiliation | Levy, Tess, Icahn School of Medicine at Mount Sinai | |
local.contributor.affiliation | Cook, Matthew, College of Health and Medicine, ANU | |
local.contributor.affiliation | Corry, Ben, College of Science, ANU | |
local.contributor.affiliation | Athanasopoulos, Vicki, College of Health and Medicine, ANU | |
local.contributor.affiliation | Vinuesa, Carola, College of Health and Medicine, ANU | |
local.bibliographicCitation.startpage | 349 | |
local.bibliographicCitation.lastpage | 356 | |
local.identifier.doi | 10.1038/s41586-022-04642-z | |
dc.date.updated | 2022-11-13T07:19:17Z | |
dcterms.accessRights | Open Access | |
dc.provenance | This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. | |
dc.rights.license | Creative Commons Attribution 4.0 International License | |
Collections | ANU Research Publications |
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