TLR7 gain-of-function genetic variation causes human lupus

Grant J. Brown, Pablo F. Cañete, Hao Wang, Arti Medhavy, Josiah Bones, Jonathan A. Roco, Yuke He, Yuting Qin, Jean Cappello, Julia I. Ellyard, Katharine Bassett, Qian Shen, Gaetan Burgio, Yaoyuan Zhang, Cynthia Turnbull, Xiangpeng Meng, Phil Wu, Eun Cho, Lisa A. Miosge, T. Daniel Andrews, Matt A. Field, Denis Tvorogov, Angel F. Lopez, Jeffrey J. Babon, Cristina Aparicio López, África Gónzalez-Murillo, Daniel Clemente Garulo, Virginia Pascual, Tess Levy, Eric J. Mallack, Daniel G. Calame, Timothy Lotze, James R. Lupski, Huihua Ding, Tomalika R. Ullah, Giles D. Walters, Mark E. Koina, Matthew C. Cook, Nan Shen, Carmen Lucas Collantes, Ben Corry, Michael P. Gantier, Vicki Athanasopoulos and Carola G. Vinuesa ()
Additional contact information
Grant J. Brown: John Curtin School of Medical Research, Australian National University
Pablo F. Cañete: John Curtin School of Medical Research, Australian National University
Hao Wang: John Curtin School of Medical Research, Australian National University
Arti Medhavy: John Curtin School of Medical Research, Australian National University
Josiah Bones: Australian National University
Jonathan A. Roco: John Curtin School of Medical Research, Australian National University
Yuke He: Shanghai Renji Hospital, Shanghai Jiaotong University
Yuting Qin: Shanghai Renji Hospital, Shanghai Jiaotong University
Jean Cappello: John Curtin School of Medical Research, Australian National University
Julia I. Ellyard: John Curtin School of Medical Research, Australian National University
Katharine Bassett: John Curtin School of Medical Research, Australian National University
Qian Shen: John Curtin School of Medical Research, Australian National University
Gaetan Burgio: John Curtin School of Medical Research, Australian National University
Yaoyuan Zhang: John Curtin School of Medical Research, Australian National University
Cynthia Turnbull: John Curtin School of Medical Research, Australian National University
Xiangpeng Meng: John Curtin School of Medical Research, Australian National University
Phil Wu: John Curtin School of Medical Research, Australian National University
Eun Cho: John Curtin School of Medical Research, Australian National University
Lisa A. Miosge: John Curtin School of Medical Research, Australian National University
T. Daniel Andrews: John Curtin School of Medical Research, Australian National University
Matt A. Field: John Curtin School of Medical Research, Australian National University
Denis Tvorogov: SA Pathology and the University of South Australia
Angel F. Lopez: SA Pathology and the University of South Australia
Jeffrey J. Babon: Walter and Eliza Hall Institute of Medical Research
Cristina Aparicio López: Hospital Infantil Universitario Niño Jesús
África Gónzalez-Murillo: Hospital Infantil Universitario Niño Jesús
Daniel Clemente Garulo: Hospital del Niño Jesus
Virginia Pascual: Drukier Institute for Children’s Health, Weill Cornell Medical College
Tess Levy: Icahn School of Medicine at Mount Sinai
Eric J. Mallack: New York-Presbyterian Hospital
Daniel G. Calame: Baylor College of Medicine
Timothy Lotze: Baylor College of Medicine
James R. Lupski: Texas Children’s Hospital
Huihua Ding: Shanghai Renji Hospital, Shanghai Jiaotong University
Tomalika R. Ullah: Hudson Institute of Medical Research
Giles D. Walters: The Canberra Hospital
Mark E. Koina: The Canberra Hospital
Matthew C. Cook: John Curtin School of Medical Research, Australian National University
Nan Shen: Shanghai Renji Hospital, Shanghai Jiaotong University
Carmen Lucas Collantes: Hospital Infantil Universitario Niño Jesús
Ben Corry: Australian National University
Michael P. Gantier: Renji Hospital, School of Medicine, Shanghai, Jiao Tong University (SJTUSM)
Vicki Athanasopoulos: John Curtin School of Medical Research, Australian National University
Carola G. Vinuesa: John Curtin School of Medical Research, Australian National University

Nature, 2022, vol. 605, issue 7909, 349-356

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-04642-z

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