TLR7 gain-of-function genetic variation causes human lupus

Nature. 2022 May;605(7909):349-356. doi: 10.1038/s41586-022-04642-z.

Grant J Brown ¹, Pablo F Cañete ^# ¹, Hao Wang ^# ¹, Arti Medhavy ¹, Josiah Bones ², Jonathan A Roco ¹, Yuke He ³, Yuting Qin ³, Jean Cappello ¹, Julia I Ellyard ¹, Katharine Bassett ¹, Qian Shen ¹, Gaetan Burgio ¹, Yaoyuan Zhang ¹, Cynthia Turnbull ¹, Xiangpeng Meng ¹, Phil Wu ¹, Eun Cho ¹, Lisa A Miosge ¹, T Daniel Andrews ¹, Matt A Field ¹ ⁴, Denis Tvorogov ⁵, Angel F Lopez ⁵, Jeffrey J Babon ⁶, Cristina Aparicio López ⁷, África Gónzalez-Murillo ⁸ ⁹, Daniel Clemente Garulo ¹⁰, Virginia Pascual ¹¹, Tess Levy ¹² ¹³, Eric J Mallack ¹⁴, Daniel G Calame ¹⁵ ¹⁶ ¹⁷, Timothy Lotze ¹⁵ ¹⁶, James R Lupski ¹⁶ ¹⁷ ¹⁸ ¹⁹, Huihua Ding ³ ²⁰, Tomalika R Ullah ²¹ ²², Giles D Walters ²³, Mark E Koina ²⁴, Matthew C Cook ¹, Nan Shen ³ ²⁰ ²⁵, Carmen de Lucas Collantes ⁷ ²⁶, Ben Corry ², Michael P Gantier ²⁰ ²¹, Vicki Athanasopoulos ¹, Carola G Vinuesa ²⁷ ²⁸ ²⁹

Affiliations

1 Centre for Personalised Immunology, Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia.
2 Research School of Biology, Australian National University, Canberra, Australian Capital Territory, Australia.
3 China Australia Centre for Personalised Immunology, Shanghai Renji Hospital, Shanghai Jiaotong University, Shanghai, China.
4 Centre for Tropical Bioinformatics and Molecular Biology, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland, Australia.
5 Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, South Australia, Australia.
6 Division of Structural Biology, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
7 Sección de Nefrología, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
8 Unidad de Terapias Avanzadas, Oncología, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
9 Fundación de Investigación Biomédica, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
10 Unidad de Reumatología, Hospital del Niño Jesus, Madrid, Spain.
11 Department of Pediatrics, Drukier Institute for Children's Health, Weill Cornell Medical College, New York, NY, USA.
12 Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
13 Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
14 Division of Child Neurology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA.
15 Division of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
16 Texas Children's Hospital, Houston, TX, USA.
17 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
18 Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
19 Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
20 Shanghai Institute of Rheumatology, Renji Hospital, School of Medicine, Shanghai, Jiao Tong University (SJTUSM), Shanghai, China.
21 Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
22 Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
23 Department of Renal Medicine, The Canberra Hospital, Canberra, Australian Capital Territory, Australia.
24 Department of Anatomical Pathology, The Canberra Hospital, Canberra, Australian Capital Territory, Australia.
25 Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
26 Departamento de Pediatría. Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Madrid, Spain.
27 Centre for Personalised Immunology, Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia. carola.vinuesa@crick.ac.uk.
28 Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, South Australia, Australia. carola.vinuesa@crick.ac.uk.
29 Francis Crick Institute, London, UK. carola.vinuesa@crick.ac.uk.
# Contributed equally.

PMID: 35477763 DOI: 10.1038/s41586-022-04642-z

Abstract

Although circumstantial evidence supports enhanced Toll-like Receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease^1-7, 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 TLR7^Y264H variant in a child with severe lupus and additional variants in other patients with lupus. The TLR7^Y264H variant selectively increased sensing of guanosine and 2',3'-cGMP^10-12, 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 TLR7^Y264H 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.

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