TLR7 gain-of-function genetic variation causes human lupus

• Published in: Nature (London) Vol. 605; no. 7909; pp. 349 - 356
• Main Authors: Brown, Grant J., Cañete, 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., López, Cristina Aparicio, Gónzalez-Murillo, África, 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.05.2022; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/21; 13/31; 13/44; 38; 38/77; 38/91; 45; 45/23; 45/70; 631/250/38; 692/420/2780/2152/569/2494; Adaptor proteins; Animals; Antibodies; Autoimmune diseases; Autoimmunity; Autoimmunity - genetics; B-cell receptor; B-Lymphocytes; Binding sites; CD11c antigen; Cell survival; Chronic conditions; CRISPR; Cyclic GMP - analogs & derivatives; Gain of Function Mutation; Genetic diversity; Genomes; Guanosine; Guanosines; Humanities and Social Sciences; Humans; Hydrogen bonds; Ligands; Lupus; Lupus Erythematosus, Systemic - genetics; Lymphocytes; Lymphocytes B; Lymphocytes T; Mice; multidisciplinary; Mutation; MyD88 protein; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - metabolism; Pathogenesis; Phenotypes; Proteins; Receptors; Science; Science (multidisciplinary); Signaling; Survival; Systemic lupus erythematosus; TLR7 protein; Toll-Like Receptor 7 - genetics; Toll-Like Receptor 7 - metabolism; Toll-like receptors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-022-04642-z

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 RNA 8 , 9 and binds to guanosine 10 – 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. The missense TLR7 Y264H gain-of-function genetic variation causes systemic lupus erythematosus in humans and mice.