TLR7 gain-of-function genetic variation causes human lupus.

TitleTLR7 gain-of-function genetic variation causes human lupus.
Publication TypeJournal Article
Year of Publication2022
AuthorsBrown, GJ, Cañete, PF, Wang, H, Medhavy, A, Bones, J, Roco, JA, He, Y, Qin, Y, Cappello, J, Ellyard, JI, Bassett, K, Shen, Q, Burgio, G, Zhang, Y, Turnbull, C, Meng, X, Wu, P, Cho, E, Miosge, LA, T Andrews, D, Field, MA, Tvorogov, D, Lopez, AF, Babon, JJ, López, CAparicio, Gónzalez-Murillo, Á, Garulo, DClemente, Pascual, V, Levy, T, Mallack, EJ, Calame, DG, Lotze, T, Lupski, JR, Ding, H, Ullah, TR, Walters, GD, Koina, ME, Cook, MC, Shen, N, Collantes, Cde Lucas, Corry, B, Gantier, MP, Athanasopoulos, V, Vinuesa, CG
JournalNature
Volume605
Issue7909
Pagination349-356
Date Published2022 May
ISSN1476-4687
KeywordsAnimals, Autoimmunity, B-Lymphocytes, Cyclic GMP, Gain of Function Mutation, Guanosine, Humans, Lupus Erythematosus, Systemic, Mice, Myeloid Differentiation Factor 88, Toll-Like Receptor 7
Abstract

Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease, 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, and binds to guanosine-. We identified a de novo, previously undescribed missense TLR7 variant in a child with severe lupus and additional variants in other patients with lupus. The TLR7 variant selectively increased sensing of guanosine and 2',3'-cGMP, 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 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.

DOI10.1038/s41586-022-04642-z
Alternate JournalNature
PubMed ID35477763
PubMed Central IDPMC9095492
Grant ListR35 NS105078 / NS / NINDS NIH HHS / United States
U01 HG011758 / HG / NHGRI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States