Title | TLR7 gain-of-function genetic variation causes human lupus. |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | Brown, 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 |
Journal | Nature |
Volume | 605 |
Issue | 7909 |
Pagination | 349-356 |
Date Published | 2022 May |
ISSN | 1476-4687 |
Keywords | Animals, 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. |
DOI | 10.1038/s41586-022-04642-z |
Alternate Journal | Nature |
PubMed ID | 35477763 |
PubMed Central ID | PMC9095492 |
Grant List | R35 NS105078 / NS / NINDS NIH HHS / United States U01 HG011758 / HG / NHGRI NIH HHS / United States UM1 HG006542 / HG / NHGRI NIH HHS / United States |
TLR7 gain-of-function genetic variation causes human lupus.
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