TLR7 gain-of-function genetic variation causes human lupus

Brown, GJ; Ca&#241;ete, 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; Andrews, TD; Field, MA; Tvorogov, D; Lopez, AF; Babon, JJ; L&#243;pez, CA; G&#243;nzalez-Murillo, &#193;; Garulo, DC; Pascual, V; Levy, T; Mallack, EJ; Calame, DG; Lotze, T; Lupski, JR; Ding, H; Ullah, TR; Walters, GD; Koina, ME; Cook, MC; Shen, N; de Lucas Collantes, C; Corry, B; Gantier, MP; Athanasopoulos, V; Vinuesa, CG

Author(s): 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; Andrews, TD; Field, MA; Tvorogov, D; Lopez, AF; Babon, JJ; López, CA; Gónzalez-Murillo, Á; Garulo, DC; Pascual, V; Levy, T; Mallack, EJ; Calame, DG; Lotze, T; Lupski, JR; Ding, H; Ullah, TR; Walters, GD; Koina, ME; Cook, MC; Shen, N; de Lucas Collantes, C; Corry, B; Gantier, MP; Athanasopoulos, V; Vinuesa, CG;
Details: Publication Year 2022-04-27,Volume 605,Issue #7909,Page 349-356
Journal Title: Nature
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 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.
Research Division(s): Structural Biology
PubMed ID: 35477763
Publisher's Version: https://doi.org/10.1038/s41586-022-04642-z
Open Access at Publisher's Site: https://doi.org/10.1038/s41586-022-04642-z
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2022-05-03 09:18:27

Last Modified: 2022-06-16 11:06:31