TY - JOUR
T1 - TLR7 gain-of-function genetic variation causes human lupus
AU - Brown, Grant J.
AU - Cañete, Pablo F.
AU - Wang, Hao
AU - Medhavy, Arti
AU - Bones, Josiah
AU - Roco, Jonathan A.
AU - He, Yuke
AU - Qin, Yuting
AU - Cappello, Jean
AU - Ellyard, Julia I.
AU - Bassett, Katharine
AU - Shen, Qian
AU - Burgio, Gaetan
AU - Zhang, Yaoyuan
AU - Turnbull, Cynthia
AU - Meng, Xiangpeng
AU - Wu, Phil
AU - Cho, Eun
AU - Miosge, Lisa A.
AU - Andrews, T. Daniel
AU - Field, Matt A.
AU - Tvorogov, Denis
AU - Lopez, Angel F.
AU - Babon, Jeffrey J.
AU - López, Cristina Aparicio
AU - Gónzalez-Murillo, África
AU - Garulo, Daniel Clemente
AU - Pascual, Virginia
AU - Levy, Tess
AU - Mallack, Eric J.
AU - Calame, Daniel G.
AU - Lotze, Timothy
AU - Lupski, James R.
AU - Ding, Huihua
AU - Ullah, Tomalika R.
AU - Walters, Giles D.
AU - Koina, Mark E.
AU - Cook, Matthew C.
AU - Shen, Nan
AU - de Lucas Collantes, Carmen
AU - Corry, Ben
AU - Gantier, Michael P.
AU - Athanasopoulos, Vicki
AU - Vinuesa, Carola G.
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/5/12
Y1 - 2022/5/12
N2 - Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease1–7, 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 TLR7Y264H variant in a child with severe lupus and additional variants in other patients with lupus. The TLR7Y264H variant selectively increased sensing of guanosine and 2',3'-cGMP10–12, 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 Tlr7Y264H 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.
AB - Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease1–7, 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 TLR7Y264H variant in a child with severe lupus and additional variants in other patients with lupus. The TLR7Y264H variant selectively increased sensing of guanosine and 2',3'-cGMP10–12, 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 Tlr7Y264H 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.
UR - http://www.scopus.com/inward/record.url?scp=85129272972&partnerID=8YFLogxK
U2 - 10.1038/s41586-022-04642-z
DO - 10.1038/s41586-022-04642-z
M3 - Article
SN - 0028-0836
VL - 605
SP - 349
EP - 356
JO - Nature
JF - Nature
IS - 7909
ER -