TLR7 gain-of-function genetic variation causes human lupus

Journal Publication ResearchOnline@JCU
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.
Matt Field
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 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'-cGMP1 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.

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Nature

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605

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1476-4687

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Pages Count

26

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Nature Publishing Group

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DOI

10.1038/s41586-022-04642-z