Journal
NATURE
Volume 605, Issue 7909, Pages 349-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-022-04642-z
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Funding
- NHMRC
- Elizabeth Greene Scholarship
- National Collaborative Research Infrastructure Strategy (NCRIS) via Phenomics Australia
- Australasian Leadership Computing Grants scheme
- Medical Research Future Fund Phenomics Translation Initiative
- U.S. National Human Genome Research Institute (NHGRI)
- National Heart Lung and Blood Institute (NHBLI) [UM1 HG006542]
- US NHGRI [U01HG011758]
- U.S. National Institute of Neurological Disorders and Stroke (NINDS) [R35NS105078]
- National Natural Science Foundation of China (NSFC) [31930037, 81873879]
- Australian Government
- Medical Research Future Fund
- NHMRC CRE
- NHMRC Ideas grant
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Enhanced Toll-like receptor 7 (TLR7) signaling has been associated with human systemic autoimmune disease, but evidence of TLR7 gene variants causing lupus is lacking. In this study, researchers identified a newly described TLR7(Y264H) variant that increased sensing of guanosine and 2',3'-cGMP and was sufficient to cause lupus in mice. Enhanced TLR7 signaling was shown to drive aberrant B cell survival and the accumulation of specific B cell subsets, while deficiency of the downstream adapter protein MyD88 rescued autoimmunity and all phenotypes. The study highlights the importance of TLR7 and guanosine-containing self-ligands in the pathogenesis of lupus and suggests potential therapeutic targets.
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 TLR7gene variants is lacking. Here we describe human systemic lupus erythematosus caused by a TLR7gain-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 ofguanosine and 2',3'-cGMP(10-12), and was sufficient to cause lupus when introduced into mice. We showthat 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 bygerminal-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 pavesthe way for therapeutic TLR7 or MyD88 inhibition.
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