TLR7 Variants Enhance Responsiveness and Broaden RNA Specificity To Drive Human Lupus

Dysregulated nucleic acid sensing underlies lethal viral infections and autoimmunity. Endosomal Toll-like receptor 7 (TLR7) recognizes guanosine and oligoribonucleotides (ORNs) from single-stranded RNA via two ligand-binding sites in its leucine-rich repeat (LRR) ectodomain. Recent genetic studies have demonstrated that TLR7 gain-of-function (GOF) variants cause childhood lupus or immune thrombocytopenic purpura by enhancing TLR7 responses to canonical TLR7 ligands. However, no study has demonstrated that altered ligand specificity of TLR7 contributes to autoimmunity. Here, we provide direct evidence that relaxation of ligand specificity by TLR7 genetic variants causes lupus in both humans and mice. We describe a pediatric systemic lupus erythematosus (SLE) patient carrying a private GOF TLR7 missense variant, V825M (VarM), located within the C-terminal region of the LRR (LRR-CT). Knock-in mice harboring VarM allele spontaneously develop lupus-like systemic inflammation, including duodenitis, recapitulating the patients clinical features. Mechanistically, the VarM variant markedly amplifies NF-{kappa}B activation by synthetic small-molecule agonists and guanosine analogs. Notably, the VarM variant broadens the spectrum of ORN sequences that can engage the receptor. Moreover, certain pathogenic TLR7 variants located at the dimerization interface display functional properties closely resembling those of VarM. Collectively, our findings establish a new paradigm in which alterations in ligand recognition specificity by TLR7 genetic variations can trigger human autoimmune disease.