TLR7 gain-of-function genetic variation causes human lupus.

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 RNA⁸,⁹ and binds to guanosine¹⁰-¹². 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 ab

SUBMITTER: Brown GJ 

PROVIDER: S-EPMC9095492 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature