Discovery of novel TLR7 variants in human lupus patients

While circumstantial evidence supports enhanced TLR7 signaling as a mechanism of human systemic autoimmune disease, we have lacked the proof afforded by lupus-causing TLR7 gene variants. Here we describe human systemic lupus erythematosus (SLE) caused by TLR7 gain-of-function (GoF). We identified a de novo, novel, missense TLR7 Y264H variant in a child with severe lupus and additional novel variants in other SLE patients. The de novo TLR7 Y264H variant selectively increased sensing of guanosine and was sufficient to cause lupus when introduced in mice