(A) In the lupus-prone MRL/lpr background, Tlr7 WT Tlr9^–/– mice show SLE-associated pathology, with splenomegaly and nephritis, and high titres of anti-RNA and anti-Smith (anti-Sm) autoantibodies. (B) To evaluate the differential role of the TLR7 and TLR9 TIR domains, the Tlr9 TIR domain was introduced into the Tlr7 locus (termed Tlr779). Tlr779 mice expressed reduced levels of TLR779 protein relative to expression level of TLR7 in A. Due to Tlr7 being X-linked, heterozygous mice were not deemed appropriate dosage controls. However, these experiments showed that TLR779 domain led to reduced spleen and lymph node cellularity, nephritis, and anti-RNA and anti-Sm autoantibodies when compared with Tlr7 WT mice in the MRL/lpr Tlr9^–/– background. Moreover, the TLR9 TIR domain induced the expression of genes involved in negative regulation, pointing to potential mechanisms underlying this effect. In the converse experiments, relative to Tlr9 WT mice on the MRL/lpr Tlr7^–/– background (C), introduction of the Tlr7 TIR domain into the Tlr9 locus (D) led to increased expression of proinflammatory signalling molecules, which translated into aggravation of disease. Unexpectedly, antinucleosome antibodies were similar between Tlr997 and Tlr9^+/– mice. Note that, while TLR997 showed reduced expression relative to TLR9 WT expression levels, this was controlled by comparing to heterozygous Tlr9^+/– mice.