The Y-linked autoimmune accelerating (Yaa) locus drives the transition to fatal 
lupus nephritis when combined with B6.Sle1 in our C57BL/6J (B6)-congenic model 
of systemic autoimmunity. We and others recently demonstrated that the 
translocation of a cluster of X-linked genes onto the Y chromosome is the 
genetic lesion underlying Yaa (Subramanian, S. et al., Proc. Natl. Acad. Sci. 
USA 2006. 103: 9970-9975; Pisitkun, P. et al., Science 2006. 312: 1669-1672). In 
male mice carrying Yaa, the transcription of several genes within the 
translocated segment is increased roughly twofold. Although the translocated X 
chromosome segment in Yaa may contain as many as 16 genes, the major candidate 
gene for causation of the Yaa-associated autoimmune phenotypes has been TLR7. To 
confirm the role of TLR7 in Yaa-mediated autoimmune phenotypes, we introgressed 
a targeted disruption of TLR7 (TLR7(-)) onto B6.Sle1Yaa to produce 
B6.Sle1YaaTLR7(-) and examined evidence of disease at 6 and 9 months of age. Our 
results demonstrate that the up-regulation of TLR7 in the B6.Sle1Yaa strain is 
responsible for splenomegaly, glomerular nephritis and the majority of the 
cellular abnormalities of B, T and myeloid cells. The up-regulation of TLR7 was 
also responsible for driving the infiltration and activation of leukocytes in 
the kidney, in which activated T cells were a primary component. However, the 
resolution of TLR7 up-regulation did not eliminate the enhanced humoral 
autoimmunity observed in B6.SleYaa, suggesting that additional elements in the 
translocation may contribute to the disease phenotype.