Yaa autoimmune phenotypes are conferred by overexpression of TLR7

Eur J Immunol. 2008 Jul;38(7):1971-8. doi: 10.1002/eji.200838138.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantibodies / immunology*
  • Autoimmunity*
  • Genes, Y-Linked*
  • Kidney / immunology*
  • Kidney / metabolism
  • Kidney / pathology
  • Lupus Nephritis / genetics
  • Lupus Nephritis / immunology*
  • Lupus Nephritis / metabolism
  • Lupus Nephritis / pathology
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Congenic
  • Phenotype
  • Protein Array Analysis
  • Spleen / immunology
  • Spleen / metabolism
  • Splenomegaly
  • Toll-Like Receptor 7 / genetics
  • Toll-Like Receptor 7 / immunology*
  • Toll-Like Receptor 7 / metabolism
  • Translocation, Genetic


  • Autoantibodies
  • Toll-Like Receptor 7