Yaa autoimmune phenotypes are conferred by overexpression of TLR7.
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.
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA. anna-marie.fairhurst@utsouthwestern.edu
Anna-Marie
AM
Fairhurst
Sun-hee
SH
Hwang
Andrew
A
Wang
Xiang-Hong
XH
Tian
Christopher
C
Boudreaux
Xin J
XJ
Zhou
Jose
J
Casco
Quan-Zhen
QZ
Li
John E
JE
Connolly
Edward K
EK
Wakeland
D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D015551:Autoimmunity; D050173:Genes, Y-Linked; D007668:Kidney / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D010641:Phenotype; D040081:Protein Array Analysis; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013163:Splenomegaly; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014178:Translocation, Genetic
D001323:Autoantibodies; D051199:Toll-Like Receptor 7