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.
Fairhurst
Anna-Marie
AM
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA. anna-marie.fairhurst@utsouthwestern.edu
Hwang
Sun-hee
SH
Wang
Andrew
A
Tian
Xiang-Hong
XH
Boudreaux
Christopher
C
Zhou
Xin J
XJ
Casco
Jose
J
Li
Quan-Zhen
QZ
Connolly
John E
JE
Wakeland
Edward K
EK
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