Selective up-regulation of intact, but not defective env RNAs of endogenous modified polytropic retrovirus by the Sgp3 locus of lupus-prone mice.
Endogenous retroviruses are implicated in the pathogenesis of systemic lupus erythematosus (SLE). Because four different classes of endogenous retroviruses, i.e., ecotropic, xenotropic, polytropic, or modified polytropic (mPT), are expressed in mice, we investigated the possibility that a particular class of endogenous retroviruses is associated with the development of murine SLE. We observed >15-fold increased expression of mPT env (envelope) RNA in livers of all four lupus-prone mice, as compared with those of nine nonautoimmune strains of mice. This was not the case for the three other classes of retroviruses. Furthermore, we found that in addition to intact mPT transcripts, many strains of mice expressed two defective mPT env transcripts which carry a deletion in the env sequence of the 3' portion of the gp70 surface protein and the 5' portion of the p15E transmembrane protein, respectively. Remarkably, in contrast to nonautoimmune strains of mice, all four lupus-prone mice expressed abundant levels of intact mPT env transcripts, but only low or nondetectable levels of the mutant env transcripts. The Sgp3 (serum gp70 production 3) locus derived from lupus-prone mice was responsible for the selective up-regulation of the intact mPT env RNA. Finally, we observed that single-stranded RNA-specific TLR7 played a critical role in the production of anti-gp70 autoantibodies. These data suggest that lupus-prone mice may possess a unique genetic mechanism responsible for the expression of mPT retroviruses, which could act as a triggering factor through activating TLR7 for the development of autoimmune responses in mice predisposed to SLE.
Yoshinobu
Kumiko
K
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
Baudino
Lucie
L
Santiago-Raber
Marie-Laure
ML
Morito
Naoki
N
Dunand-Sauthier
Isabelle
I
Morley
Bernard J
BJ
Evans
Leonard H
LH
Izui
Shozo
S
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D020077:Endogenous Retroviruses / Q000235:genetics / Q000378:metabolism*; D015686:Gene Products, env / Q000235:genetics / Q000378:metabolism*; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics*; D016415:Sequence Alignment; D051199:Toll-Like Receptor 7 / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D015854:Up-Regulation
D015686:Gene Products, env; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D012367:RNA, Viral; C479954:Sgp3 protein, mouse; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7