The Bxs6 Locus of BXSB Mice Is Sufficient for High-Level Expression of gp70 and the Production of gp70 Immune Complexes

Abstract

High levels of the retroviral envelope protein gp70 and gp70 immune complexes have been linked to a single locus on chromosome 13 (Bxs6) in the BXSB model, to which linkage of nephritis was also seen. Congenic lines containing the BXSB Bxs6 interval on a non-autoimmune C57BL/10 background were bred in the presence or absence of the BXSB Y chromosome autoimmune accelerator gene (Yaa), which accelerates disease in male mice. In these mice, we have shown that Bxs6 is sufficient to cause high-level expression of gp70 and the production of gp70 autoantibodies, independently of Yaa, with gp70 immune complex levels enhanced by Yaa. In the presence of Yaa, Bxs6 also causes mild nephritis, and interestingly the sporadic production of high levels of anti-DNA Abs in some mice. Fine mapping using rare recombinant mice suggested that Bxs6 lies between 59.7 and 74.8 megabases (Mb), although the interval of 0.6 Mb between 73.6 and 78.6 Mb on chromosome 13 cannot be excluded in this study.

Emerging roles of TLR7 and TLR9 in murine SLE

“…It is significant that the Sgp3 locus also contributes to the production of anti-gp70 autoantibodies [32,91,92]. Moreover, we have recently observed that the production of gp70 IC was almost completely suppressed in B6.Nba2 mice deficient in TLR7 [98], indicating a critical role of TLR7 in the development of the antigp70 autoimmune response.…”

“…Interval mapping of backcross progeny between lupus-prone mice and B6 or B10 mice identified a major locus controlling gp70 production in the middle of chromosome 13, designated Sgp3 or Bxs6 (the Bxs6 locus identified in BXSB mice is likely to be identical to Sgp3) [32,81,90,91]. Analysis of B6 or B10 mice congenic for the Sgp3 (or Bxs6) locus derived from either the NZB, NZW or BXSB strain revealed that all congenic mice had approximately 10-fold higher levels of gp70, as compared with wild-type B6 or B10 mice [32,91,92]. This suggested that the underlying allele of Sgp3 is shared among the three different lupusprone mice.…”

“…Thus, one could speculate that abundant and preferential expression of mPT proviruses possessing an intact env gene could facilitate the generation of replication-competent mPTderived infectious recombinant viruses. Considering the remarkable role of TLR7 in the development of SLE, it is of importance to reassess the possible role of endogenous retroviruses as a triggering factor in murine SLE; this possibility has been highlighted by the production of anti-nuclear autoantibodies in mice infected or immunized with retroviruses [104,107] and in Sgp3 and GIX congenic mice [91,92,108]. However, it is still unclear how retroviruses might promote anti-nuclear autoantibody production.…”

Sgp3 and Sgp4 control expression of distinct and restricted sets of xenotropic retroviruses encoding serum gp70 implicated in murine lupus nephritis

“…We have recently shown that the production of gp70 IC implicated in murine lupus nephritis was dependent on TLR7 [28, 43] and that the Sgp3 locus contributes to the development of anti-gp70 autoimmune responses [23]. Since it is unlikely that virion-free serum gp70 is able to trigger TLR7, Sgp3 could enhance the production of endogenous retroviral virions carrying singlestranded RNA, which would then promote the development of autoimmune responses against serum retroviral gp70 through the activation of TLR7.…”

“…This mechanism can sustain the production of IFN-α, thereby establishing a vicious cycle not only aggravating the autoimmune process but also promoting the development of autoimmune responses against a wide array of autoantigens that do not engage TLR7. Notably, endogenous retroviruses could elicit autoimmune responses against not only retroviral gp70 but also nuclear autoantigens in mice predisposed to SLE [49], and Sgp3 congenic mice produced significant titers of anti-DNA autoantibodies [22, 23]. …”