Effect of genetic background on Ea(d) transgene-mediated protection from murine lupus.

Abstract The expression of a transgene encoding the I-E α-chain, Ea d , is highly effective in the protection from systemic lupus erythematosus (SLE) in BXSB and (MRL×BXSB)F 1 male mice, in which a mutant gene, Yaa (Y-linked auto-immune acceleration), plays a critical role. To gain further insight into the protective role of the Ea d transgene, we compared the effect of the transgene in two additional lupus-prone (NZB×BXSB)F 1 and (NZW×BXSB)F 1 hybrid mice, in which both F 1 female mice develop typical SLE in the absence of the Yaa gene and their F 1 males bearing the Yaa gene develop a more accelerated form of SLE. Comparative analysis of the clinical development of SLE in these F 1 hybrid mice showed that Ea d transgene expression was much more effective in the protection from SLE occurring in the F 1 females than in their male counterparts. Our results indicate that the Ea d transgene is capable of preventing SLE by inhibiting autoimmune responses, independently of the Yaa gene-accelerating effect, and that its protective capacity is strongly influenced by the genetic susceptibility to SLE in individual strains of lupus-prone mice. In addition, this autoimmune inhibitory effect was shown to be selective for IgG, but not IgM, anti-DNA autoantibody production, and is more specific for anti-gp70 autoantibody than for anti-DNA autoantibody. These results favour the hypothesis that the transgene expression may lead to the modulation of self-peptide presentation, thereby preventing excessive T-cell-dependent activation of autoreactive B cells.