EFFECT OF GENETIC BACKGROUND ON E-ALPHA(D) TRANSGENE-MEDIATED PROTECTION FROM MURINE LUPUS

The expression of a transgene encoding the I-E alpha-chain, Ea(d), is highly effective in the protection from systemic lupus erythematosus ( SLE) in BXSB and (MRLxBXSB)F-1 male mice, in which a mutant gene, Yaa (Y-linked autoimmune acceleration), Flays a critical role. To gain fur ther insight into the protective role of the Ea(d) transgene, we compa red the effect of the transgene in two additional lupus-prone (NZB x B XSB)F-1 and (NZW x 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 male s bearing the Yaa gene develop a more accelerated form of SLE. Compara tive analysis of the clinical development of SLE in these F-1 hybrid m ice showed that Ea(d) transgene expression was much more effective in the protection from SLE occurring in the F-1 females than in their mal e counterparts. Our results indicate that the Ea(d) transgene is capab le 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 indivi dual strains of lupus-prone mice. In addition, this autoimmune inhibit ory effect was shown to be selective for IgG, but not IgM, anti-DNA au toantibody production, and is more specific for anti-gp70 autoantibody than for anti-DNA autoantibody. These results favour the hypothesis t hat the transgene expression may lead to the modulation of self-peptid e presentation, thereby preventing excessive T-cell-dependent activati on of autoreactive B cells. (C) 1998 Academic Press.