The NZB x NZW F1 mxce spontaneously develop autoimmune disease resembling human systemic lupus erythematosus (SLE). This disease is characterized by severe lupus nephritis, which develops in close association with the production of IgG class autoantibodies to double-stranded (ds) DNA and histones (Shirai et al. 1991). The occurrence of NZB x NZW F1 disease is genetically determined and is restricted by H-2 evz heterozygosity of the major histocompatibility complex (MHC), H-2 d from NZB, and H-2 z from NZW strains (Hirose et al. 1986). Together with the finding that a locus or a cluster of loci linked to the T-cell receptor (TCR)[5 chain gene complex of the NZW strain in combination with H-2 d/z heterozygosity contributed to the disease (Hirose et al. 1991), we proposed that the interaction between unique structures of the TCR and the mixed haplotype hybrid class II molecule-autoantigen complex preferentially transduces the signals for pathogenic IgG autoantibody synthesis in these mice.
Four possible Fl-specific mixed haplotype hybrid class II molecules could be expressed in NZB x NZW F1 mice, i. e., Aocd~ z, A (~z~ d, Eo~d~ z, and E~z~ d. Gotoh and co-workers (1993) have isolated from NZB x NZW F1 mice autoreactive T-cell clones restricted by the A~d[5 z. Because T-cell clones restricted by other mixed haplotype class II molecules have not been obtained, it was suggested that the Ac~a[3 z molecule may be a candidate for one predisposing genetic element to NZB x NZW F1 disease (Kimoto et al. 1993). However, the possibility remained that the E subregion is also involved in the control of SLE in these mice.
In the present study, we established an H-2-congenic NZB.GD strain carrying the H-2g 2 haplotype, by selective backcrossing of the F1 hybrid of the NZB (/-/-2 d) and B10.GD (H-2g 2) strain to NZB mice for eight generations.