Protection of murine lupus by the Ead transgene is MHC haplotype-dependent.

A high-level expression of a transgene, Ea d , encoding the I-E d α-chain is very effective in protection against murine lupus. To investigate the specific contribution of select H-2 haplotypes on the Ea d transgene-mediated disease-suppressing effect, we generated H-2 congenic (NZB × BXSB)F 1 hybrid mice bearing either H-2 b/b , H-2 d/b , or H-2 d/d haplotype, and compared the transgene-mediated protective effect on the clinical development (autoantibody production and glomerulonephritis) of lupus in these F 1 hybrids. The level of protection was most remarkable in mice bearing the I-E − H-2 b/b haplotype but was only minimal in I-E + H-2 d/d F 1 hybrids. Additional analysis demonstrated a marked suppression of lupus in I-E + H-2 k/k (MRL × BXSB)F 1 hybrid mice, indicating that the transgene is able to suppress autoimmune responses even in mice already expressing I-E molecules at a homozygous level. Our results indicate that the level of the transgene-mediated protection is dependent on the host H-2 haplotype. This suggests that the autoimmune suppressive activity of the Ea d transgene is likely to be determined through the interaction of the transgene product with the host MHC class II molecules, providing new insight into the role of MHC in lupus-like autoimmunity.