Protection of murine lupus by the Ea(d) 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 x BXSB)F₁ 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 F₁ 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) F₁ hybrids. Additional analysis demonstrated a marked suppression of lupus in I-E⁺ H-2(k/k) (MRL x BXSB)F₁ 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.