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Protection of Murine Lupus by the Ea^d Transgene Is MHC Haplotype-Dependent¹

Nabila Ibnou-Zekri^*, Masahiro Iwamoto^*, M. Eric Gershwin and Shozo Izui^2,*

^* Department of Pathology, University of Geneva, Geneva, Switzerland; and Division of Rheumatology/Allergy and Clinical Immunology, Department of Internal Medicine, University of California, Davis, CA 95616

A high-level expression of a transgene, Ea^d, encoding the I-E^d -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.

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