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Deficiency in ₂-Microglobulin, But Not CD1, Accelerates Spontaneous Lupus Skin Disease While Inhibiting Nephritis in MRL-Fas^lpr Mice: An Example of Disease Regulation at the Organ Level¹

Owen T. M. Chan^*, Vipin Paliwal, Jennifer M. McNiff, Se-Ho Park, Albert Bendelac and Mark J. Shlomchik^2,*,

^* Section of Immunobiology, Departments of Laboratory Medicine and Dermatology and Pathology, Yale University School of Medicine, New Haven, CT 06520; and Department of Molecular Biology, Princeton University, Princeton, NJ 08544

When mutations that inactivate molecules that function in the immune system have been crossed to murine lupus strains, the result has generally been a uniform up-regulation or down-regulation of autoimmune disease in the end organs. In the current work we report an interesting dissociation of target organ disease in ₂-microglobulin (₂m)-deficient MRL-Fas^lpr (MRL/lpr) mice: lupus skin lesions are accelerated, whereas nephritis is ameliorated. ₂m deficiency affects the expression of classical and nonclassical MHC molecules and thus prevents the normal development of CD8- as well as CD1-dependent NK1⁺ T cells. To further define the mechanism by which ₂m deficiency accelerates skin disease, we studied CD1-deficient MRL/lpr mice. These mice do not have accelerated skin disease, excluding a CD1 or NK1⁺ T cell-dependent mechanism of ₂m deficiency. The data indicate that the regulation of systemic disease is not solely governed by regulation of initial activation of autoreactive lymphocytes in secondary lymphoid tissue, as this is equally relevant to renal and skin diseases. Rather, regulation of autoimmunity can also occur at the target organ level, explaining the divergence of disease in skin and kidney in ₂m-deficient mice.

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