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Costimulation by B7-1 and B7-2 Is Required for Autoimmune Disease in MRL-Fas^lpr Mice¹

Koji Kinoshita^*, Greg Tesch^*, Andreas Schwarting^*, Ruth Maron, Arlene H. Sharpe and Vicki Rubin Kelley^2,*

^* Laboratory of Molecular Autoimmune Disease, Renal Division, Department of Medicine, Center for Neurological Disease, and Immunology Research Division, Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115

Autoimmune lupus nephritis is dependent on infiltrating autoreactive leukocytes and Igs. B7 costimulatory molecules (B7-1 and B7-2) provide signals essential for T cell activation and Ig class switching. In MRL-Fas^lpr mice, a model of human lupus, although multiple tissues are targeted for autoimmune injury, nephritis is fatal. We identified intrarenal B7-1 and B7-2 expression, restricted to kidney-infiltrating leukocytes, before and increasing with progressive nephritis in MRL-Fas^lpr mice. Thus, we hypothesized that the B7 pathway is required for autoimmune disease in MRL-Fas^lpr mice. To investigate the role of B7 costimulatory molecules in this autoimmune disease, we generated a MRL-Fas^lpr strain deficient in B7-1 and B7-2. Strikingly, MRL-Fas^lpr mice lacking both B7 costimulators do not develop kidney (glomerular, tubular, interstitial, vascular) pathology, or proteinuria, and survive far longer. Intrarenal downstream effector transcripts (IFN-, IL-12, monocyte chemoattractant protein-1, CSF-1) linked to nephritis remained at normal levels compared with wild-type mice. Skin lesions and lymphoid enlargement characteristic of MRL-Fas^lpr mice were diminished in B7-1/B7-2-deficient MRL-Fas^lpr mice. B7-1/B7-2-deficient MRL-Fas^lpr mice did not develop leukocytic infiltrates, elevated serum IgG and isotypes (G1,G2b,G3), autoantibodies, and intrarenal IgG deposits. Our findings demonstrate that B7-1 and B7-2 costimulatory pathways are critical to the pathogenesis of autoimmune lupus.

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