Costimulation by B7-1 and B7-2 is required for autoimmune disease in MRL-Fas(lpr) mice

Autoimmune lupus nephritis is dependent on infiltrating autoreactive leukoc ytes and Igs, B7 costimulatory molecules (B7-1 and B7-2) provide signals es sential for T cell activation and Ig class switching. In MRL-Fas(lpr) mice, a model of human lupus, although multiple tissues are targeted for autoimm une injury, nephritis Is fatal. We identified intrarenal B7-1 and B7-2 expr ession, restricted to kidney-infiltrating leukocytes, before and increasing with progressive nephritis in MRL-Fas(lpr) mice. Thus, we hypothesized tha t the B7 pathway is required for autoimmune disease in MRL-Fas(lpr) mice, T o investigate the role of B7 costimulatory molecules in this autoimmune dis ease, we generated a MRL-Fas(lpr) strain deficient in B7-1 and B7-2, Striki ngly, MRL-Fas(lpr) mice lacking both B7 costimulators do not develop kidney (glomerular, tubular, interstitial, vascular) pathology, or proteinuria, a nd survive far longer. Intrarenal downstream effector transcripts (IFN-gamm a, IL-12, monocyte chemoattractant protein-1, CSF-I) linked to nephritis re mained at normal levels compared with wild-type mice. Skin lesions and lymp hoid 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 d id not develop leukocytic infiltrates, elevated serum IgG and isotypes (G1, G2b,G3), autoantibodies, and intrarenal IgG; deposits, Our findings demonst rate that B7-1 and B7-2 costimulatory pathways are critical to the pathogen esis of autoimmune lupus.