title: Costimulation by B7-1 and B7-2 is required for autoimmune disease in MRL-Faslpr mice.
abstract: 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-Faslpr 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-Faslpr mice. Thus, we hypothesized that the B7 pathway is required for autoimmune disease in MRL-Faslpr mice. To investigate the role of B7 costimulatory molecules in this autoimmune disease, we generated a MRL-Faslpr strain deficient in B7-1 and B7-2. Strikingly, MRL-Faslpr 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-gamma, 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-Faslpr mice were diminished in B7-1/B7-2-deficient MRL-Faslpr mice. B7-1/B7-2-deficient MRL-Faslpr 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.
authors.affiliation: Laboratory of Molecular Autoimmune Disease, Renal Division, Department of Medicine, Center for Neurological Disease, and Immunology Research Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: K
authors.initials: K
authors.lastname: Kinoshita
authors.forename: G
authors.initials: G
authors.lastname: Tesch
authors.forename: A
authors.initials: A
authors.lastname: Schwarting
authors.forename: R
authors.initials: R
authors.lastname: Maron
authors.forename: A H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: V R
authors.initials: VR
authors.lastname: Kelley
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000378:metabolism; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001327:Autoimmune Diseases / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D051940:B7-2 Antigen; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D018925:Chemokines / Q000096:biosynthesis / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis / Q000502:physiology; D018450:Disease Progression; D007074:Immunoglobulin G / Q000097:blood / Q000378:metabolism; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D009393:Nephritis / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D011507:Proteinuria / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D013045:Species Specificity; D016019:Survival Analysis; D015854:Up-Regulation / Q000276:immunology
chemical_list: D000974:Antibodies, Antinuclear; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D018925:Chemokines; D016207:Cytokines; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins