title: Deletion of receptor for advanced glycation end products exacerbates lymphoproliferative syndrome and lupus nephritis in B6-MRL Fas lpr/j mice.
abstract: The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor that interacts with advanced glycation end products, but also with C3a, CpG DNA oligonucleotides, and alarmin molecules such as HMGB1 to initiate a proinflammatory reaction. Systemic lupus erythematosus is an autoimmune disorder associated with the accumulation of RAGE ligands. We generated mice invalidated for RAGE in the lupus-prone B6-MRL Fas lpr/j background to determine the role of RAGE in the pathogenesis of systemic lupus erythematosus. We compared the phenotype of these mice with that of their wild-type and B6-MRL Fas lpr/j littermates. Lymphoproliferative syndrome, production of anti-dsDNA Abs, lupus nephritis, and accumulation of CD3(+)B220(+)CD4(-)CD8(-) autoreactive T cells (in the peripheral blood and the spleen) were significantly increased in B6-MRL Fas lpr/j RAGE(-/-) mice compared with B6-MRL Fas lpr/j mice (respectively p < 0.005, p < 0.05, p < 0.001, and p < 0.001). A large proportion of autoreactive T cells from B6-MRL Fas lpr/j mice expressed RAGE at their surface. Time course studies of annexin V expression revealed that autoreactive T cells in the spleen of B6-MRL Fas lpr/j-RAGE(-/-) mice exhibited a delay in apoptosis and expressed significantly less activated caspase 3 (39.5 ± 4.3%) than T cells in B6-MRL Fas lpr/j mice (65.5 ± 5.2%) or wild-type mice (75.3 ± 2.64%) (p = 0.02). We conclude that the deletion of RAGE in B6-MRL Fas lpr/j mice promotes the accumulation of autoreactive CD3(+)B220(+)CD4(-)CD8(-) T cells, therefore exacerbating lymphoproliferative syndrome, autoimmunity, and organ injury. This suggests that RAGE rescues the apoptosis of T lymphocytes when the death receptor Fas/CD95 is dysfunctional.
authors.affiliation: Faculté de Médecine, Laboratoire de Néphrologie, Université de Reims Champagne-Ardenne, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7369 (Matrice Extracellulaire et Dynamique Cellulaire), 51100 Reims, France; Service de Néphrologie, Centre Hospitalier Universitaire de Reims, 51100 Reims, France;
authors.forename: Antoine
authors.initials: A
authors.lastname: Goury
authors.affiliation: Faculté de Pharmacie, Université de Reims Champagne-Ardenne, EA4683 (Immunité Adaptative et Fonctionnalité des Barrières Biologiques), 51100 Reims, France;
authors.forename: Aïda
authors.initials: A
authors.lastname: Meghraoui-Kheddar
authors.affiliation: Faculté de Médecine, Laboratoire de Néphrologie, Université de Reims Champagne-Ardenne, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7369 (Matrice Extracellulaire et Dynamique Cellulaire), 51100 Reims, France; Service de Néphrologie, Centre Hospitalier Universitaire de Reims, 51100 Reims, France;
authors.forename: Karim
authors.initials: K
authors.lastname: Belmokhtar
authors.affiliation: Faculté de Médecine, Laboratoire de Néphrologie, Université de Reims Champagne-Ardenne, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7369 (Matrice Extracellulaire et Dynamique Cellulaire), 51100 Reims, France; Service de Néphrologie, Centre Hospitalier Universitaire de Reims, 51100 Reims, France;
authors.forename: Vincent
authors.initials: V
authors.lastname: Vuiblet
authors.affiliation: Faculté de Médecine, Laboratoire de Néphrologie, Université de Reims Champagne-Ardenne, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7369 (Matrice Extracellulaire et Dynamique Cellulaire), 51100 Reims, France;
authors.forename: Jeremy
authors.initials: J
authors.lastname: Ortillon
authors.affiliation: Faculté de Médecine, Laboratoire de Néphrologie, Université de Reims Champagne-Ardenne, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7369 (Matrice Extracellulaire et Dynamique Cellulaire), 51100 Reims, France;
authors.forename: Stéphane
authors.initials: S
authors.lastname: Jaisson
authors.affiliation: Faculté des Sciences, Laboratoire Signalisation et Récepteurs Matriciels, Université de Reims Champagne-Ardenne, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7369 (Matrice Extracellulaire et Dynamique Cellulaire), 51100 Reims, France;
authors.forename: Jerôme
authors.initials: J
authors.lastname: Devy
authors.affiliation: Faculté de Pharmacie, Université de Reims Champagne-Ardenne, EA4683 (Immunité Adaptative et Fonctionnalité des Barrières Biologiques), 51100 Reims, France;
authors.forename: Richard
authors.initials: R
authors.lastname: Le Naour
authors.affiliation: Laboratoire d'Immunologie, Université de Reims Champagne-Ardenne, Laboratoire de Recherche en Nanosciences EA4682 et Centre Hospitalier Universitaire de Reims, Reims 51100, France; and.
authors.forename: Thierry
authors.initials: T
authors.lastname: Tabary
authors.affiliation: Laboratoire d'Immunologie, Université de Reims Champagne-Ardenne, Laboratoire de Recherche en Nanosciences EA4682 et Centre Hospitalier Universitaire de Reims, Reims 51100, France; and.
authors.forename: Jacques H M
authors.initials: JH
authors.lastname: Cohen
authors.affiliation: Diabetes Research Program, New York University, New York, NY 10016.
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Schmidt
authors.affiliation: Faculté de Médecine, Laboratoire de Néphrologie, Université de Reims Champagne-Ardenne, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7369 (Matrice Extracellulaire et Dynamique Cellulaire), 51100 Reims, France; Service de Néphrologie, Centre Hospitalier Universitaire de Reims, 51100 Reims, France;
authors.forename: Philippe
authors.initials: P
authors.lastname: Rieu
authors.affiliation: Faculté de Médecine, Laboratoire de Néphrologie, Université de Reims Champagne-Ardenne, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7369 (Matrice Extracellulaire et Dynamique Cellulaire), 51100 Reims, France; Service de Néphrologie, Centre Hospitalier Universitaire de Reims, 51100 Reims, France; ftoure@chu-reims.fr.
authors.forename: Fatouma
authors.initials: F
authors.lastname: Touré
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D053148:Caspase 3 / Q000235:genetics / Q000276:immunology; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics / Q000276:immunology; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013577:Syndrome; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
chemical_list: D000943:Antigens, Differentiation; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C505409:Casp3 protein, mouse; D053148:Caspase 3