title: A defective NF-kappa B/RelB pathway in autoimmune-prone New Zealand black mice is associated with inefficient expansion of thymocyte and dendritic cells.
abstract: New Zeland Black (NZB) mice develop an autoimmune disease involving an abnormal B cell response to peripheral self Ags. This disease is associated with defects in other cell types and thymic stromal organization. We present evidence that NZB cells of various lineages, including thymocytes, fibroblasts, and dendritic precursor cells, show impaired proliferation and enhanced cell death in culture upon stimulation compared with non-autoimmune-prone mice such as C57BL/6. This phenotype explains the reduced efficiency of maturation of bone marrow-derived dendritic cells and the loss of TNF- or IL-1-dependent thymocyte costimulation. Upon TNF-induced activation of NZB thymocytes, nuclear translocation and DNA binding of RelA- and RelB-dependent NF-kappaB heterodimers are significantly reduced. This phenotype has a transcriptional signature, since the NZB, but not the nonobese diabetic, thymic transcriptome shows striking similarities with that of RelB-deficient thymuses. This partial NF-kappaB deficiency detected upon activation by proinflammatory cytokines could explain the disorganization of thymic microenvironments in NZB mice. These combined effects might reduce the efficiency of central tolerance and expose apoptotic debris generated during inflammatory processes to self recognition.
authors.affiliation: Center d'Immunologie de Marseille Luminy, Institut Fédératif de Recherche 57, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Université Méditerranée, Marseilles, France.
authors.forename: René
authors.initials: R
authors.lastname: Valéro
authors.forename: Marie-Laurence
authors.initials: ML
authors.lastname: Baron
authors.forename: Sandrine
authors.initials: S
authors.lastname: Guérin
authors.forename: Sophie
authors.initials: S
authors.lastname: Béliard
authors.forename: Hugues
authors.initials: H
authors.lastname: Lelouard
authors.forename: Brigitte
authors.initials: B
authors.lastname: Kahn-Perles
authors.forename: Bernard
authors.initials: B
authors.lastname: Vialettes
authors.forename: Cathy
authors.initials: C
authors.lastname: Nguyen
authors.forename: Jean
authors.initials: J
authors.lastname: Imbert
authors.forename: Philippe
authors.initials: P
authors.lastname: Naquet
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics / Q000276:immunology; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000378:metabolism; D017252:CD3 Complex / Q000494:pharmacology; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology*; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000276:immunology / Q000473:pathology; D015723:Gene Library; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D007375:Interleukin-1 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008814:Mice, Inbred NZB; D018345:Mice, Knockout; D016328:NF-kappa B / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology*; D013950:Thymus Gland / Q000196:embryology / Q000276:immunology / Q000473:pathology*; D051841:Transcription Factor RelB; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D017252:CD3 Complex; D007375:Interleukin-1; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; C497594:Relb protein, mouse; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D051841:Transcription Factor RelB