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A Defective NF-B/RelB Pathway in Autoimmune-Prone New Zealand Black Mice Is Associated with Inefficient Expansion of Thymocyte and Dendritic Cells¹

René Valéro^2,*,, Marie-Laurence Baron^2,*, Sandrine Guérin^*, Sophie Béliard, Hugues Lelouard^*, Brigitte Kahn-Perles, Bernard Vialettes, Cathy Nguyen^*, Jean Imbert and Philippe Naquet^3,*

^* 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, Institut Fédératif de Recherche 57, Institut National de la Santé et de la Recherche Médicale, Unité 119, and Hôpital Sainte Marguerite, Service de Diabétologie, Université Méditerranée, Marseilles, France

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-B 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-B 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.

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