More MS news articles for June 2002

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

J Immunol 2002 Jul 1;169(1):185-192
Valero R, Baron ML, Guerin S, Beliard S, Lelouard H, Kahn-Perles B, Vialettes B, Nguyen C, Imbert J, Naquet P.
Center d'Immunologie de Marseille Luminy, Institut Federatif de Recherche 57, Institut National de la Sante et de la Recherche Medicale, Centre National de la Recherche Scientifique, Universite Mediterranee, Institut Federatif de Recherche 57, Institut National de la Sante et de la Recherche Medicale, Unite 119, and Hopital Sainte Marguerite, Service de Diabetologie, Universite Mediterranee, 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-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.