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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
immunology and microbiology
X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production
Journal of Experimental Medicine, Volume 203, No. 7, Year 2006
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Description
Germline mutations in five autosomal genes involved in interleukin (IL)-12-dependent, interferon (IFN)-γ-mediated immunity cause Mendelian susceptibility to mycobacterial diseases (MSMD). The molecular basis of X-linked recessive (XR)-MSMD remains unknown. We report here mutations in the leucine zipper (LZ) domain of the NF-κB essential modulator (NEMO) gene in three unrelated kindreds with XR-MSMD. The mutant proteins were produced in normal amounts in blood and fibroblastic cells. However, the patients' monocytes presented an intrinsic defect in T cell-dependent IL-12 production, resulting in defective IFN-γ secretion by T cells. IL-12 production was also impaired as the result of a specific defect in NEMO- and NF-κB/c-Rel-mediated CD40 signaling after the stimulation of monocytes and dendritic cells by CD40L-expressing T cells and fibroblasts, respectively. However, the CD40-dependent up-regulation of costimulatory molecules of dendritic cells and the proliferation and immunoglobulin class switch of B cells were normal. Moreover, the patients' blood and fibroblastic cells responded to other NF-γB activators, such as tumor necrosis factor-α, IL-1β, and lipopolysaccharide. These two mutations in the NEMO LZ domain provide the first genetic etiology of XR-MSMD. They also demonstrate the importance of the T cell- and CD40L-triggered, CD40-, and NEMO/NF-κB/c-Rel-mediated induction of IL-12 by monocyte-derived cells for protective immunity to mycobacteria in humans. JEM © The Rockefeller University Press.
Authors & Co-Authors
Filipe-Santos, Orchidée
France, Paris
L'institut Des Maladies Génétiques Imagine
Bustamante, Jacinta Cecilia
France, Paris
L'institut Des Maladies Génétiques Imagine
Haverkamp, Margje Helene
United States, Silver Spring
Food and Drug Administration
Netherlands, Leiden
Leids Universitair Medisch Centrum
Vinolo, Emilie
France, Paris
Cnrs Centre National de la Recherche Scientifique
Ku, Cheng-Lung
France, Paris
L'institut Des Maladies Génétiques Imagine
Puel, Anne
France, Paris
L'institut Des Maladies Génétiques Imagine
Frucht, David M.
United States, Silver Spring
Food and Drug Administration
Christel, Karin
France, Paris
L'institut Des Maladies Génétiques Imagine
von Bernuth, Horst
France, Paris
L'institut Des Maladies Génétiques Imagine
Jouanguy, Emmanuelle
France, Paris
L'institut Des Maladies Génétiques Imagine
Feinberg, Jacqueline
France, Paris
L'institut Des Maladies Génétiques Imagine
Durandy, Anne H.
France, Paris
Hôpital Necker Enfants Malades
Senechal, Brigitte
France, Paris
Institut Necker-enfants Malades Inem
Chapgier, Ariane L.A.
France, Paris
L'institut Des Maladies Génétiques Imagine
Vogt, Guillaume
France, Paris
L'institut Des Maladies Génétiques Imagine
de Beaucoudrey, Ludovic
France, Paris
L'institut Des Maladies Génétiques Imagine
Fieschi, Claire
France, Paris
L'institut Des Maladies Génétiques Imagine
France, Paris
Hôpital Saint-louis
Pïcard, Capucine
France, Paris
L'institut Des Maladies Génétiques Imagine
France, Paris
Hôpital Necker Enfants Malades
Garfa, Meriem
France, Paris
Hôpital Necker Enfants Malades
Chemli, Jalel
Tunisia, Sousse
Chu Sahloul
Béjaoui, Mohamed
Tunisia, Tunis
Centre National de Greffe de Moelle Osseuse
Tsolia, Maria N.
Greece, Athens
School of Medicine
Kütükçüler, Necil
Turkey, Izmir
Ege Üniversitesi
Plebani, Alessandro
Italy, Brescia
Università Degli Studi Di Brescia
Notarangelo, Luigi Daniele
Italy, Brescia
Università Degli Studi Di Brescia
Bodemer, Christine
France, Paris
Hôpital Necker Enfants Malades
Geissmann, Frédéric
France, Paris
Institut Necker-enfants Malades Inem
Israël, Alain
France, Paris
Institut Pasteur, Paris
Véron, Michel
France, Paris
Cnrs Centre National de la Recherche Scientifique
Knackstedt, Maike
Germany, Berlin
Charité – Universitätsmedizin Berlin
Barbouche, Mohamed Ridha
Tunisia, Tunis
Institut Pasteur de Tunis
Abel, Laurent
France, Paris
L'institut Des Maladies Génétiques Imagine
Magdorf, Klaus
Germany, Berlin
Charité – Universitätsmedizin Berlin
Gendrel, Dominique
France, Paris
Hopital Saint-vincent-de-paul
Agou, Fabrice
France, Paris
Cnrs Centre National de la Recherche Scientifique
Holland, Steven M.
United States, Silver Spring
Food and Drug Administration
Casanova, Jean Laurent
France, Paris
L'institut Des Maladies Génétiques Imagine
France, Paris
Hôpital Necker Enfants Malades
Statistics
Citations: 267
Authors: 37
Affiliations: 16
Identifiers
Doi:
10.1084/jem.20060085
ISSN:
00221007
e-ISSN:
00221007
Research Areas
Cancer
Genetics And Genomics