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X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production.

Orchidée Filipe-Santos 1 Jacinta Bustamante 1 Margje H Haverkamp 2, 3 Emilie Vinolo 4 Cheng-Lung Ku 1 Anne Puel 1 David M Frucht 5 Karin Christel 1 Horst von Bernuth 1 Emmanuelle Jouanguy 1 Jacqueline Feinberg 1 Anne Durandy 6 Brigitte Senechal 7 Ariane Chapgier 1 Guillaume Vogt 1 Ludovic de Beaucoudrey 1 Claire Fieschi 1, 8 Capucine Picard 1 Meriem Garfa 9 Jalel Chemli 10 Mohamed Bejaoui 11 Maria N Tsolia 12 Necil Kutukculer 7, 13 Alessandro Plebani 14 Luigi Notarangelo 14 Christine Bodemer 15 Frédéric Geissmann 7 Alain Israël 16 Michel Véron 4 Maike Knackstedt 17 Mohamed-Ridha Barbouche 18 Laurent Abel 1 Klaus Magdorf 17 Dominique Gendrel 19 Fabrice Agou 4 Steven M Holland 2 Jean-Laurent Casanova 1, 20, *
* Corresponding author
1 Inserm U980 - Génétique Humaine des Maladies Infectieuses
2 Laboratory of clinical infectious diseases
3 Department of Infectious Diseases
4 Régulation Enzymatique des Activités Cellulaires
5 Laboratory of Cell Biology
6 Developpement Normal et Pathologique du Système Immunitaire
7 Système des phagocytes mononucléés et immunopathologie
8 Laboratoire d'immunologie
9 Laboratoire de Microscopie confocale
10 Departement de Pediatrie
11 CNGMO - Centre National de Greffe de la Moëlle osseuse Tunis
12 Second Department of Pediatrics
13 Department of Pediatrics
14 Department of Pediatrics and Institute for Molecular Medicine Angello Nocivelli
15 Service de dermatologie [CHU Necker]
16 SMAC - Signalisation Moléculaire et Activation Cellulaire
17 Department of Pediatric Pulmonology and Immunology,
18 Laboratoire d'immunologie clinique [Institut Pasteur de Tunis]
19 Département de Pédiatrie
20 Service d'immuno-hématologie pédiatrique [CHU Necker]
Abstract : Germline mutations in five autosomal genes involved in interleukin (IL)-12-dependent, interferon (IFN)-gamma-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-kappaB 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-gamma secretion by T cells. IL-12 production was also impaired as the result of a specific defect in NEMO- and NF-kappaB/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-kappaB activators, such as tumor necrosis factor-alpha, IL-1beta, 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-kappaB/c-Rel-mediated induction of IL-12 by monocyte-derived cells for protective immunity to mycobacteria in humans.
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Orchidée Filipe-Santos, Jacinta Bustamante, Margje H Haverkamp, Emilie Vinolo, Cheng-Lung Ku, et al.. X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production.. The Journal of Experimental Medecine, The Rockefeller University Press, 2010, 203 (7), pp.1745-59. ⟨10.1084/jem.20060085⟩. ⟨pasteur-00162856⟩

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