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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, * 
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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Submitted on : Saturday, February 27, 2010 - 4:31:16 PM
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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.. Journal of Experimental Medicine, 2010, 203 (7), pp.1745-59. ⟨10.1084/jem.20060085⟩. ⟨pasteur-00162856⟩



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