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    X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production
    (Rockefeller Univ Press, 2006) Filipe-Santos, Orchidee; Bustamante, Jacinta; Haverkamp, Margje H.; Vinolo, Emilie; Ku, Cheng-Lung; Puel, Anne; Frucht, David M.; Christel, Karin; von Bernuth, Horst; Jouanguy, Emmanuelle; Feinberg, Jacqueline; Durandy, Anne; Senechal, Brigitte; Chapgier, Ariane; Vogt, Guillaume; de Beaucoudrey, Ludovic; Fieschi, Claire; Picard, Capucine; Garfa, Meriem; Chemli, Jalel; Bejaoui, Mohamed; Tsolia, Maria N.; Kutukculer, Necil; Plebani, Alessandro; Notarangelo, Luigi; Bodemer, Christine; Geissmann, Frederic; Israel, Alain; Veron, Michel; Knackstedt, Maike; Barbouche, Ridha; Abel, Laurent; Magdorf, Klaus; Gendrel, Dominique; Agou, Fabrice; Holland, Steven M.; Casanova, Jean-Laurent
    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-kappa B 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-kappa B/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-kappa B activators, such as tumor necrosis factor-alpha, IL-beta, 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-kappa B/c-Rel-mediated induction of IL-12 by monocyte-derived cells for protective immunity to mycobacteria in humans.