X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production
Makaleler > Tam Makale · 2006
Yazarlar: Orchidee FILIPE-SANTOS, Jacinta BUSTAMANTE, Margje H. HAVERKAMP, Emilie VINOLO, Cheng-Lung KU, Anne PUEL, David M. FRUCHT, Karin CHRISTEL, Horst VON BERNUTH, Emmanuelle JOUANGUY, Jacqueline FEINBERG, Anne DURANDY, Brigitte SENECHAL, Ariane CHAPGIER, Guillaume VOGT, Ludovic DE BEAUCOUDREY, Claire FİESCHİ, Capucine PICARD, Meriem GARFA, Jalel CHEMLI, Mohamed BEJAOUI, Maria N. TSOLIA, Necil KÜTÜKÇÜLER, Alessandro PLEBANI, Luigi NOTARANGELO, Christine BODEMER, Frederic GEISSMANN, Alain ISRAEL, Michel VERON, Maike KNACKSTEDT, Ridha BARBOUCHE, Laurent ABEL, Klaus MAGDORF, Dominique GENDREL, Fabrice AGOU, Steven M. HOLLAND, Jean-Laurent CASANOVA
JOURNAL OF EXPERIMENTAL MEDICINE, SCI Expanded İndekslerine Giren Dergi, Uluslararası, 2006, cilt 203, ss 1745-1759
DOI: 10.1084/jem.20050085
Özet
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.