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)

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 UniBs - Università degli Studi di Brescia = University of Brescia
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]

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.

Domains: Life Sciences [q-bio]; Biochemistry, Molecular Biology

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⟩