title: X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production.
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.
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes-Institut National de la Santé et de la Recherche Médicale (INSERM) U 550, Necker Medical School, Paris, France.
authors.forename: Orchidée
authors.initials: O
authors.lastname: Filipe-Santos
authors.forename: Jacinta
authors.initials: J
authors.lastname: Bustamante
authors.forename: Margje H
authors.initials: MH
authors.lastname: Haverkamp
authors.forename: Emilie
authors.initials: E
authors.lastname: Vinolo
authors.forename: Cheng-Lung
authors.initials: CL
authors.lastname: Ku
authors.forename: Anne
authors.initials: A
authors.lastname: Puel
authors.forename: David M
authors.initials: DM
authors.lastname: Frucht
authors.forename: Karin
authors.initials: K
authors.lastname: Christel
authors.forename: Horst
authors.initials: H
authors.lastname: von Bernuth
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Jouanguy
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Feinberg
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
authors.forename: Brigitte
authors.initials: B
authors.lastname: Senechal
authors.forename: Ariane
authors.initials: A
authors.lastname: Chapgier
authors.forename: Guillaume
authors.initials: G
authors.lastname: Vogt
authors.forename: Ludovic
authors.initials: L
authors.lastname: de Beaucoudrey
authors.forename: Claire
authors.initials: C
authors.lastname: Fieschi
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Meriem
authors.initials: M
authors.lastname: Garfa
authors.forename: Jalel
authors.initials: J
authors.lastname: Chemli
authors.forename: Mohamed
authors.initials: M
authors.lastname: Bejaoui
authors.forename: Maria N
authors.initials: MN
authors.lastname: Tsolia
authors.forename: Necil
authors.initials: N
authors.lastname: Kutukculer
authors.forename: Alessandro
authors.initials: A
authors.lastname: Plebani
authors.forename: Luigi
authors.initials: L
authors.lastname: Notarangelo
authors.forename: Christine
authors.initials: C
authors.lastname: Bodemer
authors.forename: Frédéric
authors.initials: F
authors.lastname: Geissmann
authors.forename: Alain
authors.initials: A
authors.lastname: Israël
authors.forename: Michel
authors.initials: M
authors.lastname: Véron
authors.forename: Maike
authors.initials: M
authors.lastname: Knackstedt
authors.forename: Ridha
authors.initials: R
authors.lastname: Barbouche
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.forename: Klaus
authors.initials: K
authors.lastname: Magdorf
authors.forename: Dominique
authors.initials: D
authors.lastname: Gendrel
authors.forename: Fabrice
authors.initials: F
authors.lastname: Agou
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D019013:CD40 Antigens / Q000502:physiology*; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D050172:Genes, X-Linked; D020022:Genetic Predisposition to Disease; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics*; D007223:Infant; D018664:Interleukin-12 / Q000096:biosynthesis*; D007739:L Cells; D008297:Male; D051379:Mice; D009164:Mycobacterium Infections / Q000235:genetics* / Q000276:immunology*; D010375:Pedigree; D014960:X Chromosome
chemical_list: D019013:CD40 Antigens; C491731:IKBKG protein, human; D018664:Interleukin-12; D051550:I-kappa B Kinase