X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production.
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.
Filipe-Santos
Orchidée
O
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.
Bustamante
Jacinta
J
Haverkamp
Margje H
MH
Vinolo
Emilie
E
Ku
Cheng-Lung
CL
Puel
Anne
A
Frucht
David M
DM
Christel
Karin
K
von Bernuth
Horst
H
Jouanguy
Emmanuelle
E
Feinberg
Jacqueline
J
Durandy
Anne
A
Senechal
Brigitte
B
Chapgier
Ariane
A
Vogt
Guillaume
G
de Beaucoudrey
Ludovic
L
Fieschi
Claire
C
Picard
Capucine
C
Garfa
Meriem
M
Chemli
Jalel
J
Bejaoui
Mohamed
M
Tsolia
Maria N
MN
Kutukculer
Necil
N
Plebani
Alessandro
A
Notarangelo
Luigi
L
Bodemer
Christine
C
Geissmann
Frédéric
F
Israël
Alain
A
Véron
Michel
M
Knackstedt
Maike
M
Barbouche
Ridha
R
Abel
Laurent
L
Magdorf
Klaus
K
Gendrel
Dominique
D
Agou
Fabrice
F
Holland
Steven M
SM
Casanova
Jean-Laurent
JL
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
D019013:CD40 Antigens; C491731:IKBKG protein, human; D018664:Interleukin-12; D051550:I-kappa B Kinase