Περίληψη:
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.
Συγγραφείς:
Filipe-Santos, Orchidee
Bustamante, Jacinta
Haverkamp, Margje H.
and Vinolo, Emilie
Ku, Cheng-Lung
Puel, Anne
Frucht, David
M.
Christel, Karin
von Bernuth, Horst
Jouanguy, Emmanuelle
and Feinberg, Jacqueline
Durandy, Anne
Senechal, Brigitte and
Chapgier, Ariane
Vogt, Guillaume
de Beaucoudrey, Ludovic and
Fieschi, Claire
Picard, Capucine
Garfa, Meriem
Chemli, Jalel
and Bejaoui, Mohamed
Tsolia, Maria N.
Kutukculer, Necil and
Plebani, Alessandro
Notarangelo, Luigi
Bodemer, Christine and
Geissmann, Frederic
Israel, Alain
Veron, Michel
Knackstedt,
Maike
Barbouche, Ridha
Abel, Laurent
Magdorf, Klaus and
Gendrel, Dominique
Agou, Fabrice
Holland, Steven M. and
Casanova, Jean-Laurent
