X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production
Küçük Resim Yok
Tarih
2006
Yazarlar
Filipe-Santos, Orchidee
Bustamante, Jacinta
Haverkamp, Margje H.
Vinolo, Emilie
Ku, Cheng-Lung
Puel, Anne
Frucht, David M.
Christel, Karin
von Bernuth, Horst
Jouanguy, Emmanuelle
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Rockefeller Univ Press
Erişim Hakkı
info:eu-repo/semantics/openAccess
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.
Açıklama
Anahtar Kelimeler
Kaynak
Journal of Experimental Medicine
WoS Q Değeri
N/A
Scopus Q Değeri
Q1
Cilt
203
Sayı
7
