X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production


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FILIPE-SANTOS O., BUSTAMANTE J., HAVERKAMP M. H. , VINOLO E., KU C., PUEL A., ...More

JOURNAL OF EXPERIMENTAL MEDICINE, vol.203, no.7, pp.1745-1759, 2006 (Journal Indexed in SCI) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 203 Issue: 7
  • Publication Date: 2006
  • Doi Number: 10.1084/jem.20050085
  • Title of Journal : JOURNAL OF EXPERIMENTAL MEDICINE
  • Page Numbers: pp.1745-1759

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-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.