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

J Exp Med. 2006 Jul 10;203(7):1745-59. doi: 10.1084/jem.20060085. Epub 2006 Jul 3.


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.

Publication types

  • Case Reports
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • CD40 Antigens / physiology*
  • Cell Line, Transformed
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Female
  • Genes, X-Linked*
  • Genetic Predisposition to Disease*
  • Humans
  • I-kappa B Kinase / genetics*
  • Infant
  • Interleukin-12 / biosynthesis*
  • L Cells
  • Male
  • Mice
  • Mycobacterium Infections / genetics*
  • Mycobacterium Infections / immunology*
  • Pedigree
  • X Chromosome*


  • CD40 Antigens
  • IKBKG protein, human
  • Interleukin-12
  • I-kappa B Kinase