Mutation in the signal-transducing chain of the interferon-γ receptor and susceptibility to mycobacterial infection

Susan E. Dorman, Steven M. Holland

Research output: Contribution to journalArticlepeer-review

Abstract

IFN-γ is critical in the immune response to mycobacterial infections, and deficits in IFN-γ production and response have been associated with disseminated nontuberculous mycobacterial infections. Mutations in the IFN- γ receptor ligand-binding chain (IFNγR1) have been shown to confer susceptibility to severe infection with nontuberculous mycobacteria. However, mutations in the IFN-γ receptor signal-transducing chain (IFNγR2) have not been described. We describe a child with disseminated Mycobacterium fortuitum and M. avium complex infections and absent IFN-γ signaling due to a mutation in the extracellular domain of IFNγR2. In vitro cytokine production by patient PBMCs showed 75% less PHA-induced IFN-γ production than in normal cells, while patient PHA-induced TNF-α production was normal. The normal augmentation of TNF-α production when IFN-γ was added to endotoxin was absent from patient cells. Expression of IFNγR1 was normal, but there was no phosphorylation of Stat1 in response to IFN-γ stimulation. DNA sequence analysis of the gene for IFNγR2 showed a homozygous dinucleotide deletion at nucleotides 278 and 279, resulting in a premature stop codon in the protein extracellular domain. This novel gene defect associated with disseminated nontuberculous mycobacterial infection emphasizes the critical role that IFN- γ plays in host defense against mycobacteria.

Original languageEnglish (US)
Pages (from-to)2364-2369
Number of pages6
JournalJournal of Clinical Investigation
Volume101
Issue number11
DOIs
StatePublished - Jun 1 1998

Keywords

  • Atypical mycobacterium infections
  • IFN receptors
  • IFN type II
  • Signal transduction
  • TNF- α

ASJC Scopus subject areas

  • Medicine(all)

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