Issue: 2004 > Supplement March > articles

Genetics of type-1 cytokines in human intracellular infectious diseases: a spectrum of novel genetic deficiencies demonstrates the essential role of type-1 cytokines in immunity against nontuberculous mycobacteria, M. bovis BCG and salmonellae

T.H.M. Ottenhoff


Human genetic factors play an important role in determining the outcome of infections caused by intracellular pathogens, including mycobacteria and salmonellae.[1] The genetic elements involved and the mechanisms by which these control disease susceptibility vs resistance, however, remain incompletely characterised. Recent studies on patients with idiopathic severe infections due to otherwise poorly pathogenic mycobacteria (nontuberculous mycobacteria or Mycobacterium bovis BCG) or Salmonella species have revealed that many of these patients are unable to produce or respond to IFN-g. This inability results from causative, deleterious genetic mutations in any one of five different genes in the type-1 cytokine cascade, encoding IL-12p40, IL-12Rb1, IFN-gR1, IFN-gR2 or Stat-1. The mutational events can lead to complete or partial deficiency, and are mostly autosomal recessive but can be dominant negative as well. The immunological, clinical and histopathological phenotypes resulting from the 11 groups of genetic type-1 cytokine (receptor) deficiencies that have been identified thus far differ significantly. These findings are summarised, discussed and placed in a broader context in relation to genetic disease predisposition and molecular and cellular mechanisms of protective immunity to these intracellular pathogens.