Human deficiencies in type-1 cytokine receptors reveal the essential role of type-1 cytokines in immunity to intracellular bacteria.

Human genetic factors play an important role in determining the outcome of infections caused by intracellular pathogens, including mycobacteria and salmonellae (reviewed in 1). The genetic elements involved and the mechanisms by which these control disease-susceptibility versus resistance, however, remain incompletely characterized. Recent studies on patients with idiopathic, severe infections due to poorly pathogenic mycobacteria and salmonellae have revealed that many of these patients are unable to produce or respond to IFN-gamma. This inability results from causative, deleterious genetic mutations in either one of five different genes in the type-1 cytokine cascade, encoding IL-12p40, IL-12Rbeta1, IFN-gammaR1, IFN-gammaR2 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 ten groups of genetic type-1 cytokine (receptor) deficiency distinguished thus far differ significantly. These findings are summarized, discussed and placed in a broader context in relation to protective immune mechanisms and disease susceptibility.