Human interferon-gamma-mediated immunity is a genetically controlled continuous trait that determines the outcome of mycobacterial invasion.

Individuals with inherited disorders of interferon gamma (IFN-gamma)-mediated immunity appear to be specifically vulnerable to mycobacterial infections. The severity of clinical features of affected individuals differs between cases. Some patients die of mycobacterial infection in early childhood, whereas others have long asymptomatic periods in childhood and as adults. This rare syndrome also shows high allelic and non-allelic genetic heterogeneity. Mutations in IL12B, encoding the interleukin (IL)-12 p40 subunit, and in IL12RB1, encoding the beta1 chain of the IL-12 receptor, result in impaired IFN-gamma production. Mutations in IFNGR1 and IFNGR2, encoding the two IFN-gamma receptor chains, and mutations in STAT1, encoding an essential signaling component, result in impaired cellular responses to IFN gamma. Different types of mutation define two types of complete and two types of partial IFNgammaR1 deficiency. Complete and partial IFNgammaR2 deficiency have also been described. We herein compare the genotypes, cellular phenotypes, and clinical phenotypes of healthy individuals and patients with the seven known genetic disorders impairing cellular responses to IFN-gamma. Patients with defective IFN-gamma production were not considered in this study. The mutations and clinical features of patients with IFNgammaR1, IFNgammaR2, and STAT-1 deficiency are reviewed. Selected cell lines from each of the eight groups were tested for their response to IFN-gamma. We find that individuals may be classified into four broad groups based on genotype, cellular phenotype, and clinical phenotype (normal individuals and patients with mild, intermediate, or severe disease). This correlation suggests that IFN-gamma-mediated cell activation is a genetically controlled quantitative trait and that it determines the outcome of mycobacterial invasion in man.