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)-mediat ed immunity appear to be specifically vulnerable to mycobacterial infection s. The severity of clinical features of affected individuals differs betwee n cases. Some patients die of mycobacterial infection in early childhood, w hereas others have long asymptomatic periods in childhood and as adults. Th is rare syndrome also shows high allelic and non-allelic genetic heterogene ity. Mutations in IL12B, encoding the interleukin (IL) 12 p40 subunit, and in IL12RB1, encoding the beta1 chain of the IL-12 receptor, result in impai red IFN-gamma production. Mutations in IFNGR1 and IFNGR2, encoding the two IFN-gamma receptor chains, and mutations in STAT1, encoding an essential si gnaling component, result in impaired cellular responses to IFN-gamma. Diff erent types of mutation define two types of complete and two types of parti al IFN gamma R1 deficiency. Complete and partial IFN gamma R2 deficiency ha ve also been described. We herein compare the genotypes, cellular phe notyp es, and clinical phenotypes of healthy individuals and patients with the se ven known genetic disorders impairing cellular responses to IFN-gamma. Pati ents with defective IFN-gamma production were not considered in this study. The mutations and clinical features of patients with IFN gamma R1, IFN gam ma R2, and STAT-1deficiency 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, cel lular phenotype, and clinical phenotype (normal individuals and patients wi th mild, intermediate, or severe disease). This correlation suggests that I FN gamma -mediated cell activation is a genetically controlled quantitative trait and that it determines the outcome of mycobacterial invasion in man.