Impaired interferon gamma-mediated immunity and susceptibility to mycobacterial infection in childhood

Mendelian susceptibility to poorly virulent mycobacteria such as bacillus C almette-Guerin (BCG) and environmental nontuberculous mycobacteria is a cli nically heterogeneous syndrome. The clinical features of affected children cover a continuous spectrum from disseminated lethal bacillus Calmette-Guer in infection to local recurrent nontuberculous mycobacterial infection. Dif ferent types of mutations in four genes (IFNGR1, IFNGR2, IL12B, IL12RB1) ha ve revealed both allelic and nonallelic heterogeneity and result in eight d ifferent disorders whose common pathogenic pathway is impaired interferon g amma (IFN gamma) mediated immunity. The severity of the clinical phenotype depends on the genotype. Complete IL-12 p40 and IL-12 receptor pi deficienc ies and partial IFN gamma receptor 1 (IFN gamma R1) and IFN gamma R2 defici encies generally lead to curable infections at various ages, and antibiotic s supplemented with IFN gamma if required are likely to be effective. Compl ete IFN gamma R1 and IFN gamma R2 deficiencies predispose to overwhelming i nfection in early childhood, which may respond to antibiotics but relapse w hen antibiotics are discontinued. Rapid discrimination between complete IFN gamma R1 and IFN gamma R2 deficiency and other defects, therefore, is an i mportant diagnostic step for planning clinical management.