ABNORMAL REGULATION OF INTERFERON-GAMMA, INTERLEUKIN-12, AND TUMOR-NECROSIS-FACTOR-ALPHA IN HUMAN INTERFERON-GAMMA RECEPTOR-1 DEFICIENCY

Mycobacterial infections are critically controlled by interferon-gamma (IFN-gamma) and the cellular responses it elaborates, as shown by pat ients with mutations in the IFN-gamma receptor ligand-binding chain (I FN-gamma R1) who have disseminated nontuberculous mycobacterial infect ions. The immunologic sequelae of IFN-gamma R1 deficiency were charact erized in 2 unrelated patients from the Indian subcontinent with novel homozygous recessive IFN-gamma R1 mutations. In vitro, these patients ' peripheral blood mononuclear cells produced 10% of normal IFN-gamma and interleukin-12 (IL-12) in response to phytohemagglutinin (PHA) but normal amounts of IFN-gamma in response to PHA plus IL-12. Tumor necr osis factor-alpha (TNF-alpha) production was normal in response to end otoxin and to PHA but was not augmented by the addition of IFN-gamma, An abnormal phenotype was not found in heterozygous patient relatives. These patients demonstrate the critical role that the IFN-gamma recep tor plays in the regulation of IFN-gamma, IL-12, and TNF-alpha.