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 patients with mutations in the IFN-gamma receptor ligand-binding chain (IFN-gamma R1) who have disseminated nontuberculous mycobacterial infections. The immunologic sequelae of IFN-gamma R1 deficiency were characterized 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 necrosis factor-alpha (TNF-alpha) production was normal in response to endotoxin 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 receptor plays in the regulation of IFN-gamma, IL-12, and TNF-alpha.
Holland
S M
SM
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. smh@nih.gov
Dorman
S E
SE
Kwon
A
A
Pitha-Rowe
I F
IF
Frucht
D M
DM
Gerstberger
S M
SM
Noel
G J
GJ
Vesterhus
P
P
Brown
M R
MR
Fleisher
T A
TA
D000595:Amino Acid Sequence; D002675:Child, Preschool; D005808:Genes, Recessive; D006579:Heterozygote; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology*; D018664:Interleukin-12 / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D015269:Mycobacterium avium Complex / Q000276:immunology*; D010154:Pakistan / Q000208:ethnology; D010375:Pedigree; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D000096743:Interferon gamma Receptor
D007371:Interferon-gamma; D018664:Interleukin-12; D017471:Receptors, Interferon; D014409:Tumor Necrosis Factor-alpha; D000096743:Interferon gamma Receptor