Inherited interleukin 12 deficiency in a child with bacille Calmette-Guérin and Salmonella enteritidis disseminated infection.
Interferon-gamma receptor ligand-binding chain (IFN-gammaR1) or signaling chain (IFN-gammaR2) deficiency, like interleukin 12 receptor beta1 chain (IL-12Rbeta1) deficiency, predispose to severe infections due to poorly virulent mycobacteria and salmonella. A child with bacille Calmette-Guérin and Salmonella enteritidis infection was investigated. Mutations in the genes for IFN-gammaR1, IFN-gammaR2, IL-12Rbeta1, and other molecules implicated in IL-12- or IFN-gamma-mediated immunity were sought. A large homozygous deletion within the IL-12 p40 subunit gene was found, precluding expression of functional IL-12 p70 cytokine by activated dendritic cells and phagocytes. As a result, IFN-gamma production by lymphocytes was markedly impaired. This is the first discovered human disease resulting from a cytokine gene defect. It suggests that IL-12 is essential to and appears specific for protective immunity to intracellular bacteria such as mycobacteria and salmonella.
Altare
F
F
INSERM U429, Hôpital Necker-Enfants Malades, Paris, France.
Lammas
D
D
Revy
P
P
Jouanguy
E
E
Döffinger
R
R
Lamhamedi
S
S
Drysdale
P
P
Scheel-Toellner
D
D
Girdlestone
J
J
Darbyshire
P
P
Wadhwa
M
M
Dockrell
H
H
Salmon
M
M
Fischer
A
A
Durandy
A
A
Casanova
J L
JL
Kumararatne
D S
DS
D001500:BCG Vaccine / Q000276:immunology*; D001424:Bacterial Infections / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D005260:Female; D005816:Genetic Complementation Test; D006099:Granuloma / Q000473:pathology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000172:deficiency / Q000235:genetics*; D007962:Leukocytes; D008198:Lymph Nodes / Q000473:pathology; D008969:Molecular Sequence Data; D009161:Mycobacterium / Q000276:immunology / Q000472:pathogenicity; D010375:Pedigree; D012477:Salmonella enteritidis / Q000276:immunology / Q000472:pathogenicity*; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion / Q000235:genetics; D014162:Transfection / Q000235:genetics
D001500:BCG Vaccine; D018664:Interleukin-12; D007371:Interferon-gamma