Defective monocyte costimulation for IFN-gamma production in familial disseminated Mycobacterium avium complex infection: abnormal IL-12 regulation.
We have described previously a family in which several members have disseminated Mycobacterium avium complex infection. PBMC from affected members produced abnormally low amounts of IFN-gamma upon stimulation with PHA. Using PHA-stimulated allogeneic cocultures of highly purified monocytes and T cells from familial patients and normal subjects, we have now demonstrated that familial patient monocytes are defective in accessory cell function for IFN-gamma production. Familial patient monocytes did not inhibit IFN-gamma production by normal cells, nor did inhibition of PG synthesis restore normal IFN-gamma production by familial patient cells. Familial patient cells responded to the addition of exogenous IL-12 by increasing IFN-gamma production, while addition of exogenous anti-IL-12 had an insignificant effect on their IFN-gamma production. IL-12 was undetectable in PHA-stimulated cocultures of familial patient monocytes with familial or normal T cells. In addition, IL-12 production by adherent cells from patients and their unaffected mothers was abnormally low following stimulation with fixed Staphylococcus aureus Cowan I strain. However, normal amounts of IL-12 were detected when adherent familial patient cells were stimulated with S. aureus Cowan I strain and IFN-gamma, suggesting abnormal regulation of IL-12 production by familial monocytes. This is the first report of defective IL-12 production associated with increased susceptibility to an infectious disease, a finding that supports the critical role of this cytokine in host defense.
Frucht
D M
DM
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
Holland
S M
SM
D002648:Child; D005260:Female; D006579:Heterozygote; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000172:deficiency* / Q000494:pharmacology; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000172:deficiency* / Q000494:pharmacology; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D009035:Mothers; D015270:Mycobacterium avium-intracellulare Infection / Q000235:genetics* / Q000276:immunology*; D010375:Pedigree; D010835:Phytohemagglutinins / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D010835:Phytohemagglutinins; D018664:Interleukin-12; D007371:Interferon-gamma