Up-regulation of IL-12 in monocytes: a fundamental defect in common variable immunodeficiency.
We show that LPS-stimulated circulating CD14-positive monocytes from patients with common variable immunodeficiency (CVID) express a higher proportion of intracellular IL-12-positive cells than monocytes from patients with X-linked agammaglobulinemia or normal subjects. We used four-color flow cytometry and measured IL-12 with an Ab to the p40 subunit following stimulation with LPS. The raised IL-12 is associated with an increased frequency of IFN-gamma-positive T cells, but not of IFN-gamma-positive CD56+ NK cells. These increases in frequency of cytokine-positive cells are due to a decrease in the absolute numbers of circulating monocytes and T cells that are negative for IL-12 and IFN-gamma, respectively. The increased frequency of IL-12-positive monocytes appears to be selective because TNF-alpha was not increased, and is thus unlikely to reflect a general activation. Chronic infection is also unlikely to explain our data since cells from X-linked agammaglobulinemia patients with a similar Ig deficiency do not show these changes. Our data suggest a fundamental abnormality in the IL-12/IFN-gamma circuit in CVID, with up-regulation of IL-12 being the "primary" factor. This imbalance is likely to skew the immune response away from Ab production and also explains the failure of CVID T cells to make Ag-specific memory cells and the chronic inflammatory and granulomatous complications that are a feature of CVID. This disease appears to be a rare example of a polarized Th1-type response and may in part be due to a genetic defect in the control of IL-12 production.
Cambronero
R
R
Department of Immunology, Medical Research Council Immunodeficiency Research Group, Royal Free & University College School of Medicine, London, United Kingdom.
Sewell
W A
WA
North
M E
ME
Webster
A D
AD
Farrant
J
J
D000361:Agammaglobulinemia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D018106:CD28 Antigens / Q000096:biosynthesis; D017252:CD3 Complex / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D019002:CD56 Antigen / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002452:Cell Count; D017074:Common Variable Immunodeficiency / Q000276:immunology* / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D008040:Genetic Linkage / Q000276:immunology; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000097:blood / Q000172:deficiency*; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000378:metabolism; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000494:pharmacology; D008212:Lymphocyte Depletion; D008262:Macrophage Activation; D008297:Male; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology*; D014960:X Chromosome / Q000276:immunology
D018106:CD28 Antigens; D017252:CD3 Complex; D019002:CD56 Antigen; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12