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 cytom...

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Bibliographic Details
Published in:The Journal of immunology (1950) Vol. 164; no. 1; p. 488
Main Authors: Cambronero, R, Sewell, W A, North, M E, Webster, A D, Farrant, J
Format: Journal Article
Language:English
Published: United States 01.01.2000
Subjects:
Agammaglobulinemia - genetics
Agammaglobulinemia - immunology
Agammaglobulinemia - pathology
CD28 Antigens - biosynthesis
CD3 Complex - biosynthesis
CD4-Positive T-Lymphocytes - metabolism
CD56 Antigen - biosynthesis
CD8-Positive T-Lymphocytes - metabolism
Cell Count
Common Variable Immunodeficiency - immunology
Common Variable Immunodeficiency - pathology
Dendritic Cells - immunology
Dendritic Cells - metabolism
Female
Genetic Linkage - immunology
Humans
Interleukin-12 - biosynthesis
Interleukin-12 - blood
Interleukin-12 - deficiency
Intracellular Fluid - immunology
Intracellular Fluid - metabolism
Killer Cells, Natural - metabolism
Leukocyte Count
Lipopolysaccharides - pharmacology
Lymphocyte Depletion
Macrophage Activation
Male
Monocytes - immunology
Monocytes - metabolism
T-Lymphocyte Subsets - metabolism
Tumor Necrosis Factor-alpha - biosynthesis
Tumor Necrosis Factor-alpha - metabolism
Up-Regulation - immunology
X Chromosome - immunology
ISSN:0022-1767
Online Access:Get more information
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Summary: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.
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ISSN:0022-1767
DOI:10.4049/jimmunol.164.1.488