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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Vydané v:	The Journal of immunology (1950) Ročník 164; číslo 1; s. 488
Hlavní autori:	Cambronero, R, Sewell, W A, North, M E, Webster, A D, Farrant, J
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 01.01.2000
Predmet:	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
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Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-1767
DOI:	10.4049/jimmunol.164.1.488