Up-Regulation of IL-12 in Monocytes: A Fundamental Defect in Common Variable Immunodeficiency

Abstract

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-γ-positive T cells, but not of IFN-γ-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-γ, respectively. The increased frequency of IL-12-positive monocytes appears to be selective because TNF-α 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-γ 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.

Quantification and cytokine production of circulating lymphoid and myeloid cells in acute myelogenous leukaemia

“…20 The method described in this work provides the advantage of single-cell analysis of cytokine production by four-colour flow cytometry utilising a minimal amount of whole blood per test. Both lymphoid and myeloid compartments and their respective intracellular cytokine patterns can be evaluated simultaneously and the use of standardised fluorescent counting beads provides enumeration of cytokine-producing populations.…”

cAMP elevators inhibit LPS-induced IL-12 p40 expression by interfering with phosphorylation of p38 MAPK in Murine Peritoneal Macrophages

“…In response to microbes and their products, such as LPS (lipopolysaccharides), macrophages can secret a number of pro-inflammatory cytokines, including IL-12, IL-1, IL-6 and TNF-α [1][2][3][4][5]. They can also produce a number of anti-inflammatory cytokines, such as TGF-β, IL-10 and IL-1Rα [6][7][8].…”

Immunomodulatory action of intravenous immunoglobulin

“…High-dose IVIg has no discernible effect on natural killer cell IFN-g expression following stimulation with PMA and ionomycin 47 nor on monocyte IL-12 expression. 48 Soluble cytokine receptors such as TNF-receptors increase following IVIg infusion, and there is a considerable increase (1000-fold molar excess) in IL-1Ra levels. 43 This increase in IL-1Ra post-infusion was also noted in other studies.…”