Up-regulation of IL-12 in monocytes: A fundamental defect in common variable immunodeficiency

We show that LPS-stimulated circulating CD14-positive monocytes from patien ts 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 etry 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 IF N-gamma-positive T cells, but not of IFN-gamma-positive CD56(+) NK cells. T hese increases in frequency of cytokine-positive cells are due to a decreas e in the absolute numbers of circulating monocytes and T cells that are neg ative for IL-12 and IFN-gamma, respectively. The increased frequency of IL- 12-positive monocytes appears to be selective because TNF-alpha was not inc reased, and is thus unlikely to reflect a general activation. Chronic infec tion is also unlikely to explain our data since cells from X-linked agammag lobulinemia 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 imba lance is likely to skew the immune response away from Ab production and als o explains the failure of CVID T cells to make Ag-specific memory cells and the chronic inflammatory and granulomatous complications that are a featur e of CVID, This disease appears to be a rare example of a polarized Th1-typ e response and may in part be due to a genetic defect in the control of IL- 12 production.