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Department of Immunology, Medical Research Council Immunodeficiency Research Group, Royal Free & University College School of Medicine, London, United Kingdom
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-
-positive T cells, but not of
IFN--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-, respectively. The increased frequency of
IL-12-positive monocytes appears to be selective because TNF-
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- 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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