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Decreased levels of total and reduced glutathione in CD4+ lymphocytes in
common variable immunodeficiency are associated with activation of the
tumor necrosis factor system: possible immunopathogenic role of oxidative
stress
P Aukrust, AM Svardal, F Muller, B Lunden, RK Berge and SS Froland
Medical Department A, University of Oslo, National Hospital, Norway.
We have previously shown chronic immune activation and enhanced generation
of reactive oxygen species in common variable immunodeficiency (CVI). In
the present study, we examined levels of glutathione, the dominant
intracellular thiol, that play an important protective role against
oxidative and inflammatory stress in plasma and in monocytes and lymphocyte
subsets in 20 CVI patients and in 16 healthy controls. CD4+ lymphocytes
from CVI patients had significantly lower levels of both total and reduced
glutathione as well as a lower ratio of reduced to total glutathione
compared with healthy controls. This decrease in glutathione levels in CD4+
lymphocytes was most pronounced in the CD45RA+ subset. Plasma levels of
total glutathione were also significantly decreased in CVI. In contrast,
monocytes from CVI patients exhibited increased levels of both total and
reduced glutathione compared with blood donor monocytes. CVI patients had
significantly raised serum levels of tumor necrosis factor alpha (TNF
alpha) and TNF alpha concentration was strongly associated with glutathione
depletion in CD4+ lymphocytes. Furthermore, the lowest levels of both total
and reduced glutathione were found in a subgroup of CVI patients
characterized by persistent immune activation in vivo, decreased numbers of
CD4+ lymphocytes in peripheral blood, and splenomegaly. Finally,
supplementation of cell cultures with glutathione-monoethyl ester did
significantly enhance interleukin-2 production from peripheral blood
mononuclear cells in CVI patients. These glutathione abnormalities in CVI
indicate increased oxidative stress, particularly in CD4+ lymphocytes, and
intracellular depletion of reduced glutathione of the demonstrated
magnitude may have profound implications for CD4+ lymphocyte function and
the immunodeficiency in CVI.
Volume 86,
Issue 4,
pp. 1383-1391,
08/15/1995
Copyright © 1995 by The American Society of Hematology
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