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J Clin
Invest 1999 Aug;104(4):515-523
Aberrant prostaglandin synthase 2 expression defines an antigen-presenting
cell defect for insulin-dependent diabetes mellitus.
Litherland SA, Xie XT,
Hutson AD, Wasserfall C, Whittaker DS, She JX, Hofig A, Dennis MA,
Fuller K, Cook R, Schatz D, Moldawer LL, Clare-Salzler MJ.
Department of Immunology,
Pathology, and Laboratory Medicine, College of Medicine, College
of Medicine, University of Florida, Gainesville 32610, USA.
Prostaglandins (PGs)
are lipid molecules that profoundly affect cellular processes including
inflammation and immune response. Pathways contributing to PG output
are highly regulated in antigen-presenting cells such as macrophages
and monocytes, which produce large quantities
of these molecules upon activation. In this report, we demonstrate
aberrant constitutive expression of the normally inducible cyclooxygenase
PG synthase 2 (PGS(2)/ COX-2) in nonactivated monocytes of humans
with insulin-dependent diabetes mellitus (IDDM) and those with islet
autoantibodies at increased risk of
developing this disease. Constitutive PGS(2) appears to characterize
a high risk for diabetes as it correlates with and predicts a low
first-phase insulin response in autoantibody-positive subjects.
Abnormal PGS(2)
expression in at-risk subjects affected immune response in vitro,
as the presence of a specific PGS(2) inhibitor, NS398, significantly
increased IL-2 receptor alpha-chain (CD25) expression on phytohemagglutinin-stimulated
T cells. The effect of PGS(2) on CD25 expression was
most profound in subjects expressing both DR04 and DQbeta0302 high-risk
alleles, suggesting that this cyclooxygenase interacts with diabetes-associated
MHC class II antigens to limit T-cell activation. These
results indicate that constitutive PGS(2) expression in monocytes
defines an antigen-presenting cell defect affecting immune response,
and that this expression is a novel cell-associated risk marker
for IDDM.
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