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Monocyte dysfunction in patients with Gaucher disease: evidence for
interference of glucocerebroside with superoxide generation [see comments]
Y Liel, A Rudich, O Nagauker-Shriker, T Yermiyahu and R Levy
Department of Internal Medicine C, Soroka University Hospital, Kupat-
Holim, Beer-Sheva, Israel.
Gaucher disease patients are occasionally affected by chronic or fulminant
infections. Since Gaucher cells originate from tissue phagocytes, we
studied the functional implications of glucocerbroside accumulation on
phagocytes in Gaucher disease patients. Circulating monocytes and
granulocytes from nine type I Gaucher disease patients, and matched
controls, were studied. Evaluation of phagocytic activity included (1)
maximal superoxide generation rates following stimulation by phorbol
12-myristate 13-acetate (PMA), opsonized zymosan (OZ), or
formyl-methionyl-leucylphenylalanine (FMLP); (2) nitroblue tetrazolium
reduction test (NBT); (3) chemotaxis toward FMLP; (4) phagocytosis of OZ
particles; and (5) killing activity against Staphylococcus aureus.
Superoxide generation in monocytes following PMA, OZ, and FMLP stimulation
was significantly suppressed at 52% +/- 15%, 39% +/- 8%, and 51% +/- 11% of
control, respectively. Superoxide generation in granulocytes was normal.
NBT reduction, staphylococcal killing, and phagocytosis were also markedly
decreased in monocytes, and normal in granulocytes. Mean chemotaxis rates
were normal in both monocytes and granulocytes; however, decreased
chemotactic rates were observed in some patients. The abnormality of
superoxide generation could be reproduced in a dose- and time-dependent
manner in normal circulating monocytes incubated with glucocerebroside.
Superoxide generation in glucocerebroside-conditioned normal monocytes in a
cell-free system showed normal superoxide generation, reflecting the
integrity of the NADPH oxidase complex itself. These results demonstrate
markedly compromised phagocytic functions in circulating monocytes in
Gaucher disease patients. These abnormalities can be attributed to
accumulation of glucocerebroside, since it could be reproduced in normal
monocytes incubated with glucocerebroside. Similar abnormalities in Gaucher
cells throughout the reticuloendothelial system could impair host defense,
and may be of particular importance in the pathogenesis of osteomyelitis in
Gaucher disease patients.
Volume 83,
Issue 9,
pp. 2646-2653,
05/01/1994
Copyright © 1994 by The American Society of Hematology
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