Monocyte Dysfunction in Patients With Gaucher Disease: Evidence for Interference of Glucocerebroside With Superoxide Generation

Abstract

AbstractGaucher disease patients are occasionally affected by chronic or fulminant infections. Since Gaucher cells originate from tissue phagocytes, we studied the functional implications of glucocerebroside 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-leucyl-phenylalanine (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.