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Monocyte dysfunction in patients with Gaucher disease: evidence for interference of glucocerebroside with superoxide
Y Liel1, A Rudich, O Nagauker-Shriker
1Department of Internal Medicine C, Soroka University Hospital, Kupat-Holim, Beer-Sheva, Israel.
Abstract:
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.
Insights
Gaucher disease impairs monocyte phagocytic functions due to glucocerebroside accumulation, compromising host defense. This study investigates these functional deficits in Gaucher patients.
Area of Science:
- Immunology
- Hematology
- Metabolic Disorders
Background:
- Gaucher disease is characterized by glucocerebroside accumulation.
- Gaucher cells, derived from phagocytes, may have impaired function.
- Patients with Gaucher disease are prone to infections.
Purpose of the Study:
- To investigate the functional implications of glucocerebroside accumulation on phagocytes in Gaucher disease.
- To assess phagocytic activity, including superoxide generation, NBT reduction, chemotaxis, phagocytosis, and killing activity.
Main Methods:
- Studied circulating monocytes and granulocytes from Gaucher disease patients and controls.
- Evaluated phagocytic activity using various functional assays.
- Reproduced superoxide generation abnormalities in normal monocytes incubated with glucocerebroside.
Main Results:
- Monocytes from Gaucher patients showed significantly suppressed superoxide generation, decreased NBT reduction, phagocytosis, and killing activity.
- Granulocyte functions were largely normal.
- Glucocerebroside incubation in normal monocytes mimicked the observed functional deficits.
Conclusions:
- Circulating monocytes in Gaucher disease patients exhibit markedly compromised phagocytic functions.
- Glucocerebroside accumulation is identified as the cause of these monocyte abnormalities.
- Impaired phagocyte function in Gaucher disease may contribute to increased infection susceptibility and pathogenesis, such as osteomyelitis.