Oxidative Damage to Neutrophils in Glutathione Synthetase Deficiency

Abstract

Several episodes of neutropenia were observed in a child with glutathione synthetase deficiency (5-oxoprolinuria). Studies of the patient''s glutathione-deficient neutrophils were undertaken to examine the responses of the cells to oxidative stress associated with phagocytosis. The patient''s tineutrophils contained 10-20% of normal glutathione content. Circulating neutrophils in infection-free periods appeared less mature than normal by morphologic criteria, suggesting increased cell turnover. The cells ingested particles, responded to chemotactic stimuli and oxidized I-14C glucose normally. Following ingestion of particles, the cells accumulated excess hydrogen peroxide compared with normal cells, and showed impaired protein iodination and bacterial killing. Electron micrographs revealed damage to microtubules and membranous structures in the patient''s neutrophils during phagocytosis. The glutathione level in the cells appeared inadequate to protect against peroxide generated during cell function; the cells were thus damaged and rendered less effective in bacterial killing. A protective role of glutathione in normal neutrophil function was indicated.