Interferon-gamma corrects the respiratory burst defect in vitro in monocyte-derived macrophages from glycogen storage...

Glycogen storage disease (GSD) type 1b is accompanied by decreased respiratory burst activity in peripheral blood phagocytic cells (i.e. monocytes and neutrophils). To elucidate whether this depressed respiratory burst was due to an intrinsic defect of phagocytic cells or due in part to in vivo host factors, we examined superoxide anion (O2-) production in monocytes from five GSD 1b patients cultured 9 d in vitro to allow for differentiation into macrophages (MDM). O2- production in MDM was measured in response to concanavalin A, fMet-Leu-Phe, and phorbol myristate acetate (PMA) stimulation. GSD 1b MDM had significantly depressed O2- generation with fMet-Leu-Phe and concanavalin A stimulation; however, unlike peripheral blood monocytes, GSD 1b MDM responded to PMA stimulation with O2- production comparable to healthy control donors. The cytokine interferon-gamma (IFN-gamma) has been shown to enhance O2- production in MDM. When GSD 1b MDM were cultured in the presence of IFN-gamma (1 x 10(5) U/L), O2- production in response to fMet-Leu-Phe, concanavalin A, and PMA was enhanced to rates similar to those of control MDM cultured in the presence of IFN-gamma. Thus, the respiratory burst defect observed in circulating phagocytic cells is also present in vitro in cultured GSD 1b MDM. However, in contrast to circulating phagocytic cells, depressed O2- production in GSD 1b MDM is selective to receptor-mediated activation, but not to PMA stimulation. This defect is correctable after short-term treatment with IFN-gamma, suggesting a role for IFN-gamma in treating the phagocytic defect in this disease.