Variant chronic granulomatous disease: modulation of the neutrophil defect by severe infection

Abstract The present studies document the cellular and biochemical processes involved in granulocyte O2- production in three patients from two kindreds with variant chronic granulomatous disease (CGD). Rates of O2- production were 9% to 30% of normal, depending on the individual tested and the stimulus; the two brothers from one family responded to each stimulus with rates very similar to each other. Kinetic analysis of NADPH-dependent O2- production in subcellular fractions revealed all three to have NADPH oxidases with both diminished substrate affinity for NADPH (high Kmapp) and decreased maximal velocities of O2- production. Their granulocytes had normal lag times for activation of the respiratory burst but abnormal rates of stimulus-induced membrane depolarization. Cytochrome b was not found in granulocytes or subcellular fractions despite the use of a spectrophotometric assay sensitive enough to detect the cytochrome if its content were proportional to the residual rate of O2- generation. A striking finding in one patient from each kindred was a threefold to tenfold decrease in the rate of O2- production accompanying serious infection. The residual O2(-)-generating activity of CGD variants helps to explain their relative freedom from the recurrent infections of the classic disease. However, the marked decrease described in the present study indicates the potential for a vicious cycle in which an infection, once established, leads to increasing impairment of host defense.