Variant chronic granulomatous disease: modulation of the neutrophil defect
by severe infection
PE Newburger, FW Luscinskas, T Ryan, CJ Beard, J Wright, OS Platt, ER Simons and AI Tauber
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.
Volume 68,
Issue 4,
pp. 914-919,
10/01/1986
Copyright © 1986 by The American Society of Hematology
