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From the Department of Renal Immunobiology,*
MRC Centre
for Immune Regulation, The Medical School, University of Birmingham,
Edgbaston, Birmingham, England; and the Centre for Inflammation
Research,
University of Edinburgh, Department
of Clinical and Surgical Sciences, Internal Medicine, Royal Infirmary,
Edinburgh, Scotland
This study assessed whether anti-neutrophil
cytoplasmic antibodies (ANCAs) interfere with the safe deletion of
neutrophils by apoptosis and phagocytic clearance. Tumor necrosis
factor (TNF)-primed neutrophils were incubated with normal IgG (N
IgG) or ANCA IgG for up to 36 hours. Compared with N IgG, ANCAs
accelerated constitutive apoptosis of TNF-
primed
neutrophils, as assessed by morphology and confirmed by DNA
laddering pattern on gel electrophoresis, and accelerated
progression to secondary necrosis. The accelerated apoptosis induced by
ANCA was dependent on reactive oxygen species generation, as
primed neutrophils from patients with chronic granulomatous disease
failed to show an effect of ANCAs on apoptosis. However, there
was no change in the rate at which neutrophils exhibited annexin V
binding, indicating that externalization of phosphatidylserine
was not accelerated by ANCAs. Furthermore, when ANCA-treated
primed neutrophils were interacted with human or murine peritoneal
macrophages after 12 hours there was significantly less phagocytosis by
human macrophages and no difference in phagocytosis by murine
peritoneal-derived macrophages when compared with N IgG-treated
controls. In conclusion, ANCAs accelerate apoptosis and
secondary necrosis in TNF-primed neutrophils by a mechanism dependent
on the generation of reactive oxygen species, with uncoupling
of nuclear and surface membrane changes, resulting in a
"reduced window of opportunity" for phagocytic recognition and
engulfment before disintegration.
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