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Phagocytosis of sickle erythrocytes: immunologic and oxidative determinants
of hemolytic anemia
RP Hebbel and WJ Miller
Hemolytic anemia in sickle disease involves both intravascular and
extravascular destruction of erythrocytes. Since the latter presumably
involves the reticuloendothelial system, we have examined interactions
between sickle erythrocytes and macrophages. In erythrophagocytosis assays,
18.9 +/- 7.2% of human marrow macrophages ingest sickle RBCs, while only
3.1 +/- 2.1% ingest normal RBCs. This abnormality is not explained by
reticulocytosis, and it is strongly dependent upon RBC density. The
interaction between sickle RBCs and macrophages appears to be partly
immunologic, since it is partially blocked by Fc receptor blockade. Also,
admixture of sickle RBCs (pretreated with rabbit anti- human-Ig) and
Fc-receptor-bearing K562 cells results in 15.6 +/- 10.6% K562-RBC rosette
formation compared with only 0.5 +/- 1.2% for normal RBCs. Regarding other
factors that might promote erythrophagocytosis, sickle RBCs are found to
spontaneously generate twice-normal amounts of dialdehyde byproducts of
lipid peroxidation ("malondialdehyde" or MDA). Peroxide or reagent-MDA
treatment of normal RBCs significantly enhances their phagocytosis, and MDA
is at least 50 times more potent than other aldehydes studied here.
Oxidative and immunologic effects may be related, since exposure of
MDA-treated RBCs to immunoglobulin- containing human sera results in a
further significant enhancement of erythrophagocytosis. For comparison of
different sickle patients, an adherence assay demonstrates that sickle RBCs
are 1.03 to 6.85 times more adherent to macrophages than are normal RBCs,
and degree of adherence correlates significantly with irreversibly sickled
cell (ISC) counts and hematologic variables reflecting hemolytic rate. We
conclude that propensity for RBC interaction with macrophages is likely to
be a determinant of hemolytic rate in sickle disease. Pertinent mechanisms
appear to involve modification of RBC membranes by dialdehyde byproducts of
excessive autoxidation and the abnormal acquisition of surface
immunoglobulin on sickle RBCs, although participation of other membrane
defects has not been excluded. Interestingly, the data further suggest the
possibility that appearance of the "senescence antigen" in old normal RBCs
represents modification of the membrane by "MDA."
Volume 64,
Issue 3,
pp. 733-741,
09/01/1984
Copyright © 1984 by The American Society of Hematology
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