The relationship between CR3 deficiency and neutrophil actin assembly
FS Southwick, TH Howard, T Holbrook, DC Anderson, TP Stossel and MA Arnaout
Infectious Disease Division, University of Pennsylvania School of Medicine,
Philadelphia 19104.
Polymorphonuclear leukocytes (PMN) with a deficiency of the complement
receptor type 3 (CR3) membrane glycoprotein family have impairments in the
ability to adhere to surfaces as well as chemotactic and phagocytic
defects, processes that require a functional contractile apparatus. PMN
from the patient with neutrophil actin dysfunction (NAD) displayed similar
functional characteristics to those with CR3 deficiency suggesting the two
disorders may be the same disease. In order to evaluate the relationship
between CR3 deficiency and actin assembly, actin filament assembly was
measured in PMN from six previously reported homozygotes (two severe and
four moderate CR3-deficient patients) as well as five heterozygotes for CR3
deficiency. PMN from all patients had normal unstimulated concentrations of
F-actin and after exposure to the chemotactic peptide FMLP (5 x 10(-7)
mol/L for 5 to 40 seconds at 25 degrees C) assembled actin normally.
Pretreatment of normal PMN with concentrations of monoclonal anti-alpha CR3
antibody, capable of blocking PMN adherence, also failed to impair FMLP-
induced actin filament assembly. CR3 glycoprotein expression was measured
in PMNs from the mother, father, and older sister of the NAD patient (N
Engl J Med 291:1093, 1974). Actin filament assembly was recently shown to
be defective in PMNs from all three family members. The total
concentrations of the alpha and beta CR3 subunits were below normal in PMN
detergent extracts from the mother (25% of simultaneous controls) and older
sister (56% of control). PMN surface expression of these two subunits was
also found to be depressed (mother, 50%; older sister, 63% of control).
These findings suggest these two NAD family members are heterozygote
carriers for CR3 deficiency as well as NAD. Simultaneous studies of the
father, however, demonstrated normal total concentrations of both the alpha
and beta CR3 subunits (126% of controls) as well as normal surface
expression of both subunits after phorbol myristate acetate stimulation and
incubation at 37 degrees C (mean, 112% of controls) but slightly lower than
normal levels after FMLP stimulation (mean, 83%). These findings indicate
that CR3 deficiency generally is not associated with defective actin
filament assembly and support the conclusion that NAD represents a unique
kindred in which PMN actin function differs from previously reported
genotypes of CR3 deficiency.
Volume 73,
Issue 7,
pp. 1973-1979,
05/15/1989
Copyright © 1989 by The American Society of Hematology
