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Receptors and Opsonizes Particles for Phagocytosis1
*
Veterans Affairs Medical Center; and Departments of
Medicine and
Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM 87108
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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R). We now
report that SAP also binds to FcR and opsonizes particles for
phagocytosis by human polymorphonuclear leukocytes (PMN). Specific,
saturable binding of SAP to FcRI, FcRIIa, and FcRIIIb
expressed on transfected COS cells was detected using SAP-biotin and
PE-streptavidin. Zymosan was used to test the functional consequences
of SAP and CRP binding to FcR. Both SAP and CRP bound to zymosan and
enhanced its uptake by PMN. This enhanced phagocytosis was abrogated by
treatment of PMN with wortmannin, a phosphatidylinositol-3 kinase
inhibitor, or with piceatannol, a Syk inhibitor, consistent with uptake
through FcR. Treatment of PMN with phosphatidylinositol-specific
phospholipase C to remove FcRIIIb also decreased phagocytosis of
SAP-opsonized zymosan, but not CRP-opsonized zymosan. These results
suggest that SAP may function in host defense. In addition, as SAP
binds to chromatin, a major immunogen in systemic lupus erythematosus,
it may provide a clearance mechanism for this Ag through FcR bearing
cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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SAP is a constitutive protein in human blood, where it is present at
concentrations of 
40 µg/ml (4). In the mouse, SAP is
a major acute-phase reactant (5). SAP is the precursor of
tissue amyloid P component, where it may actually promote the formation
of pathogenic amyloid deposits and prevent their degradation. SAP binds
to microbial polysaccharides and matrix components through carbohydrate
determinants, including heparin, 6-phosphorylated mannose, 3-sulfated
saccharides, and the 4,6-cyclic pyruvate acetal of galactose (6, 7), in addition to its binding to amyloid fibrils.
More recently, it has been recognized that SAP binds to chromatin and to DNA with high affinity (8). These molecules are major autoantigens in the human autoimmune disease systemic lupus erythematosus (9). It has recently been demonstrated that mice genetically deficient in SAP develop systemic lupus erythematosus with proliferative glomerulonephritis and characteristic autoantibodies (10). The mechanism of this effect is not known but is felt to involve alterations in the clearance of these nuclear Ags from the circulation. Consistent with this possibility, we previously demonstrated that SAP slows the clearance of chromatin from the circulation (11). The reduction in the rate of clearance was associated with increased uptake by the liver and decreased deposition in the kidneys.
The existence of a receptor for SAP on mouse macrophages and human
polymorphonuclear leukocytes (PMN) has been previously reported
(12, 13). However, the nature of the receptor and its
function were unknown. Becasue we recently determined that the
receptors for the related pentraxin CRP are the IgG Fc receptors
(FcR) (14, 15, 16, 17), we tested whether FcR would also
bind SAP. When tested using transfected COS cells, all three classes of
FcR were found to bind SAP. One of the most important activities of
FcR is the mediation of phagocytosis (18). To determine
whether SAP is capable of inducing phagocytosis, we used zymosan, a
yeast to which SAP binds. SAP, as well as CRP, was shown to be an
opsonin for yeast particles. Inhibition studies showed that
opsonization by SAP and CRP used the same signaling pathway as IgG. SAP
and CRP attached directly to beads also enhanced phagocytosis,
indicating a direct interaction with phagocytic receptors.
These results imply that SAP is an opsonin like CRP that could be
an important part of the innate immune system with a role in the
clearance of autoantigens. The ability of the pentraxins to interact
with FcR could also affect the presentation of autoantigens to T
cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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FITC-zymosan and rabbit anti-zymosan (zymosan-opsonizing reagent) were obtained from Molecular Probes (Eugene, OR). M-280 Dynabeads (tosyl-activated polystyrene beads coated with polyurethane) were purchased from Dynal Biotech (Lake Success, NY). Dynabeads were coated with CRP, SAP, or human IgG according to the manufacturer’s instructions using 5 µg protein/107 beads. Beads were blocked with Tris rather than albumin. Piceatannol, wortmannin, cytochalasin D, and phosphatidylinositol-specific phospholipase C (PIPLC) were purchased from Sigma (St. Louis, MO).
Antibodies
Abs were purchased as follows: FITC anti-CD16 (mAb 3G8) was purchased from BD PharMingen (San Diego, CA), FITC anti-CD32 (mAb AT10) from Serotec (Raleigh, NC), anti-CD64 (mAb 32.2) from Medarex (Annandale, NJ), PE-anti-CD32 (mAb C1KM5) and PE-F(ab')2 goat anti-mouse IgG (PE-GAM) from Caltag (Burlingame, CA), PE-anti-CD16 (mAb 3G8) from Calbiochem (San Diego, CA), PE anti-CD11b from Dako (Carpinteria, CA), and Alexa Fluor 488-F(ab')2-GAM and Alexa Fluor 594-F(ab')2 goat anti-human IgG from Molecular Probes. The hybridoma cell line producing mAb 2C10, a murine IgG1 anti-human CRP, was the generous gift of Dr. L. Potempa (ImmTech International, Evanston, IL) and was used as culture supernatant at 5 µg/ml. The mAb SAP-5, a murine IgG2a anti-human SAP, was purchased from Sigma and used as ascites at 5 µg/ml.
Isolation of CRP and SAP
Human CRP was purified from pleural fluid by affinity chromatography and ion exchange chromatography as previously described (19). SAP was prepared as a side product of factor IX purification and generously provided to us by Dr. W. Kisiel (Department of Pathology, University of New Mexico, Albuquerque, NM). Briefly, SAP was copurified with coagulation factor IX from Proplex by immunoaffinity chromatography as described (20). SAP was then separated from factor IX by Q Sepharose Fast Flow chromatography. Minor contaminants were removed from SAP by anion exchange chromatography on a Mono Q column using FPLC (Pharmacia, Piscataway, NJ) with a 0.15–0.5 M NaCl gradient in 20 mM Tris (pH 7.8) (21). SAP-biotin was prepared by coupling biotin to the carbohydrate moiety of SAP via a hydrazide linkage. SAP was oxidized with 10 mM sodium metaperiodate for 30 min in the dark. After the reaction was stopped with 15 mM glycerol, SAP was dialyzed overnight and treated with 5 mM biotin-LC-hydrazide (EZ-Link; Pierce, Rockford, IL) at pH 7 for 2 h. For flow cytometric binding studies, SAP-biotin was detected using PE-streptavidin (Caltag).
Cells
Blood from normal volunteers was drawn into heparinized tubes. PMN were obtained by gradient separation using MonoPoly resolving medium (ICN Pharmaceuticals, Aurora, OH). In some cases, PMN were treated with 1 U/ml of PIPLC for 60 min at 37°. COS-7 cells were obtained from the American Type Culture Collection (Manassas, VA) and were maintained in DMEM with 10% FCS and 50 µg/ml gentamicin.
Cell transfections
The human FcRI cDNA clone, FcRIaI in pRC/CMV, was obtained
from Dr. R. P. Kimberly (University of Alabama, Birmingham, AL).
The human FcRIIA cDNA clone in the pcDSR
296 transient
transfection vector (22) was obtained from Dr. K. Moore
(DNAX Research Institute, Palo Alto, CA). The human FcRIIIb gene in
pRC/CMV was obtained from Dr. E. Brown (University of California, San
Francisco, CA). Cells were transfected using the GenePORTER
transfection reagent from Gene Therapy Systems (San Diego, CA) as
previously described (14). Mock-transfected cells received
GenePORTER reagent only.
SAP binding assay
Cells were washed twice in ice-cold PBS containing 0.05% azide
and 0.1% globulin-free BSA and resuspended in this medium with
SAP-biotin at the concentrations indicated. Cells were incubated for
1 h in the presence of SAP, then washed twice. Cells were then
incubated for 30 min at 4°C with PE-streptavidin. Cells were washed
twice and analyzed by flow cytometry. FcRI expression was measured
using mAb 32.2 and PE-GAM. Levels of FcRII were determined by
binding of FITC-AT10. FcRIII was determined using PE-3G8 or
FITC-3G8. The percentage of dead cells was determined using
7-aminoactinomycin D according to the manufacturer’s directions
(Molecular Probes).
Flow cytometry
Cells were analyzed using a BD Biosciences (Mountain View, CA) FACSCalibur flow cytometer equipped with CellQuest software. The population analyzed was gated by forward and side scatter to exclude dead cells. A minimum of 30,000 cells was collected. For all measurements of SAP binding, the binding of PE-streptavidin has been subtracted. The results are expressed as the geometric mean channel fluorescence (GMCF).
Data analysis
Dose-dependent binding curves of SAP to cells, as well as Scatchard plots, were generated using GraphPad Prism software (GraphPad, San Diego, CA). Binding of SAP was analyzed by nonlinear regression. Affinity constants were derived from the sum of least squares analysis by computer fitting, which is preferable to linear regression of the transformed data (23, 24). Scatchard graphs were created for graphic simplicity of data interpretation. Data shown are representative of at least two experiments. For phagocytosis assays, means were compared by two-tailed t tests.
Phagocytosis assays
To measure phagocytosis, 2 x 106 FITC-zymosan were added to 5 x 105 PMN in RPMI 1640 supplemented with 5% FBS and 1 mM MnCl2. Tubes were centrifuged briefly (1 min at 200 x g) and incubated for 30 min at 37°C. Phagocytosis was scored visually on a Nikon fluorescent microscope (Nikon, Melville, NY). The fluorescence of the noningested yeast particles was quenched by the addition of trypan blue to a final concentration of 0.02%. The results are expressed as the phagocytic index (number of ingested yeast cells per 100 PMN).
Similar phagocytosis assays were done using coated Dynabeads, except that, after incubation with PMN, uningested beads were stained with mAb to CRP or SAP and Alexa Fluor 488-GAM, or Alexa Fluor 594-anti-human IgG for IgG beads. Beads associated with phagocytic cells were determined by light microscopy and were scored as ingested or attached based on fluorescence.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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R in transfected COS cells
We have recently demonstrated that the human leukocyte
receptors for CRP are FcRIIa and FcRI (16, 25).
Binding of CRP to each of these receptors can be demonstrated in
transfected COS cells. Because SAP closely resembles CRP in both
structural and binding characteristics, we decided to test whether SAP
was capable of binding to FcR as well. As shown in Fig. 1
, SAP shows saturable binding to COS
cells expressing either FcRI or FcRIIa compared with
mock-transfected COS cells. These binding curves were determined using
SAP-biotin detected with PE-streptavidin. Unmodified SAP was not used
as an inhibitor of biotin-SAP due to the observed and previously
reported tendency of SAP to undergo self-association at higher
concentrations (26). Binding of unmodified SAP was
demonstrated using a mAb to SAP and PE-GAM (data not shown). The
calculated Kd values for these binding
curves are 7.8 x 10-8 M for FcRI and
1.4 x 10-7 M for FcRIIa, which are
close to the physiological concentration of SAP (40 µg/ml or
3.5 x 10-7 M in serum). SAP binding to COS
cells transfected with the human neutrophil receptor FcRIIIb was
also shown (Fig. 2). The binding curve is
shown in Fig. 2A with a calculated
Kd of 9.4 x
10-7 M. CRP does not bind to
FcRIIIb-transfected COS cells, which is consistent with our earlier
results using peripheral blood leukocytes (data not shown). Fig. 2B shows two-color fluorescent analysis of
FcRIIIb-transfected COS cells after staining with PE-streptavidin
for SAP-biotin binding and FITC-anti-CD16 for expression of
FcRIIIb. There was a strong association between the two markers with
28% double-positive cells, 57% double-negative cells, and <10% of
cells positive for either single marker.
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Although CRP has long been recognized as an opsonin, to our
knowledge, the ability of SAP to enhance phagocytosis of microorganisms
has not previously been demonstrated. Because phagocytosis is an
important function of FcR, we decided to test the effect of SAP on
the phagocytosis of a model microbial particle. Previous studies have
demonstrated the ability of both CRP and SAP to bind to zymosan, and we
confirmed this (27). To determine whether SAP is an
opsonin, human PMN were isolated and incubated with FITC-zymosan that
had been treated with a saturating concentration of SAP (200 µg/ml)
or rabbit IgG (zymosan-opsonizing reagent), and phagocytosis was
determined by fluorescent microscopy (Fig. 3A). SAP and IgG treatment
enhanced the uptake of FITC-zymosan from a phagocytic index of 25 for
unopsonized zymosan to 61 for SAP (p = 0.007)
and 71 for IgG (p = 0.010). In subsequent
experiments, SAP was added to the incubation mixture containing PMN and
FITC-zymosan. A dose-dependent enhancement of phagocytosis was observed
when >33 µg/ml SAP was added, with maximum effect at 100 µg/ml SAP
(Fig. 3B). SAP had a greater effect when it was added to the
incubation mixture than when it was used to preopsonize FITC-zymosan.
This is most likely due to a loss of SAP during washing, as SAP has a
relatively low affinity for zymosan (3 x
10-5 M) (28). The addition of 10
µg/ml polymyxin B to bind endotoxin in the phagocytosis assay did not
affect the results.
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The signaling pathways required for phagocytosis by PMN through
FcR have been described (29). To determine
whether enhanced uptake of SAP-zymosan was mediated by
FcR, we tested the ability of specific inhibitors of
FcR-mediated phagocytosis to block SAP and CRP
opsonization. Wortmannin is a selective inhibitor of
phosphatidylinositol-3 kinase and inhibits a number of Fc
receptor-initiated responses including phagocytosis (29, 30). As shown in Fig. 4, treatment
of PMN with wortmannin (10 nM) reduced the phagocytosis of SAP (72
± 12% decreased; p = 0.008), CRP (73 ± 3%
decreased; p < 0.001), and IgG-opsonized zymosan
(62 ± 11% decreased; p = 0.012) to the level
observed with unopsonized zymosan. Piceatannol is a specific inhibitor
of the tyrosine kinase Syk, which is required for
FcR-mediated phagocytosis but not for uptake of latex
beads, bacteria, or complement-opsonized yeast (31, 32).
As shown in Fig. 5, treatment of PMN with
piceatannol (2–10 µM) also inhibited the phagocytosis of
SAP-opsonized (33 ± 10% decreased; p = 0.051)
and CRP-opsonized (68 ± 9% decreased; p = 0.005)
zymosan to the level observed with unopsonized zymosan. IgG induced
phagocytosis of zymosan was reduced by 52 ± 9%
(p = 0.021). Uptake of unopsonized zymosan was
not significantly decreased by either inhibitor. These results indicate
that both SAP and CRP enhanced phagocytosis of zymosan requires
phosphatidylinositol-3 kinase and Syk. This is consistent with
FcR-mediated phagocytosis.
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We previously reported that FcRIIa is the primary
CRP receptor on human PMN. PMN express 10 times more
FcRIIIb than FcRIIa. Because SAP binds to
FcRIIIb as well as FcRIIa, we wished to
determine the role of FcRIIIb in SAP opsonization.
FcRIIIb is a GPI-anchored protein and can therefore be
removed by treatment of cells with PIPLC. The results in Fig. 6 demonstrate reduced phagocytosis by SAP
(44 ± 12% decreased; p = 0.039) and IgG (43
± 8% decreased; p = 0.013) using PIPLC-treated PMN.
Uptake of CRP-opsonized zymosan was not affected (16 ± 4%
decreased). B shows the selective removal of
FcRIIIb and not FcRIIa or CD11b by the
PIPLC treatment.
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Because PMN can ingest unopsonized zymosan through CD11b/CD18, it
was possible that SAP and CRP were providing an activating signal for
uptake of zymosan through these receptors (33) rather than
directly binding to FcR to promote ingestion of zymosan.
Therefore, we also tested the ability of SAP and CRP to opsonize
Dynabeads, which are not bound or ingested by PMN in the absence of
opsonins (phagocytic and attachment indexes <10). Dynabeads were
coated with CRP, SAP, and IgG and tested for phagocytosis by PMN. All
three opsonins promoted both adherence and ingestion of these inert
beads (p < 0.05 for each opsonin compared with
controls), providing further evidence for a direct interaction between
SAP or CRP and phagocytic receptors. Dynabeads coupled to either human
serum albumin or BSA were phagocytosed less efficiently than
Tris-blocked beads.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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R and, second, that SAP
effectively opsonizes zymosan and polystyrene beads for phagocytosis by
human PMN. The importance of FcR in SAP-mediated phagocytosis was
shown by experiments using inhibitors of FcR signaling. Taken
together, these results suggest that SAP, like CRP, interacts with
FcR to mediate phagocytosis. These findings establish a potentially
important role for SAP in the innate immune system.
The interaction of SAP with FcR on transfected cells was found to be
specific and saturable with binding affinities within the physiological
range of SAP. SAP levels vary from 20–50 µg/ml in normal
individuals, with males having slightly higher levels than females
(34). The binding of SAP to human PMN was previously
demonstrated by Landsmann et al. (13). These investigators
reported that SAP bound to human PMN with high affinity and that CRP
and SAP competed for binding. The binding of SAP to PMN showed
heterogeneity of affinities consistent with multiple binding sites. The
highest affinity sites had a Kd of
5 x 10-8 M. Although our studies cannot
precisely determine binding affinities due to the use of flow
cytometry, we detected binding of similar affinity to FcRI and
FcRIIa. Binding of SAP to FcRIIIb was of lower affinity. The
finding of multiple binding sites on PMN with different affinity is
consistent with binding to FcRII and FcRIII, as FcRI is not
present on resting PMN. Siripont et al. (12) also reported
the presence of a high affinity receptor for mouse SAP on mouse
macrophages. However, the binding appeared to occur in a
calcium-dependent manner. Furthermore, the binding was inhibited by
mannose and is therefore unlikely to be related to the findings
described here.
Because phagocytosis is an important activity mediated by FcR
(18), we tested the ability of SAP to opsonize zymosan for
phagocytosis by PMN. To our knowledge, this is the first description of
the opsonic activity of SAP. The phagocytosis of a fungal cell suggests
that SAP could be involved in protection of the host from infection
similar to CRP, which has been demonstrated to protect mice from
infection with Streptococcus pneumoniae (35, 36). Experiments designed to examine this possibility are
currently in progress.
Selective inhibitors of FcR-mediated phagocytosis were used to
determine whether SAP opsonization was mediated through binding to
FcR. Both wortmannin, a phosphatidylinositol-3 kinase inhibitor, and
piceatannol, a Syk kinase inhibitor, decreased the uptake of SAP- and
CRP-opsonized zymosan to the level of unopsonized zymosan. These
inhibitors block FcR signaling pathways including FcR-mediated
phagocytosis (29). Syk is required for phagocytosis of
IgG-opsonized ligands but not complement-opsonized zymosan or bacteria
(31, 32). Thus, the finding that treatment of PMN with
these inhibitors prevented opsonization by SAP and CRP is consistent
with pentraxin binding to and stimulating phagocytosis through
FcR.
An alternative mechanism by which SAP and CRP could enhance phagocytosis would be through activation of other receptors for zymosan. PMN phagocytose unopsonized zymosan through CD11b/CD18 (37). Attachment of monocyte-derived macrophages to SAP-coated wells was previously found to increase uptake of erythrocytes opsonized with complement (C3b or iC3b), which is mediated through complement receptor type 1 and CD11b/CD18. Therefore, to confirm that SAP and CRP are directly opsonic, they were conjugated to polystyrene beads. The unopsonized beads were poorly recognized by PMN with <10 beads attached or ingested by 100 PMN. However, SAP, CRP, and IgG-conjugated beads readily attached to and were ingested by PMN. Thus, CRP and SAP are capable of mediating phagocytosis in the absence of surface ligands for other receptors.
The interaction of SAP with FcR may be especially relevant to the
clearance of self Ags. The interaction of SAP with chromatin and DNA
that are released from apoptotic and necrotic cells has been described
(38, 39). SAP may play an important role in the handling
of the potent autoantigens that may lead to immunization on one hand
and, on the other hand, tissue deposition leading to immune
complex-mediated inflammation. It is still unclear whether SAP will
cause a proinflammatory response associated with phagocytosis.
It is of interest to compare the binding of SAP to FcR with the
recently described interaction of CRP with FcR. The two molecules
are closely related, and both are conserved molecules that preceded the
development of Ig. It is likely that these two molecules evolved early
on as primitive defense molecules that recognized pathogens through
pattern recognition of carbohydrates and other ligands on pathogens. We
have speculated that the Fc receptors may have evolved first as
pentraxin receptors and, with development of Ig, were used by Ig as
surface receptors.
Although both CRP and SAP have now been shown to bind to phagocytic
cells through FcR, they appear to differ in their affinity for the
individual FcR. CRP binds to both FcRI and FcRIIa, but no
binding to FcRIII was detected. In contrast, SAP binds to all three
classes of FcR. Consistent with the binding data, PIPLC treatment of
PMN to remove GPI-anchored proteins including FcRIII decreased
phagocytosis of SAP-opsonized zymosan but had little effect on uptake
of CRP-opsonized zymosan. Recently, we have characterized the binding
of SAP to FcR in the mouse through the use of FcR-deficient mouse
strains (27). The results in the mouse are similar to those using human
FcR: both pentraxins stimulate phagocytosis through FcRI and SAP,
but CRP does not induce phagocytosis through FcRIII.
The findings reported here suggest that SAP is an important mediator of phagocytosis in vitro at physiological concentrations. Thus, it is likely that SAP may function as an opsonin for natural ligands, which include damaged cells, chromatin, and DNA, as well as for foreign particles such as microorganisms. Because SAP has been shown to activate complement and enhance phagocytosis, it may an important role in host defense and in clearance of autoantigens.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Terry W. Du Clos, Veterans Affairs Medical Center, Research Service 151, Building T-12A, 1501 San Pedro Southeast, Albuquerque, NM 87108. E-mail address: tduclos{at}unm.edu
3 Abbreviations used in this paper: CRP, C-reactive protein; SAP, serum amyloid P component; PMN, polymorphonuclear leukocytes; PIPLC, phosphatidylinositol-specific phospholipase C; PE-GAM, PE-F(ab')2 goat anti-mouse IgG; GMCF, geometric mean channel fluorescence.
Received for publication August 11, 2000. Accepted for publication March 19, 2001.
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 K. D. Puri, T. A. Doggett, J. Douangpanya, Y. Hou, W. T. Tino, T. Wilson, T. Graf, E. Clayton, M. Turner, J. S. Hayflick, et al. Mechanisms and implications of phosphoinositide 3-kinase {delta} in promoting neutrophil trafficking into inflamed tissue Blood, May 1, 2004; 103(9): 3448 - 3456. [Abstract] [Full Text] [PDF]
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D. Pilling, C. D. Buckley, M. Salmon, and R. H. Gomer Inhibition of Fibrocyte Differentiation by Serum Amyloid P J. Immunol., November 15, 2003; 171(10): 5537 - 5546. [Abstract] [Full Text] [PDF]
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 C. VAN DER MEER-VAN KRAAIJ, E. M. M. VAN LIESHOUT, E. KRAMER, R. VAN DER MEER, and J. KEIJER Mucosal pentraxin (Mptx), a novel rat gene 10-fold down-regulated in colon by dietary heme FASEB J, July 1, 2003; 17(10): 1277 - 1285. [Abstract] [Full Text] [PDF]
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C. Mold, W. Rodriguez, B. Rodic-Polic, and T. W. Du Clos C-Reactive Protein Mediates Protection from Lipopolysaccharide Through Interactions With Fc{gamma}R J. Immunol., December 15, 2002; 169(12): 7019 - 7025. [Abstract] [Full Text] [PDF]
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 J W. Dieker, J van der Vlag, and J H. Berden Triggers for anti-chromatin autoantibody production in SLE Lupus, December 1, 2002; 11(12): 856 - 864. [Abstract] [PDF]
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 G. J. Randolph, G. Sanchez-Schmitz, R. M. Liebman, and K. Schakel The CD16+ (Fc{gamma}RIII+) Subset of Human Monocytes Preferentially Becomes Migratory Dendritic Cells in a Model Tissue Setting J. Exp. Med., August 19, 2002; 196(4): 517 - 527. [Abstract] [Full Text] [PDF]
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M. Chi, S. Tridandapani, W. Zhong, K. M. Coggeshall, and R. F. Mortensen C-Reactive Protein Induces Signaling Through Fc{gamma}RIIa on HL-60 Granulocytes J. Immunol., February 1, 2002; 168(3): 1413 - 1418. [Abstract] [Full Text] [PDF]
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