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Rs1
,
Department of
*
Molecular Genetics and Microbiology,
Veterans Affairs Medical Center, and
Department of Medicine, University of New Mexico, Albuquerque, NM 87131
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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R. Mice deficient in FcR were used to assess the role of these
receptors in phagocytosis by pentraxins using zymosan as a ligand.
Phagocytosis of zymosan by bone marrow macrophages (BMM) was enhanced
by opsonization with SAP or CRP. BMM from mice deficient in all three
FcR or in -chain ingested unopsonized zymosan, but phagocytosis
of SAP- or CRP-opsonized zymosan was not enhanced. SAP binding to BMM
from -chain-deficient mice was also greatly reduced, indicating
little or no binding of SAP to FcRII. SAP and CRP opsonized zymosan
for phagocytosis by BMM from mice deficient in FcRII or FcRIII.
SAP, but not CRP, opsonized zymosan for uptake by neutrophils that
express only low levels of FcRI. Together these results indicate
that FcRI and FcRIII are receptors for SAP in the mouse.
Opsonization of zymosan by CRP is mediated through FcRI. Pentraxins
are major proteins of the innate immune system and arose earlier in
evolution than Igs. The use of FcR by the pentraxins links innate
and adaptive immunity and may have important consequences for
processing, presentation, and clearance of the self-Ags to which these
proteins bind. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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SAP and C-reactive protein (CRP) are members of the pentraxin family of proteins. These proteins are characterized by cyclic pentameric structure, sequence homology, and calcium-dependent interactions with ligands (3). Like other molecules of the innate immune system, SAP and CRP recognize ligands from necrotic and apoptotic cells as well as determinants on microorganisms. 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 (4, 5). Other physiological ligands of SAP include DNA, chromatin, and histones in cell nuclei as well as in solution (6). The interaction of SAP with nuclear Ags has been proposed to be a primary function of this molecule. This hypothesis is supported by findings in recently described SAP-deficient mice that spontaneously developed anti-nuclear Abs and glomerulonephritis (7). These studies, as well as earlier experiments in which SAP was injected or induced by an acute-phase stimulus (8), demonstrate a slower clearance of chromatin from the bloodstream in the presence of SAP. The reduced clearance rate of chromatin and nucleosomes in the presence of SAP was associated with increased uptake by the liver and decreased localization in the kidneys (8).
Despite these observations on the effects of SAP on chromatin clearance, there have been few studies of SAP binding to receptors on phagocytic cells and to our knowledge no demonstration that SAP can act as an opsonin. It has been reported that SAP binds to peritoneal macrophages from mice in a saturable manner (9). The binding was calcium dependent and inhibitable by mannose and mannose phosphates, leading the authors to conclude that the mannose 6-P receptor is the receptor for SAP. High- and low- affinity binding of SAP to human PMN has also been described (10). This binding was calcium dependent and could be inhibited by CRP and to a lesser extent by aggregated IgG.
We recently determined that CRP binds to both human and mouse receptors
for IgG (FcR) (11, 12). CRP has long been recognized as
an opsonin, and like SAP it binds to both microbial determinants and
components of damaged cells (13). Because of the
similarities in structure and activities between SAP and CRP, we
decided to determine whether SAP also binds to FcR and to compare
the receptors used by these two proteins for opsonization. We studied
SAP and CRP opsonization of zymosan, because both SAP and CRP bind to
zymosan and zymosan has been widely used in studies of
phagocytosis.
Three classes of FcR are present in mice (14). The
high-affinity receptor for IgG, FcRI, is expressed primarily on
monocytes and macrophages in association with the -chain. Two
low-affinity receptors for IgG have been described, FcRII and
FcRIII. FcRII is present on lymphocytes, macrophages, PMN,
platelets, and mast cells. Macrophages from mice expressing only
FcRII bind but do not ingest IgG-coated E (15).
FcRIII is also associated with the -chain and is expressed as a
transmembrane protein on PMN, macrophages, NK cells, and mast cells.
FcRIII, like FcRI, is capable of mediating phagocytosis. The
relative contributions of the different FcR classes to inflammation
and phagocytosis have recently been elucidated by the development of
mice genetically deficient in FcR (15, 16, 17). These
deficient mice were used in the current study to examine the role of
FcR in phagocytosis of zymosan opsonized by CRP or SAP.
The results demonstrate opsonization of zymosan by both SAP and CRP and
that phagocytosis of SAP- and CRP-opsonized zymosan proceeds through
phagocytic FcR. In the case of CRP, phagocytosis proceeds through
FcRI only. However, phagocytosis of SAP-opsonized zymosan is
mediated by either FcRI or FcRIII. These studies identify the
phagocytic SAP receptors in the mouse and provide a possible mechanism
for the SAP-mediated clearance of chromatin by Kupffer cells. They
further point to distinct differences in specificity of CRP and SAP for
FcR. These results may help elucidate the common and disparate
activities of CRP and SAP in the inflammatory response.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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FITC-zymosan was obtained from Molecular Probes (Eugene, OR). PE-conjugated F(ab')2 goat anti-mouse IgG (PEGAM) and PE-conjugated F(ab')2 goat anti-rat IgG were purchased from Caltag (Burlingame, CA). The hybridoma cell line producing rat mAb 2.4G2 was purchased from American Type Culture Collection (Manassas, VA), and the mAb was purified from culture supernatants by affinity chromatography on protein G-agarose. The mAb SAP-5, a murine IgG2a anti-human SAP, was purchased from Sigma (St. Louis, MO) and was used as ascites at 5 µg mAb/ml for immunofluorescence. Mouse IgG1 and IgG2a isotype control mAb were obtained from Sigma. Rat anti-mouse F4/80 (Serotec, Raleigh, NC) and Ly-6G (PharMingen, San Diego, CA) were used to identify macrophages and neutrophils (PMN) in peritoneal exudate cells (PEC) and bone marrow cell preparations. Mouse anti-sheep E Ab of the IgG2b isotype was obtained from Accurate Scientific (Westbury, NY). Sheep blood was obtained from Colorado Serum Company (Denver, CO). FMLP was obtained from Sigma.
Isolation of CRP and SAP
Human CRP was purified from pleural fluid by affinity chromatography and ion exchange chromatography as previously described (18). SAP was prepared as a side product of factor IX purification and generously provided to us by Dr. Walter 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 (19). SAP was then separated from factor IX by Q Sepharose Fast Flow (Pharmacia, Piscataway, NJ) 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 (20).
Mice
Male C57BL/6Ncr mice were purchased from the National Cancer
Institute (Frederick, MD) and were used as controls for the
-chain-deficient and FcRIII-deficient mice. Male B6x129
F2J mice were purchased from The Jackson
Laboratory (Bar Harbor, ME) and were used as controls for the FcRII-
and the -chain/FcRII-deficient mice. Male -chain-deficient
(15), FcRII-deficient (17), and
-chain/FcRII-deficient mice were purchased from Taconic Farms
(Westminster, NY). FcRIII-deficient mice were purchased from The
Jackson Laboratory. All mice were housed conventionally and were used
between 3 and 5 mo of age. Paired cultures of bone marrow macrophages
(BMM) from age-matched deficient and control mice were compared in each
phagocytosis experiment. All animal studies were approved by the
Veterans Affairs Animal Committee Review Board.
Cells
BMM were prepared as previously described (21). Briefly, mice were killed, femurs were isolated under sterile conditions, the ends of the femurs were excised and bone marrow was flushed from the femurs in HBSS with 0.2% human serum albumin (HSA). Cells were resuspended in 12–15 ml DMEM with 2% FBS and 2% L cell conditioned medium (LCM, a source of M-CSF) and allowed to adhere to tissue culture dishes for 2 h. Nonadherent cells were removed and cultured in tissue culture flasks in DMEM, 2% FBS, 15% LCM for 7–10 days. Nonadherent cells were removed after overnight culture, and cultures were fed after 4 days. BMM were removed from tissue culture flasks with 10 mM EDTA for use in binding or phagocytosis assays. BMM were resuspended in MEM, 2% FBS, 15% LCM with 1 mM MnCl2 for phagocytosis assays or in PBS containing 0.1% BSA and 0.05% sodium azide (PAB) for staining.
Bone marrow PMN were purified from C57BL/6- and -chain-deficient
mice using NIM-2 isolation medium (Cardinal Associates, Santa Fe, NM).
Bone marrow leukocytes were resuspended in RPMI 1640 with 10 mM HEPES,
5% FCS, and 1 mM MnCl2 at 4 x
106 PMN/ml. The percentage of PMN was determined
by cresyl violet staining and was 49% for wild-type and 48% for
deficient mice.
Elicited PEC were obtained by peritoneal lavage of mice injected with 1 ml of 3% thioglycollate medium (Difco, Detroit, MI) 5 days prior to harvest. Cells were collected in 10 ml of HBSS without calcium and magnesium. PEC prepared in this way were >50% macrophages determined by staining with DiffQuik (Dade International, Miami, FL).
Opsonization
Sheep E were opsonized with mouse IgG2b or IgG2a monoclonal anti-sheep E as previously described (22), washed, and resuspended at 5 x 108/ml in dextrose-gelatin Veronal-buffered saline. FITC-zymosan was incubated for 30 min at 37°C with 100 µg/ml SAP or CRP in HBSS containing CaCl2 and MgCl2, washed, and resuspended at 4 x 108/ml in the same buffer.
Phagocytosis assays
To measure phagocytosis 4 x 105 BMM or PMN in 100 µl culture medium were centrifuged briefly (1 min at 200 x g) with opsonized FITC-zymosan (2 x 106/tube for BMM and 4 x 106/tube for PMN) and incubated for 30 min at 37°C. The fluorescence of the noningested yeast particles was quenched by the addition of trypan blue to a final concentration of 0.02%. Phagocytosis was scored visually on a Zeiss Axiovert fluorescent microscope. The results are expressed as the phagocytic index (PI) (number of ingested yeast cells or E per 100 BMM or PMN). For E-IgG2b or E-IgG2a, 7.5 x 106/tube were added, and noningested E were lysed prior to analyzing phagocytosis by phase microscopy.
The relative PI was calculated by dividing the PI of opsonized zymosan by the PI of unopsonized zymosan. Mean values of different mouse strains were compared by t tests.
SAP and CRP binding assays
BMM were released from culture flasks with EDTA, washed, and incubated with the indicated concentrations of SAP in PAB for 1 h on ice. Cells were washed twice with PAB and incubated with mAb SAP-5 or rat anti-mouse F4/80. Following a 30-min incubation on ice, cells were washed twice and incubated for 30 min with PE-conjugated secondary Abs. Cells were washed twice, resuspended in PAB, and analyzed on a Becton Dickinson FACScalibur flow cytometer (Mountain View, CA). For inhibition experiments, heat-aggregated human IgG (63°C for 45 min) was added to cells during the incubation with SAP. Forward and side scatter characteristics of BMM were determined by F4/80 binding and used to collect cells for fluorescent analysis.
Zymosan was washed with HBSS (containing calcium and magnesium), counted, and distributed into tubes. Zymosan (106 particles/tube) was incubated with the indicated concentrations of CRP or SAP for 30 min at 37°C. Zymosan was washed and binding determined by incubation with 5 µg/ml mAb (2C10 for CRP and SAP-5 for SAP) for 30 min on ice. After washing, zymosan was incubated with PEGAM and analyzed on a Becton Dickinson FACScalibur flow cytometer.
Fluorescence was analyzed using CellQuest software (Becton Dickinson). Fluorescence data were collected on a log scale, and data are reported as the difference in geometric mean fluorescent intensity (GMFI) in the presence of CRP or SAP compared with mAb and PEGAM alone. Binding curves were generated by nonlinear regression analysis using GraphPad Prism software (GraphPad Software, San Diego, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As SAP closely resembles CRP in both structural and binding
characteristics and because we have recently demonstrated that CRP
binds to FcR, we decided to test whether SAP was capable of
enhancing the phagocytosis of zymosan. Although previous studies have
demonstrated the ability of both CRP and SAP to bind to zymosan, the
optimal concentrations for binding of the two pentraxins were unknown.
Therefore, preliminary studies were performed to examine the binding of
SAP and CRP to zymosan (Fig. 1
). SAP and
CRP bound to zymosan with similar avidity. The total amount of
pentraxin bound at saturation was comparable. The normal concentration
of SAP in human serum is 
50 µg/ml (23), and CRP
concentrations range from <5 µg/ml at baseline to >200 µg/ml
during an acute-phase response (24). For subsequent
experiments, FITC-zymosan was opsonized with 100 µg/ml SAP or
CRP.
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R
Pretreatment of FITC-zymosan with different concentrations of SAP
enhanced its phagocytosis by BMM in a dose-dependent manner (data not
shown). Maximal enhancement of phagocytosis was seen at 50 µg/ml
SAP, consistent with the binding data. To determine whether FcR were
involved in the phagocytosis of particles opsonized by SAP, BMM from
various strains of FcR-deficient mice were tested. BMM from mice
deficient in all three FcR were cultured in parallel with BMM from
control mice. FITC-zymosan was opsonized with 100 µg/ml of SAP or
buffer, and phagocytosis was measured (Fig. 2). Uptake of zymosan by BMM from
wild-type mice was enhanced following opsonization with SAP. BMM from
FcR-deficient mice ingested unopsonized zymosan as efficiently as
wild-type BMM, but opsonization with SAP did not enhance ingestion.
Significant phagocytosis of unopsonized zymosan by BMM occurred due to
the uptake of zymosan through other receptors. However, SAP enhanced
the level of phagocytosis of zymosan by BMM from wild-type but not
FcR-deficient mice in three experiments.
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R were most important for the uptake of
opsonized zymosan, three additional strains of mice were tested. First,
phagocytosis of zymosan was examined in -chain-deficient mice. These
mice do not express FcRI or FcRIII, both of which require the
-chain for expression. Macrophages from -chain-deficient mice
express only FcRII and do not phagocytose E-IgG (15).
As expected, these mice also showed markedly decreased phagocytosis of
SAP-opsonized zymosan (Fig. 3). The
ability of CRP to opsonize FITC-zymosan was examined in the same assay.
Consistent with our previous identification of FcRI and FcRII as
CRP receptors in the mouse (12), CRP opsonized zymosan for
phagocytosis by wild-type but not -chain-deficient BMM.
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RII-deficient mice. Enhanced phagocytosis
of FITC-zymosan mediated by either SAP or CRP was unchanged compared
with wild-type controls (Fig. 4).
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R-deficient mice is shown in Table I.
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-chain expression
SAP binding to wild-type and -chain-deficient BMM was
determined by flow cytometry using mAb SAP-5 and PEGAM (Fig. 5). The apparent
KD of the interaction of SAP with
wild-type BMM determined by nonlinear regression analysis of the
binding curve was 7.5 x 10-7 M. BMM from
-chain-deficient mice bound much less SAP than did wild-type BMM.
SAP binding to F4/80-positive PEC from -chain-deficient mice was
also greatly reduced compared with the same PEC from wild-type mice
(data not shown). The binding of 50 µg/ml SAP to PEC was inhibited
>95% in the presence of 100 µg/ml aggregated IgG, further
supporting a requirement for FcR in SAP binding. These results
differ from previous binding studies using CRP in which significant
binding to peritoneal macrophages from -chain-deficient mice was
observed indicating binding to FcRII (12). Thus, SAP
shows dose-dependent and saturable binding to mouse macrophages with a
moderate affinity. This interaction requires one or both receptors
associated with the -chain. Because SAP is multivalent and its
binding to microbial cells occurs through highly repetitive
determinants on the surface, the physiological interaction between SAP
and cellular receptors is likely to involve multiple receptors
resulting in increased avidity of binding.
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RI
Both FcRI and FcRIII are capable of mediating phagocytosis
in vivo, and there is evidence that FcRIII may be more efficient
than FcRI (25). To examine the role of FcRI, the
ability of BMM derived from FcRIII-deficient mice to phagocytose
zymosan was examined. As shown in Fig. 6
and Table I
, BMM from these mice showed little or no decrease in their
ability to phagocytose zymosan opsonized by SAP or CRP. These results
suggest that the phagocytosis of zymosan via SAP and CRP can be
mediated by FcRI. Whether FcRIII also contributes to the uptake
of zymosan opsonized with SAP or CRP cannot be determined from this
experiment. Soluble IgG1, IgG2a, and the rat mAb 2.4G2 to mouse
FcRII/III all failed to inhibit SAP-mediated phagocytosis by
wild-type BMM (data not shown).
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RI to mediate phagocytosis of CRP- or SAP-opsonized
zymosan was also examined by selective digestion of FcRI from BMM
with trypsin. Trypsin has been shown to selectively remove FcRI from
mouse macrophages (26). BMM were treated with 20 µg/ml
trypsin for 30 min at 37°C, and phagocytosis of zymosan, opsonized
zymosan and E-IgG2a was tested (26). The phagocytosis of
E-IgG2a was decreased by 70%, indicating a loss of FcRI, whereas
ingestion of unopsonized zymosan was unchanged, indicating that general
phagocytic responses were not affected. With this loss of FcRI, the
phagocytosis of CRP-zymosan was decreased by 55% and the phagocytosis
of SAP-zymosan was decreased by 24%. Thus, CRP-mediated opsonization
of zymosan appeared to be dependent on the presence of FcRI, whereas
SAP-mediated opsonization was less affected. As FcRII is not a
phagocytic receptor on mouse BMM, it appears that phagocytosis of
SAP-opsonized zymosan may proceed through either FcRI or
FcRIII.
Enhanced phagocytosis of SAP- but not CRP-opsonized zymosan can be
mediated by FcRIII
As FcRI 
-chain-deficient mice have only recently been
produced and were not available for these studies, we tested the
phagocytosis of zymosan by PMN, which express low levels of FcRI, to
further examine whether SAP- or CRP-opsonized zymosan could be taken up
through FcRIII. Bone marrow PMN bound very low levels of monomeric
IgG2a and did not ingest E-IgG2a, indicating a lack of functional
FcRI on these cells (data not shown). PMN were isolated from bone
marrow and incubated with SAP- or CRP-opsonized zymosan or E-IgG2b as a
positive control for FcRIII-mediated phagocytosis. The ability of
SAP and CRP to opsonize zymosan for phagocytosis by PMN from wild-type
and -chain-deficient mice was tested. Phagocytosis was also examined
in the presence of FMLP, which enhances phagocytosis through FcR
(22). As shown in Fig. 7, ingestion of E-IgG2b and SAP-zymosan by PMN was greater for wild-type
compared with -chain-deficient mice, indicating that phagocytosis
was mediated by FcRIII. In contrast to the results with BMM (Fig. 3), CRP-zymosan was poorly ingested by PMN, and there was no difference
between PMN from control and -chain-deficient mice. This finding is
consistent with the inability of CRP to bind to mouse FcRIII and
indicates that there is insufficient FcRI present to mediate
phagocytosis. Similar results were seen in the presence of FMLP, with
higher levels of phagocytosis for E-IgG2b and SAP-zymosan, but no
increase in the uptake of CRP-zymosan or unopsonized zymosan. Thus
these results indicate that SAP can opsonize zymosan for phagocytosis
through either FcRIII (Fig. 7) or FcRI (Fig. 6).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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R.
Although CRP-enhanced phagocytosis was previously demonstrated in
murine (27) and human phagocytes (28) a
unique receptor was felt to be responsible (27). These
studies suggest that both CRP and SAP are opsonins that act through
specific binding through FcR on phagocytic cells. SAP has been demonstrated to bind to a wide variety of ligands in vitro including heparin, laminin (29), heparan sulfate (30), fibronectin, and C4b binding protein (31) as well as a number of microbial polysaccharides (4, 5). The binding site is thought to be the calcium-dependent ligand binding site that specifically recognizes phosphoethanolamine. The relative physiological significance of these interactions is not known. SAP also binds to chromatin and DNA in the circulation (6). Recently, SAP has been shown to be an important mediator of the clearance and processing of chromatin (8). The development of autoantibodies to chromatin in SAP-deficient mice suggests an important role for this protein in the prevention of autoimmunity (7).
Saturable binding of SAP to phagocytic cells was previously demonstrated but the nature of the receptor was not identified (9, 10). Contrary to CRP, for which evidence of opsonic activity was presented early on, studies of the ability of SAP to enhance phagocytosis of bacterial or fungal pathogens are limited.
We have previously shown that CRP interacts with FcRI and FcRII
in the mouse (12). Therefore, we wanted to determine
whether the receptor for SAP was also an FcR. The present results
confirm that both SAP and CRP opsonize zymosan for phagocytosis by
mouse BMM and that FcR are required. The interaction of SAP with
mouse FcR differs from that of CRP. Both CRP and SAP are capable of
binding FcRI and FcRI may be important for phagocytosis through
both pentraxins. However, SAP was capable of enhancing phagocytosis in
PMN, which express only low levels of FcRI and in BMM after
selective removal of FcRI by trypsin, suggesting that FcRIII is
sufficient for SAP-mediated opsonization. Furthermore, SAP-mediated
phagocytosis was enhanced by FMLP treatment of PMN. FMLP preferentially
enhances phagocytosis through FcR as opposed to complement receptors
(22). This finding supports the role of FcR in
opsonization by SAP. Ongoing studies to be presented separately suggest
that similar differences in FcR binding specificity occur in the
human as well. It is likely that these differences in receptor
specificity will be reflected in different activities of SAP and CRP
in vivo.
SAP binding was -chain dependent and inhibited by aggregated IgG,
consistent with binding to FcRI and FcRIII. Both of these
receptors can invoke a stimulatory response by the cell and are
therefore likely to enhance the inflammatory response in the mouse.
CRP, but not SAP, binds to FcRII as well (12). FcRII
in mice is known to provide an anti-inflammatory signal through the
recruitment of the inositol phosphatase Src homology 2
domain-containing inositol phosphatase (SHIP) (32).
Although CRP binds to FcRII, no increase in uptake of CRP-opsonized
zymosan by BMM was observed in FcRII-deficient mice. This is in
contrast to the enhanced phagocytosis of E-IgG2b by PEC from
FcRII-deficient mice (33). These results may be
explained by the interaction of CRP with FcRI, whereas phagocytosis
of E-IgG2b is predominately mediated by FcRIII.
The interaction of SAP with phagocytic receptors, its ability to activate complement, and its abundance in the serum suggest that SAP may play a role in host defense as well. SAP has been shown to bind a number of human pathogens, especially fungal organisms. Singh et al. (34) reported that SAP enhanced the ability of mouse macrophages to kill Listeria monocytogenes. This listericidal activity was not associated with enhanced ingestion of the bacteria by SAP or with SAP binding to Listeria. Thus the nature of this effect was not determined. CRP was previously shown to provide protection from infection with Streptococcus pneumoniae (35).
It is now known that both CRP and SAP bind to FcR in the human and
the mouse. The evolutionary significance of these findings is of
considerable interest as the pentraxins appeared earlier in evolution
than the Igs. The pentraxins are present in the horseshoe crab, whereas
the Igs do not appear until the jawed fishes (36).
Therefore, it is possible that Fc receptors preceded the appearance of
Ig and served as receptors for pentraxins.
The interaction of CRP and SAP, which are both capable of interacting
with altered self and with microorganisms, identify the pentraxins as
innate immune recognition molecules. However, the finding that they
interact with FcR bridges the gap between innate and acquired
immunity. This connection may have served to facilitate the development
of the adaptive immune system. It remains to be determined whether SAP
and CRP are most important for the recognition of foreign Ags as
exemplified by the protection afforded mice by CRP (35) or
whether their role in regulating autoimmunity as suggested by
studies of CRP and SAP in down-regulating the autoimmune response in
systemic lupus erythematosus is more important (7, 37).
The function of SAP has long remained unknown despite extensive studies
of its binding activities, its interaction with the complement system,
and its role in the pathogenesis of amyloidosis. The finding that SAP
can specifically interact with FcR should help to delineate the in
vivo functions of this ancient member of the innate immune system.
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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, 1501 San Pedro SE, Albuquerque, NM 87108.
3 Abbreviations used in this paper: SAP, serum amyloid P component; BMM, bone marrow macrophages; CRP, C-reactive protein; GMFI, geometric mean fluorescence intensity; HSA, human serum albumin; PAB, PBS containing 0.1% BSA and 0.05% sodium azide; PEC, peritoneal exudate cells; PEGAM, PE-conjugated F(ab')2 goat anti-mouse IgG; PI, phagocytic index; PMN, neutrophils; LCM, L cell conditioned medium.
Received for publication June 23, 2000. Accepted for publication October 18, 2000.
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 R. Bang, L. Marnell, C. Mold, M.-P. Stein, K. T. D. Clos, C. Chivington-Buck, and T. W. D. Clos Analysis of Binding Sites in Human C-reactive Protein for Fc{gamma}RI, Fc{gamma}RIIA, and C1q by Site-directed Mutagenesis J. Biol. Chem., July 1, 2005; 280(26): 25095 - 25102. [Abstract] [Full Text] [PDF]
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S. Black, I. Kushner, and D. Samols C-reactive Protein J. Biol. Chem., November 19, 2004; 279(47): 48487 - 48490. [Abstract] [Full Text] [PDF]
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M Bijl, H Bootsma, Y van der Geld, P C Limburg, C G M Kallenberg, and M H van Rijswijk Serum amyloid P component levels are not decreased in patients with systemic lupus erythematosus and do not rise during an acute phase reaction Ann Rheum Dis, July 1, 2004; 63(7): 831 - 835. [Abstract] [Full Text] [PDF]
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 A. Paul, K. W.S. Ko, L. Li, V. Yechoor, M. A. McCrory, A. J. Szalai, and L. Chan C-Reactive Protein Accelerates the Progression of Atherosclerosis in Apolipoprotein E-Deficient Mice Circulation, February 10, 2004; 109(5): 647 - 655. [Abstract] [Full Text] [PDF]
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 A. Tomkins Assessing Micronutrient Status in the Presence of Inflammation J. Nutr., May 1, 2003; 133(5): 1649S - 1655. [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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N. N. Gorgani, B. A. Smith, D. H. Kono, and A. N. Theofilopoulos Histidine-Rich Glycoprotein Binds to DNA and Fc{gamma}RI and Potentiates the Ingestion of Apoptotic Cells by Macrophages J. Immunol., November 1, 2002; 169(9): 4745 - 4751. [Abstract] [Full Text] [PDF]
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 M.-K. Chang, C. J. Binder, M. Torzewski, and J. L. Witztum From the Cover: C-reactive protein binds to both oxidized LDL and apoptotic cells through recognition of a common ligand: Phosphorylcholine of oxidized phospholipids PNAS, October 1, 2002; 99(20): 13043 - 13048. [Abstract] [Full Text] [PDF]
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C. Mold, B. Rodic-Polic, and T. W. Du Clos2 Protection from Streptococcus pneumoniae Infection by C-Reactive Protein and Natural Antibody Requires Complement But Not Fc{gamma} Receptors J. Immunol., June 15, 2002; 168(12): 6375 - 6381. [Abstract] [Full Text] [PDF]
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 K. A. Marr, M. Koudadoust, M. Black, and S. A. Balajee Early Events in Macrophage Killing of Aspergillus fumigatus Conidia: New Flow Cytometric Viability Assay Clin. Vaccine Immunol., November 1, 2001; 8(6): 1240 - 1247. [Abstract] [Full Text] [PDF]
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D. Bharadwaj, C. Mold, E. Markham, and T. W. Du Clos Serum Amyloid P Component Binds to Fc{{gamma}} Receptors and Opsonizes Particles for Phagocytosis J. Immunol., June 1, 2001; 166(11): 6735 - 6741. [Abstract] [Full Text] [PDF]
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