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Receptors1
,
Departments of
* Molecular Genetics and Microbiology and
Internal Medicine, School of Medicine, University of New Mexico, and
U.S. Department of Veterans Affairs Medical Center, Albuquerque, NM 87108
 |
Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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R. In this study,
FcR- and complement-deficient mice were used to compare the
mechanisms of protection conferred by CRP and anti-PC Ab. Injection
of CRP protected wild-type, FcR-chain-, FcRIIb-, and
FcRIII-deficient mice from infection. Complement was required for
the protective effect of CRP as cobra venom factor treatment eliminated
the effect of CRP in both -chain-deficient and wild-type mice, and
CRP failed to protect C3- or C4-deficient mice from infection.
Unexpectedly, -chain-deficient mice were extremely sensitive to
pneumococcal infection. This sensitivity was associated with low levels
of natural anti-PC Ab. -chain-deficient mice immunized with
nonencapsulated S. pneumoniae produced both IgM- and IgG
PC-specific Abs, were protected from infection, and were able to clear
the bacteria from the bloodstream. The protection provided by
immunization was eliminated by complement depletion. The results show
that in this model of systemic infection with highly virulent S.
pneumoniae, protection from lethality by CRP and anti-PC
Abs requires complement, but not FcR. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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receptors has
provided a critical tool for understanding the roles of these receptors
in inflammation, autoimmunity, and host defense (1). Mice
deficient in the FcR -chain lack FcRI and FcRIII as well as
Fc
RI (2). -chain-deficient mice and mice deficient
in FcRIII have reduced immune complex clearance, decreased
inflammatory responses to immune complexes, and are protected from
Ab-mediated autoimmune diseases (1, 3). In contrast,
FcRIIb-deficient mice generally have enhanced Ab responses and
increased susceptibility to autoimmune disease (1, 4, 5, 6).
The role of FcR in protection against infection has been studied to
a more limited extent with different results depending on the pathogen.
Passive protection of mice by IgG1 Ab against Cryptococcus
neoformans is decreased in -chain-deficient mice
(7), whereas passive protection against malaria is
apparently FcR-independent (8). Conversely, FcR are
required to establish infection in a mouse model of cutaneous
leishmaniasis, in which FcR provide a means for invasion of
macrophages by the parasite (9).
Streptococcus pneumoniae is an important pathogen in humans
and is the number one cause of community-acquired pneumonia (10, 11). The clinical importance of this disease has increased with
the evolution of antibiotic resistant strains (12). Very
young and very old individuals are most susceptible to systemic
infection and although protective anti-capsular Ab can be produced
following immunization, the innate immune response is clearly important
in controlling this infection in the nonimmune host. Innate resistance
to systemic infection with S. pneumoniae has been studied
extensively in mice. Naturally occurring Abs of the T15 idiotype, which
bind the phosphocholine
(PC)3 moiety of the
pneumococcal cell wall C-polysaccharide (PnC), are protective
(13). These natural Abs are produced in response to normal
gut flora and are derived from a single germline
VH gene
(VH1) (14). Mice
lacking these protective anti-PC Abs as a result of the
xid mutation (13), neonatal suppression by
anti-T15 treatment (13, 15), or targeted genetic
deletion of the VH1 gene
(16) all have increased susceptibility to S.
pneumoniae infection. T15-idiotype-positive mAb of the IgM, IgG2a,
IgG2b, and IgG3 isotypes can passively protect mice against infection
(17, 18). All of the protective Abs activate complement
(18, 19). However, IgG Abs are 10-fold more protective
than IgM Abs suggesting a role for FcR as well
(20).
C-reactive protein (CRP) is an acute-phase reactant named for its
ability to undergo calcium-dependent interaction with PnC. The
demonstration that passively administered CRP protected mice from
S. pneumonia infection established a role for CRP in host
defense (15, 21). More recently, mice transgenic for human
CRP were found to be protected from pneumococcal infection as well as
Salmonella enterica infection (22, 23). CRP
activates the classical complement pathway (24) and the
importance of complement in CRP-mediated host defense has been studied
(19, 25, 26). The results of these studies indicated that
CRP protection in pneumococcal infection involves both
complement-dependent and complement-independent mechanisms. The
proposed mechanism of CRP protection against S. pneumoniae
infection is opsonization of bacteria by CRP and complement for
phagocytosis and killing. The identification of FcR as the receptors
for CRP on leukocytes makes it possible to examine the relative roles
of direct interaction of CRP with FcR and CRP activation of
complement in protection against pneumococcal infection (27, 28). The purpose of the present study was to examine the role of
FcR and complement in protection against systemic S.
pneumoniae infection by CRP and anti-PC Ab.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Human CRP was purified from pleural fluid by affinity, gel filtration, and ion exchange chromatography as previously described (29). The purity of the CRP preparations was determined by 12.5% SDS-PAGE on overloaded and normal samples. The gels were stained with a sensitive silver stain. No bands other than the major 25 kDa CRP band were seen. Specifically, no contamination by IgG was seen. PC-BSA was produced according to the method of Chesebro and Metzger (30). The molar coupling ratio of PC to BSA was 15:1.
Mice
FcRIIb-deficient (4) and FcR -chain-deficient
mice (2) were bred at the Department of Veterans Affairs
Animal Facility (Albuquerque, NM) from breeder pairs purchased
from The Jackson Laboratory (Bar Harbor, ME). The -chain deficient
mice do not express FcRI, FcRIII, or FcRI. The FcRIIb- and
FcRIII-deficient (3) mice lack individual receptor
expression only. FcRIII-deficient mice and control mice (B6 x
129F2 and C57BL/6) that were age and sex-matched to
the deficient mice were purchased from The Jackson Laboratory. B6 x
129F2 mice served as controls for -chain- and
FcRIIb-deficient mice. C57BL/6 mice served as controls for
FcRIII-deficient mice. C3- (31) and C4-deficient
(32) mice were bred from heterozygous breeder pairs
purchased from The Jackson Laboratory. Mice were genotyped by PCR using
the primer sequences provided by The Jackson Laboratory and
homozygous-deficient and homozygous wild-type mice from the same colony
were used. Mice were used between 7 and 12 wk of age. Both male and
female mice were used. The number of male and female control and
deficient mice was matched in each individual experiment and the males
and females were distributed equally among treatment groups in each
experiment. There was no apparent effect of sex on the results in any
of the experiments. All experimental procedures involving animals were
approved by the Institutional Review Board of the Veterans Affairs
Medical Center (Albuquerque, NM).
Bacteria and infection
S. pneumoniae serotype 3 (Pn3) and R36A (a nonencapsulated variant of type 2 S. pneumoniae) were purchased from the American Type Culture Collection (Manassas, VA). Pn3 were passaged through mice to maintain virulence and stored at -80°C. One or two colonies from an overnight blood agar plate were inoculated into Todd-Hewitt broth containing 0.5% yeast extract and grown to log phase. The concentration of Pn3 was estimated by absorbance at 600 nm. Pn3 were diluted in saline and injected i.v. into the retro-orbital plexus into mice in 0.1 ml. Plate counts of the inoculum were used to determine the CFU injected. Where indicated, CRP was injected i.v. via the contralateral retro-orbital plexus 15 min before Pn3. Mortality was measured for 7 days with no deaths occurring later than 4 days after infection.
Mice were immunized by i.p. injection of 5 x 107 heat-killed R36A as described (33) and challenged 7 days later. Mice were depleted of complement by treatment with cobra venom factor (CVF (Naja naja kaouthia); Quidel, San Diego, CA) as previously described (34). Complement depletion was induced by three i.p. injections of 4 U CVF at 12-h intervals beginning 36 h before study.
Clearance
Mice were injected in the left retro-orbital plexus with
5 x 104 CFU Pn3 in 0.2 ml of saline.
Blood samples (50 µl) were collected from the right retro-orbital
plexus in capillary pipettes at 1 min, 1 h, and 4 h, diluted
in PBS and plated on blood agar plates. CFU recovered per mouse were
calculated from the blood counts and body weight.
Ab levels
Anti-PC and anti-DNP Ab levels in serum from control and deficient mice were determined by ELISA. Immulon II microtiter plates (Dynatech Laboratories, Alexandria, VA) were coated with 5 µg/ml PC-BSA (conjugated in our laboratory) or DNP-BSA (Sigma-Aldrich, St. Louis, MO), washed, blocked, and incubated with a 1/50 dilution of the serum to be tested. Plates were developed with biotinylated isotype-specific Abs to mouse IgG, IgA, and IgM (Caltag Laboratories, Burlingame, CA), HRP-conjugated streptavidin, and substrate (3,3',5,5' tetramethylbenzidine; BD Biosciences, San Diego, CA). Absorbance was read at 450 nm.
Data analysis
Graphical and statistical analyses were performed using GraphPad Prism software (San Diego, CA). Survival curves were plotted by the method of Kaplan and Meier and compared by the log-rank test (Mantel-Haenszel test). This analysis takes into account the time of death as well as the absolute numbers of mice surviving. Throughout Results, the term "protection" indicates significantly enhanced survival.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, chain
CRP binds to FcRI and FcRIIb on mouse leukocytes
(27). The opsonic activity of CRP requires FcRI, and is
absent in phagocytes from -chain-deficient mice
(35). Therefore, -chain-deficient mice were used to
determine the role of CRP interaction with phagocytic FcR in
protection from S. pneumoniae infection. B6 x 129
control mice and -chain-deficient mice were injected with 0, 100, or
200 µg of CRP and Pn3 and survival was measured for 7 days (Fig. 1
). CRP provided protection against
lethality in wild-type mice, increasing survival from 20% in the
absence of CRP to >85% in mice injected with 200 µg of CRP. CRP
provided partial protection in -chain-deficient mice as well,
increasing survival from 0% in the absence of CRP to 50% in mice
injected with 200 µg of CRP.
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-chain-deficient mice were treated with CVF 2 days
before challenge (Fig. 1
) and then with 200 µg of CRP and Pn3. All of
the complement-depleted mice died from the infection despite injection
of CRP. These results indicate that in this model, CRP-mediated
protection requires complement and can be provided by complement alone
in the absence of FcR. CRP-mediated protection against pneumococcal infection requires the classical complement pathway
S. pneumoniae activate the alternative complement
pathway in the absence of CRP, but primarily activate the classical
pathway in the presence of CRP (36, 37). CVF-treated mice
lack the major complement opsonins (C3b and iC3b) generated by all
pathways of activation. The failure of CRP to protect against Pn3 in
CVF-treated mice could be due either to a requirement for CRP
activation of the classical pathway or to a combination of alternative
pathway activation by the bacteria and direct opsonization by CRP. C3-
and C4-deficient mice were used to distinguish between these
possibilities. C3-deficient mice are similar to CVF-treated in mice in
lacking C3b and iC3b. C4-deficient mice lack only the classical
pathway. Both strains of mice were highly susceptible to Pn3 infection
and neither was protected by 100 µg CRP (Fig. 2). These results indicate that
CRP-mediated protection against Pn3 requires the classical pathway.
Innate immunity to Pn3 was also decreased in both C3- and
C4-deficient mice as shown by the greater mortality of deficient mice
than wild-type mice in the absence of CRP. No additional role for the
alternative pathway was apparent as there was no difference between
survival curves in C3- and C4-deficient mice either in the presence or
absence of CRP.
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RIII
or FcRIIb
The -chain is required for expression and signaling through
FcRI and FcRIII, both of which mediate phagocytosis
(2). Binding and functional studies indicate that CRP
binds to FcRI and to FcRIIb. FcRIIb is a nonphagocytic
receptor found on lymphocytes as well as phagocytic cells. Mice
deficient in FcRIII or FcRIIb were used to determine the roles of
these receptors in CRP-mediated protection. For FcRIII- and
FcRIIb-deficient mice, CRP provided nearly complete protection from
infection (Fig. 3A). Survival
curves were not significantly different between FcRIII- and
FcRIIb-deficient mice and control mice injected with CRP. In
addition, neither FcRIII- nor FcRIIb-deficient mice showed the
increased susceptibility to Pn3 infection that was seen in the
-chain-deficient mice (Fig. 3B). A different wild-type
strain (C57BL6) was used as the control strain for FcRIII-deficient
mice. Survival of C57BL/6 mice did not differ from B6 x 129 mice in
the absence of CRP (Fig. 3B). Survival of C57BL/6 mice
following CRP treatment and Pn3 infection was not significantly
different from survival of B6 x 129 mice treated in the same way (not
shown).
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-chain-deficient mice
In the experiments described above, it was apparent that
-chain- and complement-deficient mice were more susceptible to
infection than wild-type mice. This was evident both in the survival
time and in percent survival (Figs. 1 and 2). The survival curves for
FcRIII-deficient, FcRIIb-deficient, B6 x 129 and C57BL6 mice
injected with 700 CFU were not significantly different (Fig. 3B). Complement-deficient mice have been reported to be more
susceptible to infection (31), but to our knowledge
-chain-deficient mice have not (1). To further compare
the susceptibility to infection between wild-type and
-chain-deficient mice, decreasing doses of Pn3 were injected. Nearly
40% of wild-type mice survived challenge with 70 CFU and 50% survived
challenge with 7 CFU of Pn3 (Fig. 4).
None of the -chain-deficient mice survived even the lowest dose of
Pn3, although the survival time was prolonged (20.5-h median survival
with 7 CFU and 17.5-h median survival for mice infected with 70 CFU).
The median survival time for wild-type mice was 72.5 h for mice
infected with 70 CFU. At each dose of bacteria, the difference in
survival curves between wild-type mice and -chain-deficient mice was
significant at the p < 0.0001 level.
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-chain-deficient mice have lower levels of IgM anti-PC Abs
than wild-type mice
The increased susceptibility of -chain-deficient mice to
pneumococcal infection suggested a role for IgG in innate immunity.
Natural Abs to PC have been shown to provide protection against
S. pneumoniae (13). Therefore, the levels of
anti-PC Abs in control and -chain-deficient mice were measured.
Surprisingly, -chain-deficient mice had significantly lower levels
of IgM anti-PC Abs than wild-type mice (Fig. 5A; p =
0.032). This was not a general defect in natural Abs, as levels of IgM
and IgG Ab to DNP were normal in -chain-deficient mice (Fig. 5B). Very low levels of IgG anti-PC Abs were found in
both wild-type and -chain-deficient mice, and IgA anti-PC was
undetectable in serum from either strain. IgM anti-PC Ab levels in
C57BL/6 mice and FcRIIb-deficient mice were similar to IgM
anti-PC Ab levels of B6 x 129 mice and higher than those of
-chain-deficient mice (not shown). All of the strains of mice were
housed in the same room and the FcRIIb-deficient mice were bred in
the same facility as the -chain-deficient mice.
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-chain-deficient mice produce anti-PC following immunization
and are protected from pneumococcal infection
To determine whether -chain-deficient mice lacked the ability
to respond to PC, mice were immunized with a single injection of
heat-killed nonencapsulated S. pneumoniae, R36A.
Immunization with R36A results in anti-PC Abs with peak levels
appearing after 7 days (33). The -chain-deficient mice
produced high levels of IgM and lower levels of IgG anti-PC Abs
following immunization (Fig. 6). These Ab
levels were equivalent to those of immunized B6 x 129 mice.
Furthermore, immunized -chain-deficient mice were protected from
infection with 70 CFU S. pneumoniae (Fig. 7A). Immunity was mediated by
Ab and complement, because depletion of complement with CVF before
infection abrogated the protection (Fig. 7A).
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-chain-deficient mice were
injected with Pn3 and viable bacteria in the bloodstream were measured
over the next 4 h (Fig. 7B). Nonimmune
-chain-deficient mice did not clear Pn3. Immunized
-chain-deficient mice cleared the bacteria beginning at 1 h,
and this clearance was eliminated in mice treated with CVF to deplete
complement. These results indicate that -chain-deficient mice can be
protected from Pn3 infection by anti-PC Ab as well as by CRP and
that for either opsonin, complement is also required. The increased
susceptibility of -chain-deficient mice to S. pneumoniae
arises from a lack of natural Abs to PC, and not from a failure of
FcR-mediated clearance functions during infection. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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R to
protect mice from infection. Third, -chain-deficient mice are
extremely sensitive to death from S. pneumoniae infection.
This increased susceptibility apparently results from a failure of
-chain-deficient mice to produce protective PC-specific Abs in
response to natural immunogens in the gut.
The protective effect of CRP in pneumococcal bacteremia has been
described (15, 21, 23). In previous studies, complement
depletion decreased, but did not eliminate the protective effect of CRP
(19, 25), suggesting that direct opsonization by CRP might
play a role as well. The leukocyte receptors for CRP have recently been
identified by our laboratory as FcR (27, 28, 38, 39).
CRP binds to FcRI and FcRII on both human and mouse leukocytes.
In the mouse, where FcRII is a nonphagocytic receptor, direct
opsonic activity of CRP requires the -chain-associated receptor
FcRI (35). Thus, -chain-deficient mice lack
phagocytic receptors for CRP and can be used to test the role of direct
opsonization by CRP in protection from infection. CRP was protective in
-chain-deficient mice, indicating that CRP binding to FcRI is not
required for protection. Complement was required. Previous studies
(19, 25) have observed a protective effect of CRP in
complement-depleted mice. However, this effect was not observed in the
present study using highly virulent Pn3. Therefore a role for FcR in
the protective effect of CRP on pneumococcal infection in the absence
of complement could not be evaluated. While this paper was in review,
it was reported that CRP expression from a transgene decreased
bacteremia in FcR -chain-deficient mice following pneumococcal
infection (40). These findings are consistent with the
data presented in this study. However, those studies did not assess
survival.
It is of some interest that mouse CRP is expressed at low levels in
mice and increases slightly during the acute phase response to levels
of 2–3 µg/ml. It is unclear whether these low levels of CRP
contribute to natural protection from S. pneumoniae
infection. However, these mice are much less resistant to infection
than mice given human CRP suggesting that mouse CRP is of minor
importance. The major acute phase reactant in the mouse, serum amyloid
P component, fails to protect mice from S. pneumoniae
infection (21).
The relative requirements for the alternative and classical pathways of complement activation in CRP-mediated protection were examined. Complement-deficient mice were highly susceptible to infection and were not protected by CRP. By comparing C3-deficient mice, lacking opsonization through all pathways, and C4-deficient mice, lacking only the classical pathway, these studies demonstrate that classical pathway activation by CRP is required for protection. CRP activates complement only through the classical pathway and increases the amount of C3b and iC3b bound to S. pneumoniae (37, 41). The requirement for C4 in CRP-mediated protection indicates that it is complement activation by CRP that is essential rather than cooperation between CRP and complement deposited on the bacteria through the alternative pathway. The requirement for C4 also indicates that CRP regulation of complement activation by recruiting factor H is not of primary importance, because this function of CRP does not require the classical pathway (36).
The decreased resistance of -chain-deficient mice to S.
pneumoniae was unexpected. Despite the importance of FcR in
inflammatory responses, deficiencies in these receptors, unlike
complement deficiencies, have not generally been associated with
increased susceptibility to infection in the nonimmune host
(1). One previously reported host defense defect in these
mice was an inability of passive Abs to protect mice from
Cryptococcus neoformans infection (7). Another
study demonstrated no defect in the natural sensitivity to influenza
virus infection but found that immunized -chain-deficient mice were
not protected from infection despite normal Ab responses
(42).
There are several possible mechanisms for the increased susceptibility
to infection in the -chain-deficient mice. It seemed likely that the
mice could be deficient in clearance of bacteria due to the lack of
FcRI or FcRIII. FcRIII-deficient mice did not display
increased susceptibility to infection. This suggested the hypothesis
that resistance to infection was normally mediated by natural IgG Abs,
directed against bacterial Ags interacting with FcRI. This is also
consistent with previous findings that passively administered IgG
anti-PC Abs are protective at lower doses than IgM anti-PC Abs
in xid mice (18).
Surprisingly, the defect in -chain-deficient mice was related to
reduced levels of PC-specific IgM. Levels of IgG and IgA anti-PC
Abs were very low in both control and -chain-deficient mice. There
were no differences in the levels of anti-DNP Abs between the
strains suggesting that the decrease was not a general deficiency in
natural Abs. Decreased IgM anti-PC was also not related to breeding
conditions, because FcRIIb-deficient mice from the same facility had
normal Ab levels. The decreased Ab to PC was not due to an inability to
respond to PnC, as -chain-deficient mice produced substantial levels
of IgM and IgG anti-PC Abs in response to immunization with R36A.
Immunized -chain-deficient mice were protected from S.
pneumoniae infection with nine of ten mice surviving challenge
with 70 CFU of Pn3. Thus, -chain-deficient mice are able to produce
PC-specific protective Abs, and FcR are not required for such Abs to
be effective. Protection of immunized -chain-deficient mice was
complement-dependent as it was eliminated by CVF treatment before
challenge.
A novel and as yet incompletely understood finding is the decrease in
the levels of "natural" Abs to PC in -chain-deficient mice. It
is known that the development of these Abs is dependent on the
presentation of Ags on bacteria of the gut flora as they are not
present in germfree mice (14). The lack of natural Abs in
-chain-deficient mice suggests a defect in the presentation of these
Ags to the immune system. The only -chain-associated receptor that
has been implicated in Ag presentation is FcRI. Targeting Ag to this
receptor enhances presentation to Ag-specific T cells by 100- to
1000-fold (43). Studies in deficient mice showed that
FcRI, but not FcRIII or FcRI, was required for enhanced
responses to immune complexes (44). Although
polysaccharide Ags have not been thought to require presentation to T
lymphocytes, it has recently been shown that dendritic cells pulsed
with R36A induce T cell-dependent anti-PC responses
(45). Therefore, one possible explanation for the
decreased natural Ab levels is the reduced ability to present Ags.
These mice are clearly able to mount an immune response to PC as
demonstrated by the response induced by R36A immunization shown in this
study. However, at suboptimal amounts of Ag, the role of FcRI may be
important. The direct importance of FcRI, as opposed to other
-chain-associated receptors, will be addressed in future studies
using mice specifically deficient in FcRI.
In summary, these findings support the central role of complement in
the protection of mice from pneumococcal bacteremia. The role of
complement is to clear the bacteria through opsonophagocytosis
(46). Although both Ab and CRP can interact with Fc
receptors, their role in protection from this pathogen is probably
minor.
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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, U.S. Department of Veterans Affairs Medical Center, Research Service 151, 1501 San Pedro S.E., Albuquerque, NM 87108. E-mail address: tduclos{at}unm.edu
3 Abbreviations used in this paper: PC, phosphocholine; PnC, S. pneumoniae cell wall C-polysaccharide; CRP, C-reactive protein; Pn3, S. pneumoniae serotype 3; CVF, cobra venom factor.
Received for publication January 24, 2002. Accepted for publication April 10, 2002.
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References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
chain deletion results in pleiotropic effector cell defects. Cell 76:519.[Medline]
RIII (CD16) deficient mice. Immunity 5:181.[Medline]
RII-deficient mice. Nature 379:346.
receptors. J. Exp. Med. 191:1611. receptor IIB-deficient mice develop Goodpasture’s syndrome upon immunization with type IV collagen: a novel murine model for autoimmune glomerular basement membrane disease. J. Exp. Med. 191:899. receptors. J. Immunol. 164:1514.RII. J. Exp. Med. 190:585. receptors. J. Immunol. 166:1200.RI in transfected COS cells. J. Immunol. 155:2185.[Abstract]
RIIa on human monocytes and neutrophils is allele specific. J. Clin. Invest. 105:369.[Medline]
receptor (monocyte/macrophage)-specific immunogens. J. Immunol. 149:3477.[Abstract]
chain-deficient mice and increased in FcRII-deficient mice. J. Immunol. 163:618.This article has been cited by other articles:
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M. V. Suresh, S. K. Singh, D. A. Ferguson Jr., and A. Agrawal Role of the Property of C-Reactive Protein to Activate the Classical Pathway of Complement in Protecting Mice from Pneumococcal Infection J. Immunol., April 1, 2006; 176(7): 4369 - 4374. [Abstract] [Full Text] [PDF]
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 G. K. Paterson and T. J. Mitchell Innate immunity and the pneumococcus Microbiology, February 1, 2006; 152(2): 285 - 293. [Abstract] [Full Text] [PDF]
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J. Yuste, M. Botto, J. C. Paton, D. W. Holden, and J. S. Brown Additive Inhibition of Complement Deposition by Pneumolysin and PspA Facilitates Streptococcus pneumoniae Septicemia J. Immunol., August 1, 2005; 175(3): 1813 - 1819. [Abstract] [Full Text] [PDF]
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S. Black, A. Wilson, and D. Samols An Intact Phosphocholine Binding Site Is Necessary for Transgenic Rabbit C-Reactive Protein to Protect Mice against Challenge with Platelet-Activating Factor J. Immunol., July 15, 2005; 175(2): 1192 - 1196. [Abstract] [Full Text] [PDF]
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 P A J Krijnen, C Ciurana, T Cramer, T Hazes, C J L M Meijer, C A Visser, H W M Niessen, and C E Hack IgM colocalises with complement and C reactive protein in infarcted human myocardium J. Clin. Pathol., April 1, 2005; 58(4): 382 - 388. [Abstract] [Full Text] [PDF]
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 M. V. Suresh, S. K. Singh, and A. Agrawal Interaction of Calcium-bound C-reactive Protein with Fibronectin Is Controlled by pH: IN VIVO IMPLICATIONS J. Biol. Chem., December 10, 2004; 279(50): 52552 - 52557. [Abstract] [Full Text] [PDF]
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 A. Lanoue, M. R. Clatworthy, P. Smith, S. Green, M. J. Townsend, H. E. Jolin, K. G.C. Smith, P. G. Fallon, and A. N.J. McKenzie SIGN-R1 Contributes to Protection against Lethal Pneumococcal Infection in Mice J. Exp. Med., December 6, 2004; 200(11): 1383 - 1393. [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. R. Clatworthy and K. G.C. Smith Fc{gamma}RIIb Balances Efficient Pathogen Clearance and the Cytokine-mediated Consequences of Sepsis J. Exp. Med., March 1, 2004; 199(5): 717 - 723. [Abstract] [Full Text] [PDF]
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S. Knapp, C. W. Wieland, C. van 't Veer, O. Takeuchi, S. Akira, S. Florquin, and T. van der Poll Toll-Like Receptor 2 Plays a Role in the Early Inflammatory Response to Murine Pneumococcal Pneumonia but Does Not Contribute to Antibacterial Defense J. Immunol., March 1, 2004; 172(5): 3132 - 3138. [Abstract] [Full Text] [PDF]
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 W. Schroedl, L. Jaekel, and M. Krueger C-Reactive Protein and Antibacterial Activity in Blood Plasma of Colostrum-Fed Calves and the Effect of Lactulose J Dairy Sci, October 1, 2003; 86(10): 3313 - 3320. [Abstract] [Full Text] [PDF]
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E. Saeland, G. Vidarsson, J. H. W. Leusen, E. van Garderen, M. H. Nahm, H. Vile-Weekhout, V. Walraven, A. M. Stemerding, J. S. Verbeek, G. T. Rijkers, et al. Central Role of Complement in Passive Protection by Human IgG1 and IgG2 Anti-pneumococcal Antibodies in Mice J. Immunol., June 15, 2003; 170(12): 6158 - 6164. [Abstract] [Full Text] [PDF]
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 J. S. Brown, T. Hussell, S. M. Gilliland, D. W. Holden, J. C. Paton, M. R. Ehrenstein, M. J. Walport, and M. Botto The classical pathway is the dominant complement pathway required for innate immunity to Streptococcus pneumoniae infection in mice PNAS, December 24, 2002; 99(26): 16969 - 16974. [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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