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* Division of Clinical Immunology and Rheumatology, Department of Medicine, and
Department of Microbiology, University of Alabama, Birmingham, AL 35294
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, IFN-
) and chemokines (macrophage-inflammatory
protein-1, RANTES, monocyte chemoattractant protein-1); and 3) CRP
increases IL-10 production. All three of these actions are realized in
vitro only in the presence of high concentrations of human CRP. The
combined data suggest that during the acute phase of inflammation
accompanying EAE, the high level of circulating human CRP that is
achieved in CRP-transgenic mice inhibits the damaging action of
inflammatory cells and/or T cells that otherwise support onset and
development of EAE. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RI (CD64) and
FcRII (CD32) expressed on monocytes, neutrophils, and lymphocytes
(8, 9, 10, 11) and by binding to and opsonizing apoptotic cells
(12). In addition to its elevation in the blood in
response to infection, clinical studies have established that CRP blood
levels also rise substantially (up to 1000-fold) in response to
noninfectious inflammatory conditions including trauma, cancer,
autoimmune diseases, and atherosclerosis (13, 14, 15).
Regardless of the underlying mechanisms involved, the beneficial
effects of CRP likely are not limited to defense against microbes.
Unlike its human counterpart, mouse CRP is synthesized only in trace
amounts (16). Taking advantage of this species difference,
Ciliberto et al. (17) constructed human CRP-transgenic
(CRPtg) mice in which human CRP is expressed as an acute phase protein.
We used C57BL/6-congenic descendants of these constructs to verify the
antimicrobial activity of human CRP in an in vivo setting (2, 5, 6). Herein to determine whether human CRP might also have a
beneficial role against aseptic inflammatory disease, we induced
experimental allergic encephalomyelitis (EAE) in CRPtg mice. EAE serves
as an animal model of multiple sclerosis (MS) and is characterized by
demyelination and infiltration of the CNS by Th1, neuroantigen-specific
T cells, monocytes, and macrophages. The disease can be induced
actively in C57BL/6 mice by immunization with myelin oligodendrocyte
protein (MOG) or immunodominant peptides derived from MOG, and a
passive form of EAE can be induced in susceptible recipients by
adoptive transfer of encephalitogenic T cells (18). We
found that in CRPtg females onset of active EAE was delayed compared
with sex-matched C57BL/6 controls. The delay in disease onset was
coincident with acute phase expression of the CRP transgene. In male
CRPtg, which express significantly higher amounts of human CRP than do
females, EAE severity is further attenuated, and CNS infiltration by T
cells and monocytes/macrophages is prevented. Like its actively induced
counterpart, EAE induced passively by transfer of encephalitogenic T
cells is delayed in CRPtg recipients. In vitro experiments demonstrated
that human CRP reduces the proliferation of MOG peptide-stimulated
encephalitogenic T cells and inhibits the production of proinflammatory
Th1 cytokines (TNF- and IFN-) and chemokines
(macrophage-inflammatory protein-1 (MIP-1), RANTES, and monocyte
chemoattractant protein-1 (MCP-1)). In contrast, human CRP increases
expression of the anti-inflammatory Th2 cytokine IL-10. On the
basis of these observations, we speculate that human CRP exerts its
protective effect in EAE in the fluid phase and during the acute
phase response by inhibiting the development of a Th1-mediated immune
response and by reducing the capacity of encephalitogenic T cells to
recruit phagocytes to the CNS. These data suggest a role for CRP per se
in authentic MS and indicate that in addition to its recognized
antimicrobial activity, CRP might have an immunoregulatory
function.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The CRP transgene (17) and its human-like pattern of expression in CRPtg mice has been fully described (4, 5, 6, 17, 19). CRPtg mice carry a 31-kb human DNA fragment containing the CRP gene; the gene per se is flanked by regions that include all the known cis-acting regulatory elements (i.e., the entire human promoter) and the CRP pseudogene. Human CRP is expressed by CRPtg on endotoxin treatment or infection and reaches blood levels comparable with those observed in human diseases (up to 1 mg/ml). cis-acting regulatory elements included in the human CRP transgene are responsible for both tissue specificity and acute phase inducibility of its expression in CRPtg mice, and the trans-acting factors required for its correct regulation are conserved from mice to humans. We discovered a sexually dimorphic pattern of expression of the CRPtg (reviewed in Ref. 6), viz baseline and acute phase expression of human CRP, is a magnitude higher in CRPtg males than in females.
We backcrossed CRPtg to wild-type C57BL/6J (The Jackson Laboratory, Bar Harbor, ME) for 10 generations to produce C57BL/6-congenic CRPtg and wild-type littermates for our studies. Mice were screened for inheritance of the CRP transgene using a human CRP-specific PCR (19) and were used in experiments when 8–12 wk old. All animal studies were approved by the Institutional Animal Care and Use Committee of the University of Alabama (Birmingham, AL).
Induction of active EAE
CRPtg and littermate non-tg mice were immunized with MOG peptide 35–55 as described (18). MOG peptide was synthesized by standard 9-fluorenylmethoxycarbonyl chemistry and was >95% pure as determined by reversed phase HPLC (Research Genetics, Huntsville, AL). On days 0 and 7, mice received s.c. an injection of 150 µg MOG peptide emulsified in CFA containing 500 µg heat-killed Mycobacterium tuberculosis (Difco, Detroit, MI). On days 0 and 2, mice received i.p. an injection of pertussis toxin (500 ng; List Biological Laboratories, Campbell, CA). Development of EAE symptoms was monitored twice daily using a standard clinical scale ranging from 0 to 6 as follows: 0, asymptomatic; 1, loss of tail tone; 2, flaccid tail; 3, incomplete paralysis of one or two hind limbs; 4, complete hind limb paralysis; 5, moribund (animals were humanely euthanized); 6, dead. Mice were observed for at least 30 days, and only mice with a score of at least 2 for >2 consecutive days were judged to have fully developed EAE. The maximum clinical score achieved by each animal during the 30-day observation period was used to calculate average maximum clinical scores for each experimental group. To study the time course of disease development, average clinical scores were calculated daily for each group of mice and plotted. When determining the average day of onset of EAE, animals that did not develop any symptoms of EAE during the 30-day survey period were assigned a day of onset of 31.
Induction of passive EAE
Two weeks after induction of active EAE, the spleens of non-tg donors were removed and used to make a single-cell suspension in RPMI 1640 (Life Technologies, Gaithersburg, MD). After treatment with ammonium chloride to lyse erythrocytes, encephalitogenic T cells were enriched by passage through nylon wool. These MOG peptide-sensitized cells were transferred to RPMI supplemented with 10% FCS, 5 x 10-5 2-ME, and penicillin/streptomycin (100 µg/ml) before seeding into six-well tissue culture plates. The cells (4 x 106) were then restimulated in vitro for 24 h with MOG peptide (20 µg/ml) in the presence of 2 x 106 freshly irradiated (naive) splenic APCs. IL-2 (20 U/ml) was added, and after an additional 24 h of culture, encephalitogenic T cells were purified by gradient centrifugation using Ficoll-Hypaque (Pharmacia, Peapack, NJ). Passive EAE was induced in non-tg and CRPtg littermate recipients by injecting them i.v. with 5 x 106 purified T cells.
Measurement of T cell proliferation and cytokine and chemokine production
All of these in vitro assays were performed using 96-well flat-bottom microtiter plates and a 200-µl reaction volume. Nylon wool-enriched T cells were isolated from non-tg mice undergoing active EAE as described in Induction of passive EAE, and 3 x 105 cells were cocultured (duplicate wells) for 72 h with 5 x 105 irradiated non-tg APCs, MOG peptide (5 µg/ml), and 0 to 100 µg/ml purified human CRP (Sigma, St. Louis, MO). The human CRP used for these studies was >99% pure as assessed by SDS-PAGE, it was recognized by the human CRP-specific mAb HD2–4 (20), it was endotoxin free as judged by Limulus amebocyte lysate assay, and in direct and competitive binding assays it bound to its natural ligand phosphorylcholine but not to MOG peptide (data not shown). Importantly, trypan blue dye exclusion tests confirmed that T cells cultured for 72 h in the presence of human CRP or in its absence had equal viability (data not shown). After addition of the stimulants, the cells were pulsed with 0.5 µCi [ 3H]thymidine/well, harvested and lysed 6 h later, and assessed for radioisotope incorporation (cpm). For comparison, the proliferation assay was also performed using naive T cells isolated from healthy non-tg mice. Proliferation of T cells is reported as the fold-increase in cpm relative to background incorporation by T cells from the same donors achieved in the presence of APCs but without addition of MOG peptide and human CRP (viz 2208 ± 742 cpm). The data are pooled from four separate experiments.
The in vitro cytokine and chemokine assays were performed essentially as described for the proliferation assay, except that both non-tg and CRPtg T cells were used. Duplicate cultures were either left untreated, stimulated with MOG peptide alone (5 µg/ml) or human CRP alone (50 µg/ml), or costimulated with MOG peptide plus human CRP. Culture supernatants were routinely collected at 6, 16, 24, and 48 h for use in cytokine and chemokine ELISAs, but only the 48-h data are shown. Cytokine and chemokine production by cultures of CRPtg and non-tg cells is reported as the percent of their respective maximal MOG peptide-induced response. The data are pooled from three separate experiments.
Acute phase protein, cytokine, and chemokine ELISAs
Human CRP was measured by ELISA as previously described
(19), using sheep anti-CRP antiserum (ICN
Pharmaceuticals, Costa Mesa, CA) as the capture Ab and mAb
HD2–4 as the reporter. The assay does not detect mouse CRP and has a
lower limit of detection of 20 ng human CRP/ml mouse serum. The mouse
acute phase protein serum amyloid P component (SAP) also was measured
by ELISA (19). The lower limit of detection of mouse SAP
is 40 ng SAP/ml serum. ELISA kits for murine cytokines (TNF-,
IFN-, IL-4, IL-2, IL-12, IL-10, TGF-
) and chemokines (MIP-1,
RANTES) were purchased from R&D Systems (Minneapolis, MN),
and an ELISA for the mouse chemokine MCP-1 was purchased from BioSource
(Hopkinton, MA). Each assay was performed according to the
manufacturer’s instructions.
Immunohistochemistry
CRPtg males and their non-tg littermates (n = 3 each) were sacrificed 4–9 wk after induction of active EAE, and their lumbothoracic spinal cords were removed and snap-frozen in liquid nitrogen. Immunohistochemistry was performed using the Vectastain ABC kit (Vector Laboratories, Burlingame, CA) on representative 10-µm-thick frozen transverse sections of tissue using mouse anti-CD11b mAb (BD PharMingen, San Diego, CA) to detect monocytes/macrophages and rat anti-mouse CD3 mAb (Serotec, Kidlington, U.K.) to detect T cells.
Statistical analyses
Differences in the day of onset of EAE (mean ± SD), maximum clinical scores (mean ± SD), [ 3H]thymidine incorporation during proliferation (cpm; mean ± SEM), and relative production of cytokines and chemokines (mean ± SEM) between CRPtg and control groups were evaluated with Student’s t tests. A value of p < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and Table I). However, once disease was
established in CRPtg, its progression
paralleled that in non-tg (Fig. 1), and its severity was not lessened
(Table I). Human CRP was up-regulated in CRPtg during the inductive
phase of disease (Fig. 2), achieving peak
levels 
10-fold above baseline. Surprisingly, elevation of human CRP
was only transient. Importantly, the duration of the human CRP acute
phase response approximated the delay in disease development between
CRPtg and non-tg females (Fig. 1 and Table I), and the onset of active
EAE in CRPtg females coincided with the recovery of approximately
baseline expression of human CRP (compare Figs. 1 and 2). Like human
CRP, the mouse SAP acute phase response was rapid, and peak levels of
mouse SAP were 10-fold above initial values (Fig. 2). However,
unlike human CRP, mouse SAP acute phase levels were maintained
throughout the 30-day observation period (Fig. 2). Thus, despite the
transient nature of the human CRP acute phase response, the prolonged
elevation of mouse SAP suggests maintenance of an inflammatory state
throughout the 30-day symptomatic phase.
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A). In male CRPtg, onset of
disease was also delayed compared with same-sex controls (Fig. 3B and Table I
). Unlike observations in females, once EAE
was established in male CRPtg, average and maximum disease severity was
significantly reduced compared with controls (Fig. 3B and
Table I, respectively). Although we did not exhaustively analyze the
spinal cords of these mice, sections obtained from CRPtg males
sacrificed 4–8 wk after induction of active EAE revealed little
infiltration of the CNS by CD3+ T cells and
CD11b+ monocytes/macrophages (data not shown).
Furthermore, of 12 CRPtg males injected with MOG peptide, 3 remained
asymptomatic up to 70 days afterward. Fig. 4 shows the results of experiments in
which encephalitogenic T cells obtained from non-tg mice were
injected into non-tg vs CRPtg recipients. Similar to the outcome of
actively induced disease (Figs. 1 and 3), the onset of passively
induced EAE was reproducibly delayed in CRPtg compared with non-tg
recipients (Fig. 4).
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A), proliferation of encephalitogenic T cells
elicited by stimulation with MOG peptide is in fact inhibited or
completely abolished (Fig. 5). Because
development of EAE is dependent on a number of cytokines and chemokines
(21, 22), modification of their expression could also
contribute to the beneficial effects of human CRP that we observed. To
investigate this possibility, we tested whether or not human CRP alters
the MOG peptide-induced production of encephalitogenic cytokines and
chemokines by cultures of non-tg T cells. Human CRP significantly
inhibited the production by MOG peptide specific T cells of the
cytokines TNF-, IFN-, and TGF- (Fig. 6) and also the chemokines MIP-1,
RANTES, and MCP-1 (Fig. 7). In
comparison, human CRP significantly enhanced IL-2 and IL-10 (Fig. 6)
but had no effect on the production of IL-4 and IL-12.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Despite the known contribution of complement in EAE (24) and the ability of human CRP to modulate complement activation (7), a fully functional complement system is not required for CRP-mediated protection in EAE. We know this because we crossed CRPtg mice with C3- and factor B-deficient mutants (24), thus producing CRPtg mice with impaired complement systems, and found that the protective effect of human CRP against MOG peptide-induced EAE was still fully expressed in the CRPtg/complement-deficient hybrids (data not shown). Furthermore, as seen in rabbits with slowly progressing EAE (23), we did not detect local deposition of human CRP in the CNS (Ref. 25 and data not shown). Thus, the in vivo data suggest that human CRP exerts its protective effect during the inductive phase of the disease and likely before destabilization of the blood-brain barrier. We speculate that the major mechanism by which human CRP promotes protection in EAE is via its direct inhibitory action on encephalitogenic cells. On one hand, human CRP protects CRPtg mice from active EAE by delaying or preventing infiltration of inflammatory cells into the CNS; on the other hand, it protects them from passive EAE by reducing the disease-inducing capacity of transferred T cells. The strength of the inhibitory effect in CRPtg mice depends intimately on the level of human CRP in circulation; as long as sufficiently high levels of the protein are maintained a detrimental outcome is averted. Consequently, for CRPtg females with low baseline expression of the transgene, the human CRP acute phase response is protective and onset of EAE is delayed until its resolution. CRPtg males that express a magnitude higher level of human CRP than females do exhibit delayed disease with reduced severity, and sometimes EAE is prevented altogether. Given that MS is at least 2-fold more common in women than in men (26), the fact that human CRP exerts a sex-dependent influence on the outcome of EAE in CRPtg mice may prove to be clinically relevant.
On the basis of our findings and in light of previously reported
observations, we propose that the ability of human CRP to lessen
production of the C-C chemokine MIP-1 is the crucial protective step
in EAE. According to our model (Fig. 8),
reduction of MIP-1 by acute phase human CRP is the initiating step
of an inhibitory cascade that leads to reduced CNS infiltration and
impaired T cell activation. MIP-1 has varied proinflammatory effects
(27); thus, any reduction in its level would clearly
benefit the host. Furthermore, MIP-1 is a major stimulus for
production of proinflammatory cytokines including TNF-
(28), and thus reduction of MIP-1 also leads
secondarily to reduced levels of additional potent proinflammatory
molecules. Presumably, this weakens the Th1 response, which explains
the lowered levels of the proinflammatory Th1 signature cytokine,
IFN-. Expression of RANTES and MCP-1, both also proinflammatory C-C
chemokines, is driven by TNF- and IFN- (29). Thus,
their levels also are reduced. Lowered amounts of these detrimental
cytokines and chemokines, resulting either directly or indirectly from
the actions of human CRP on encephalitogenic cells, culminates in the
same protective effect, viz reduced T cell activation, chemotaxis, and
parenchymal infiltration. Also it might be highly relevant that human
CRP elevates IL-10 production. IL-10 further contributes to inhibition
of TNF- (30), and IL-10 is a Th2 signature cytokine in
the mouse (31); by increasing IL-10 production human CRP
might contribute to immune deviation from a Th1 phenotype to a less
pathogenic Th2. Our model is in accordance with a variety of
observations made about EAE using different cytokine- and
chemokine-deficient mouse mutants. Like the expression of human CRP in
CRPtg, lack of expression of TNF- in TNF--deficient mice delays
onset of active EAE and prevents inflammatory cell infiltration into
the parenchyma but has no effect on disease progression (32, 33). Likewise, MCP-1-deficient mice resist EAE
(34).
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Efforts are now under way to identify the exact encephalitogenic
cell(s) with which human CRP presumably interacts to evoke protection
in EAE, and the mode of this interaction. Human CRP is known to bind to
Ag-induced T cells (44) and also to B cells
(45), and it was recently established that human CRP binds
with high affinity to the activation receptor FcRI and the
inhibitory receptor FcRIIb in both mice and humans
(8, 9, 10, 11). Notably, there is growing evidence that FcRIIb
plays a major inhibitory role in controlling the emergence of
autoimmune disease (46, 47). Despite the fact that MOG
peptide-induced EAE can develop fully in the absence of B cells
(48), FcRIIb-inhibitory signals induced by human CRP
binding to APCs could possibly contribute to the protective
anti-inflammatory response we observed in CRPtg mice.
Regardless of the mechanism of human CRP/encephalitogenic cell interaction and the identity of the effector cell(s) involved, it is clear from our results that human CRP can alter the disease-inducing potential of inflammatory cells contributing to the development of murine EAE, i.e. dendritic cells, monocytes, macrophages, and neutrophils. The relevance of this finding to the MS disease process in humans was made clear in a recent clinical study, wherein it was reported that of seven serum markers of inflammation examined in MS patients, only CRP levels correlated with development of cerebral atrophy and change in cerebral volume (49). Importantly, MS patients with lower CRP levels tended to develop more severe cerebral symptoms (49). Our ongoing animal studies seek to determine whether active EAE in non-tg mice can be blocked by administration of purified human CRP and whether treatment of female CRPtg with androgens (to increase expression of human CRP) induces the highly resistant phenotype we observed in CRPtg males. A positive outcome would raise the possibility that CRP might have therapeutic value in MS and that the gender-bias in multiple sclerosis in humans might be mediated, at least in part, by CRP.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Alexander J. Szalai, Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama, Birmingham, AL 35294-0006. E-mail address: Alex.Szalai{at}ccc.uab.edu
3 Abbreviations used in this paper: CRP, C-reactive protein; EAE, experimental allergic encephalomyelitis; CRPtg, CRP transgenic; non-tg, nontransgenic; MS, multiple sclerosis; MOG, myelin oligodendrocyte protein; MIP-1, macrophage-inflammatory protein-1; MCP-1, monocyte chemoattractant protein 1; SAP, serum amyloid P component.
Received for publication December 7, 2001. Accepted for publication March 25, 2002.
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References |
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RI in transfected COS cells. J. Immunol. 155:2185.[Abstract]
receptor II. J. Exp. Med. 190:585. receptors. J. Immunol. 164:1514.RIIa on human monocytes and neutrophils is allele-specific. J. Clin. Invest. 105:369.[Medline]
and interferon- synergistically activate the RANTES promoter through nuclear factor 
B and interferon regulatory factor 1 (IRF-1) transcription factors. Biochem. J. 350:131.
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and •) and human CRP (
) were measured
during the course of active EAE in female wild-type mice (non-tg;
n = 18) and littermate CRPtg (n
= 13). Each point represents the mean ± SEM from three
experiments.
; n = 13) are reproduced from
Fig. 1
, Significantly less (TGF-
