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Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The most extensively used small animal model of RA is type II
collagen-induced arthritis (CIA) (3, 4, 5, 6, 7), in which
immunization of mice with heterologous type II collagen in adjuvant
induces a cross-reactive immune response to murine type II collagen.
This autoimmune reaction is mediated by immune complex formation and
shares many characteristics with human RA (reviewed in Ref.
8). Synovial inflammation (synovitis) can be induced with
single mAbs specific for type II collagen (9), and
mixtures of type II collagen-specific mAbs against specific regions of
collagen cannot only induce synovitis, but also cause clinical
arthritis (10), indicating that anti-collagen Ab
deposition in the joints triggers the complete range of arthritic
symptoms. The CIA model has also been useful for studies of cytokine
expression in the synovium and synovial fluid compartments
(8), determination of the relative roles of complement
(6) and Ig Fc receptors in disease initiation and
pathogenesis (reviewed in Ref. 11), and development of
effective anti-inflammatory therapeutics such as neutralizing Abs
to IL-1 (12, 13) and TNF-
(14, 15, 16).
Recently, a spontaneous murine disease with most of the characteristics
of human RA was fortuitously discovered by breeding the KRN
transgenic TCR, specific for bovine RNase
(42–56)/I-Ak, mouse to the nonobese diabetic
(NOD) background (17). The F1
generation between KRN and NOD (abbreviated K/BxN) spontaneously
develops a progressive joint-specific autoimmune disease between 3 and
5 wk of age, characterized by rapid symmetrical onset of peripheral
joint inflammation that is restricted primarily to the joints of the
front and rear limbs. Pathology of disease in K/BxN mice is similar to
human RA, with pannus formation, synovial hyperplasia, increased
synovial fluid volume, cellular infiltrates, and chaotic remodeling of
cartilage and bone in the distal joints in later stages. The K/BxN
mouse model also exhibits elevated expression of proinflammatory
cytokines, hypergammaglobulinemia, and autoreactive Ab production
(18), all of which can be found in human RA patients. One
difference between the two diseases is the absence of detectable
rheumatoid factor in K/BxN mice (17), although
20–30% of human RA patients are also negative for serum rheumatoid
factor (19). Immune complexes of rheumatoid factor-IgG and
potentially other Ab-Ag immune complexes can be found in the joints of
human RA patients (20), but their role in joint pathology
and disease progression has yet to be ascertained.
In the K/BxN model, KRN TCR transgenic cells recognize a mouse (self)-derived peptide bound to I-Ag7, presented by B cells and other MHC class II-positive APCs (18). The autoantigen for both K/BxN arthritogenic Ig and KRN T cells was recently identified (21) as glucose-6-phosphate isomerase (GPI), an ubiquitous cytoplasmic enzyme that catalyzes the interconversion of fructose-6-phosphate and glucose-6-phosphate during glycolysis. Our laboratory has recently established the molecular basis for the dual ability of the KRN TCR to recognize RNase (42–56)/I-Ak and GPI (282–294)/I-Ag7 (22, 23). A working model of K/BxN disease initiation postulates that GPI-specific B cells endocytose GPI via surface Ig receptors and present the I-Ag7-restricted epitope to incompletely tolerized CD4+ KRN T cells, which in turn provide specific help in maturation and Ig isotype switching, leading to autoantibody production (17, 18, 21) and subsequent induction of joint inflammation.
Transfer of serum or purified Ig from arthritic K/BxN mice induces a synchronized joint-specific inflammatory reaction that mimics the K/BxN disease (18), indicating that arthritogenic Ig can induce synovitis and rheumatoid-like arthritic disease. The disease induced by a single administration of serum eventually resolves, unless arthritogenic Ig is repeatedly transferred into recipients (18). The development of an easily inducible model of RA with a rapid, synchronized onset facilitates the study of the pathogenic mechanisms involved in the initiation of joint autoimmunity.
In this study, we found that neutrophils play an indispensable role in disease initiation in the K/BxN serum transfer model of RA. We used a mAb to deplete neutrophils in recipient mice and found that this treatment completely blocked the acute joint-specific inflammatory response normally induced by K/BxN serum transfer, and caused rapid and profound reversal of joint inflammation in diseased mice. Furthermore, we determined that neither the inducible NO synthase (iNOS)2 nor gp91phox gene products are required for the serum-induced joint inflammation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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NOD mice (6–8 wk old) were obtained from Taconic Farms (Germantown, NY). KRN TCR transgenic mice on a B6 background (K/B, the generous gift of D. Mathis and C. Benoist, Harvard Medical School, Boston, MA) were bred to NOD mice to generate K/BxN mice. Mice deficient for iNOS2 (24) or gp91phox (25) gene expression, C57BL/6J, B6.AKR (H-2k), CB.17-SCID, and B6.AKR-RAG1-/- mice were obtained from The Jackson Laboratory (Bar Harbor, ME), and bred and housed under specific pathogen-free conditions in the animal colony at Washington University (St. Louis, MO). All mice were sex matched and age matched for experiments, and were between 6 and 10 wk of age.
Arthritic serum
Serum was separated from blood obtained from arthritic K/BxN mice (6–12 wk old) and frozen at -70°C. To prepare larger pools for in vivo experiments, frozen serum samples were thawed, centrifuged at 12,000 rpm for 10 min, pooled and sterile filtered, and frozen in aliquots at -70°C. Before injection, serum aliquots were thawed, centrifuged, and diluted with PBS. Each batch of pooled serum was titrated in B6.AKR mice (groups of 3–5 mice per dose) for its ability to transfer joint-specific disease and to determine an effective dose of serum for subsequent serum transfer experiments. A dose of 250 µl per mouse was selected, as it consistently gave disease induction in 100% of the mice.
Antibodies
The rat IgG2b mAb RB6-8C5 (26) was purified using protein G-Sepharose 4 Fast Flow affinity matrix (Pharmacia, Piscataway, NJ) from ascites produced in SCID mice. GK1.5 mAb (27) against mouse CD4 (rat IgG2b) was purified from ascites by saturated ammonium sulfate precipitation (45% final) and dialysis against PBS, pH 7.4, before being stored at -70°C.
Ab depletion in vivo
For in vivo neutrophil depletion, 250 µg RB6-8C5 mAb was
diluted to 0.5 ml with PBS and injected i.p. at 3-day intervals
beginning 1 day before serum transfer, except for the experiment
described in Fig. 4
. This dose of Ab is equal to or greater than has
been shown previously to be efficacious in completely eliminating
neutrophils in vivo (28, 29, 30). We determined in early
experiments that a single injection of RB6-8C5 is not sufficient to
completely block joint inflammation for more than 5–6 days, as
demonstrated by the appearance of clinical signs of inflammation and
measurable thickening of the ankle joints. We attribute this to
clearance of the RB6-8C5 Ab from the bloodstream and tissues and the
maturation and release of new neutrophils from the bone marrow.
Previous studies of peripheral blood cell types in RB6-8C5-treated mice
have established that macrophage, NK, and T and B lymphocyte
populations are not significantly affected by such methods
(31, 32, 33, 34, 35, 36, 37). Several studies have demonstrated that RB6-8C5
Ab fails to bind to mature macrophages, monocytes, or splenic B and T
lymphocytes by either flow cytometry analysis (32, 36) or
immunofluorescent microscopy (33).
CD8+ T cells have been previously reported to be
moderately affected by RB6-8C5 treatment (36, 38, 39), but
the effect on CD8+ cells occurs several days
after neutrophils are depleted (38), and would be of no
consequence in this model, as T cell-deficient RAG1 mice are equally
susceptible to disease (see Fig. 2, D and E). For
the control anti-CD4 Ab, 50 µl ammonium sulfate-precipitated
GK1.5 mAb was diluted to 0.5 ml with PBS and injected i.p. Depletion
was monitored by flow cytometry using biotinylated RB6-8C5 and GK1.5
(PharMingen, San Diego, CA) and streptavidin-R-PE (Caltag, Burlingame,
CA) using standard procedures. A minimum of 20,000 total events was
collected using a FACSCalibur and analyzed using CellQuest software (BD
Biosciences, Mountain View, CA). Gates and histograms were set using
untreated B6.AKR peripheral blood stained with RB6-8C5 or GK1.5.
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Serum as prepared above was injected i.p., and clinical scores were determined daily based upon evidence of redness and swelling, using a scale ranging from 0 to 4, as described previously (17). Physical measurement of ankle thickness was performed using a Fowler Metric Pocket Thickness Gauge (Ralmikes Tool-A-Rama, Middlesex, NJ). Ankle measurements were made above the footpad, axially across the ankle joint, and rounded off to the nearest 0.05 mm. Data are presented as the mean of individual ankle thicknesses within a group of mice (3–6 mice per group). Mean percent inhibition of ankle swelling due to RB6-8C5 depletion was calculated using the following formula: 1 - (experimental mean ankle thickness - experimental baseline mean ankle thickness)/(PBS mean ankle thickness - PBS baseline mean ankle thickness). Student t tests for paired data were performed using Kaleidagraph software (Synergy Software, Reading, PA) on calculated values from data of three identical experiments, with a total of 12 mice per experimental condition.
Histology
Tissue samples were prepared by fixing tissues 24–48 h in 10% phosphate-buffered Formalin (J. T. Baker, Phillipsburg, NJ). Fixed joints were decalcified by treatment with Decal Overnight Bone Decalcifier solution (Decal Chemical, Congers, NY) for 2 days with gentle rocking and daily replacement of the Decal solution. Samples were then washed with PBS, dehydrated with a series of ethanol washes (50% ethanol, followed by 70% ethanol), and embedded in paraffin. Sections of tissue 4 µm thick were stained with H&E. Representative sections from individual mice within groups of three to six mice were selected to illustrate the general state of each group’s ankle joints.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To determine the timing of inflammatory cell recruitment to
affected joints following K/BxN serum transfer, we performed
histological studies on ankle joints over time. Injection of serum
reproducibly resulted in rapid bilateral ankle swelling (Fig. 1A) and increased clinical
index scores (Fig. 1B) in B6.AKR mice within 24–48 h post
transfer. Ankles continued to increase in size up to 7 days post
transfer.
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, A and B) and wrist joint (data not
shown) were inflamed, with redness (erythema), tenderness, and
measurable ankle swelling. Histological examination at 24 h (Fig. 1D, x50 magnification) revealed a slight increase in the
size of the articular space contained within the synovium, as evidenced
by a larger gap between the talus and the synovial membrane, consistent
with observed edema in the region. The synovial fluid space was clear
and free of cellular infiltrate, and the synovial membrane appeared
normal (data not shown). Thirty-six to forty hours after serum
transfer, ankle joints continued to increase in thickness and clinical
index severity, with nearly all of the extremities involved (Fig. 1, A and B). Histology of the ankle joints at this
time showed an increased synovial fluid volume and the presence of
neutrophils in the synovial fluid surrounding the talus, calcaneus, and
distal tibia/fibula (Fig. 1, E, x50 magnification, and
F, x500 magnification). Neutrophils also began to
accumulate in the loose connective tissue posterior to the ankle joint
between the Achilles tendon and the talus, and also in the tissues
surrounding the synovium on the lateral and anterior portions of the
ankle joint.
At 48 h, all of the mice showed significant outward signs of
ankle joint inflammation and swelling, with mean ankle sizes increased
20% in diameter (Fig. 1A). Histological analysis at
48 h showed initial signs of synovial membrane expansion
surrounding the articular spaces of the joint, with neutrophils and
other infiltrating cells in close proximity to the joint spaces and in
the synovial fluid (Fig. 1, G and H, x500
magnification). Neutrophil numbers were greatly increased, infiltrating
the low density connective tissue found posterior to the ankle joints,
and also on the sides of the ankle joint just below the malleoli of the
tibia and fibula (data not shown).
Neutrophil depletion in vivo dramatically blocked the ability of K/BxN arthritogenic serum to induce joint-specific inflammatory reactions in serum transfer recipients
To further investigate the role of neutrophils in the serum
transfer model, we used a depleting mAb (RB6-8C5) specific for a
neutrophil-restricted surface marker (Ly-6G), which has been used in
numerous unrelated studies to deplete neutrophils in vivo
(31, 32, 33, 34, 35, 36, 37). B6.AKR mice were treated with purified RB6-8C5
rat mAb or vehicle alone (PBS) on days -1, 2, and 5 by i.p. injection
(250 µg per injection), and K/BxN serum was injected i.p. on day 0.
Clinical score and ankle thickness were monitored for 7 days after
serum transfer, and the efficiency of neutrophil depletion in
peripheral blood was monitored by flow cytometry. Data from two such
RB6-8C5 depletion experiments and their associated FACS monitoring of
peripheral blood are shown in Fig. 2. In
the first experiment (Fig. 2, A–C), B6.AKR mice were
treated with either three doses of RB6-8C5, PBS, or the isotype-matched
CD4-depleting rat Ab GK1.5 beginning 1 day before serum transfer (day
-1). Mice treated with RB6-8C5 showed no signs of clinical disease
through day 7 post transfer (Fig. 2, A and B). We
found that there was no observable difference between groups treated
with either PBS or GK1.5 in either the severity of ankle swelling (Fig. 2A) or clinical index scores (Fig. 2B). There
also was no difference in the time of onset for inflammation, as both
groups of mice showed measurable swelling at 2 days post transfer and
peaked on days 6–7. The extremities of the PBS- and GK1.5-treated
groups became reddened and inflamed within 48 h, while the ankles
and wrists of RB6-8C5-treated mice showed no signs of inflammatory
response and were indistinguishable from those of control mice that did
not receive serum.
Depletion of RB6-8C5-positive peripheral blood leukocytes was
essentially complete 1 day after treatment and remained extremely low
(<1% of total PBL) throughout the experiment (Fig. 2C).
Additionally, analysis of FACS plots of forward light scatter vs side
light scatter demonstrated the near-total absence of cells in the
neutrophil region of the plot, which in normal mice is >95% positive
for RB6-8C5 staining (data not shown). CD4+ T
cells were completely absent from the peripheral blood of GK1.5-treated
mice by FACS analysis (data not shown), yet the progression and
severity of serum-transferred disease were unaffected, showing that the
protective effect was specific for the depletion of neutrophils.
In addition to its effect on neutrophils, RB6-8C5 mAb treatment has
been reported to lead to a slow reduction in the number of
CD8+ T cells over the course of several days
(36, 38, 40). To ensure that the protective effect of
RB6-8C5 mAb treatment was not due to depletion of
CD8+ T cells, serum transfer disease was
evaluated in RAG1-deficient mice (RAG1-/-),
which lack B and T cells. There was no significant difference between
RAG1-deficient B6.AKR and wild-type B6.AKR mice in relation to the
onset of inflammation, progression, or severity of disease following
serum transfer, demonstrating that T and B lymphocytes were dispensable
in the serum transfer model. Furthermore, RB6-8C5 mAb treatment
protected RAG1-deficient mice from disease induction (Fig. 2, D and E). Collectively, the results demonstrated
that K/BxN Ig were unable to induce this joint-specific reaction in
recipient mice in the absence of a normal neutrophil compartment. This
indicates that RB6-8C5-positive neutrophils play an important role in
initiating this Ab-mediated disease.
Protection against K/BxN serum-induced joint swelling by RB6-8C5 neutrophil depletion correlates with normal ankle morphology and absence of cellular infiltrates
The ankles of RB6-8C5-treated mice showed remarkably normal
morphology at 5 and 7 days postserum transfer, virtually
indistinguishable from that of a normal mouse ankle. Ankles from
RB6-8C5-treated mice 5 days after serum transfer showed no signs of
inflammatory infiltrate or synovial hyperplasia (Fig. 3, C and D). In
contrast, ankles of PBS-treated mice demonstrated massive inflammatory
infiltrate, increased synovial fluid volume, and synovial hyperplasia
with large numbers of neutrophils present in the synovial fluid (Fig. 3, A and B). The lack of detectable infiltration
and synovial hypertrophy in these histological studies of
neutrophil-depleted mice correlates with the absence of measurable
swelling (Fig. 2A) or visible inflammation (Fig. 2B), indicating that the presence and infiltration of
neutrophils are obligatory for the characteristic changes induced by
transfer of K/BxN serum. Therefore, neutrophils must possess
properties or functions that are important or even indispensable for
the inflammatory response triggered by K/BxN Ig transfer.
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To begin to determine the mechanism(s) by which neutrophils may
act to induce joint disease, we assessed the responses of mice
deficient for iNOS2 (iNOS2 knockout mice), which are unable
to generate NO (24), and
gp91phox-deficient mice that are unable to
generate hydrogen peroxide by the NADPH-dependent pathway
(25). Results from one of three experiments are shown in
Fig. 4, in which we found that relative
to congenic B6 mice, gp91phox-deficient mice
and iNOS2 knockout mice developed arthritis with similar
kinetics (Fig. 4, A and B). In two of three
experiments, we observed slightly enhanced inflammation in
iNOS2 knockout mice relative to B6 and
gp91phox-deficient mice. Neither strain proved
to be more resistant than B6 mice to the inflammation induced by K/BxN
serum transfer. Histological analysis of ankle joints from these
strains of mice failed to reveal any gross differences in joint
morphology (data not shown), suggesting that neither reactive
intermediate pathway is critical for the neutrophil-dependent
inflammatory response to K/BxN serum.
Reversal of K/BxN serum transfer inflammation with neutrophil depletion via RB6-8C5 treatment
The depletion of neutrophils before serum transfer prevents disease. It was next important to determine whether neutrophil depletion could affect disease progression after the transfer of serum. Groups of B6.AKR mice were treated with a single i.p. injection of 250 µg RB6-8C5 on days -1, 0, 1, 2, or 3 days after K/BxN serum was transferred. This protocol differed from our previous ones, in that we were only administering a single dose of RB6-8C5.
A single injection of RB6-8C5 was equally effective in completely
preventing joint inflammation for 6 days, regardless of whether it
was administered 1 day before serum transfer (day -1) or at the same
time as serum (day 0, Fig. 5, B and C). At 1 day after serum transfer, the
remaining untreated groups of mice demonstrated visible signs of
inflammation similar to mice in Figs. 1 and 2 (data not shown) and
only slightly elevated ankle measurements (Fig. 5, D–G).
Treatment with RB6-8C5 beginning 1 day after serum transfer (day +1)
immediately and effectively blocked inflammation and clinical
manifestations of the disease within 24 h of treatment (Fig. 5D). Treatment with RB6-8C5 2 and 3 days after serum
transfer quickly reversed the joint-specific inflammatory reaction, as
measured by ankle swelling and clinical scores. Mice that received
RB6-8C5 on day 4 (G) and day 5 (H) also showed a
rapid decline in ankle thickness beginning 1 day after treatment,
indicating that at this time the inflammation is also reversible or at
least can be ameliorated by neutrophil depletion. All of the treated
groups showed significant benefit from neutrophil depletion, as
determined by reduction in erythema, puffiness, and joint thickness
(data not shown). Inhibition of ankle swelling by neutrophil depletion
became less effective when initiated after day 3 of serum transfer
(Fig. 5I). Mice were analyzed for the extent of neutrophil
depletion on days 0, 2, 4, and 7 by FACS analysis. By day 5–6 after
RB6-8C5 mAb injection, neutrophils began to reappear in peripheral
blood due to clearance of Ab from the bloodstream and tissues and
maturation and release of neutrophils from the bone marrow. There is a
clear correlation between the time of recovery of
RB6-8C5+ peripheral neutrophils and the onset or
resumption of joint inflammation (data not shown). These studies
revealed that the early stages of experimental immune complex-induced
arthritis, up to day 3, could be completely reversed by depletion of
neutrophils, and disease severity was ameliorated up through day 5.
These experiments indicate that not only are neutrophils critically
involved during the first 3–5 days of the disease, but they are also
required for the continuation and progression of the immune
complex-mediated inflammatory state.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This model disease can be transferred to normal mice with purified
GPI-specific IgG from arthritic mice (21), strongly
suggesting that the initial triggering event is the formation and/or
deposition of GPI-IgG immune complexes in the joint spaces. Therefore,
it is likely to share features with other immune complex-triggered
autoimmune models (11, 41, 42). Local mononuclear cells
and possibly mast cells (43) become activated by immune
complex-activated complement fragments (44, 45), tissue
damage, and/or Fc
R cross-linking (11, 46), and release
proinflammatory cytokines such as IL-1
and TNF- (43, 47) in or near the affected tissue (e.g., joints), which induces
some relatively low level of neutrophil recruitment. These few initial
neutrophils become activated, extravasate, and home to the joints,
where they proceed to help create a proinflammatory cytokine milieu
that is necessary to maintain and expand the joint inflammatory
response. In a rat model of arthritis unrelated to the K/BxN model,
repeated injection of streptococcal cell wall extract causes joint
inflammation, which has also been shown to be neutrophil dependent and
requires P-selectin, ICAM-1, and macrophage-inflammatory protein-2
(48), suggesting these molecules are likely to be
important in the K/BxN model for neutrophil recruitment. In the CIA
model, it has been clearly demonstrated that autoreactive Abs to type
II collagen initiate inflammation by binding to articular cartilage and
causing activation of complement, C3 deposition (44), and
eventual cleavage of C5 (45). Although the K/BxN RA model
is also autoantibody mediated and shares pathology with CIA, the Ag
(GPI) is not joint specific (21), and deposition of
GPI-autoantibody immune complexes in the joints of mice has yet to be
demonstrated, and remains an intriguing question.
Potential neutrophil effector mechanisms that may be critical for the
induction and progression of joint inflammation in the murine K/BxN
serum transfer model include release of granules containing degradative
enzymes, and the production and release of proinflammatory cytokines.
Neutrophil granule contents such as myeloperoxidase, elastase, matrix
metalloproteinases, and collagenase (41, 49) can cause
further damage to the tissue and amplify the neutrophil response, which
has been observed in an Ab-mediated model of bullous pemphigoid
(50). Alternatively, activated neutrophils are also
capable of releasing proinflammatory cytokines such as TNF-, IL-1,
IL-6, and TGF (51, 52), potentially affecting the
activities of both neutrophils and other cell types, such as resident
mononuclear cells and chondrocytes. TNF- is at the apex of a
proposed cascade model of proinflammatory cytokines in rheumatoid
synovial tissue (2), and the role of TNF- as a dominant
proarthritogenic cytokine has been demonstrated with mice transgenic
for human TNF- (53). Neutrophils may also interfere
with the balance of IL-1 and endogenous IL-1 receptor antagonist
(IL-1ra) activity in the joint (54), either by direct
secretion of IL-1 or through TNF--mediated IL-1 induction. Mice that
are deficient in the endogenous IL-1ra develop a chronic, progressive
joint inflammation disease on certain mouse backgrounds, illustrating
the importance of a balance between IL-1 and IL-1ra in normal joint
physiology and homeostasis of inflammatory cytokines.
Finally, TGF is another proinflammatory cytokine found in synovial
tissue and fluid (55) and is a powerful neutrophil
chemoattractant (56). As with TNF- and IL-1,
neutrophils can both produce and respond to TGF, providing a
potential amplification mechanism for continued neutrophil activation
and recruitment. In combination with their capacity to make
TNF- and IL-1, one can propose a model for K/BxN serum
transfer in which initial mononuclear cell activation and cytokine
release in the joint tissues induces some level of initial neutrophil
recruitment. The initial wave of recruited neutrophils would
then be largely responsible for amplifying and sustaining recruitment
of neutrophils to the inflamed tissues through the continued generation
and release of proinflammatory cytokines such as TNF-, IL-1, and
TGF.
In contrast to cytokine secretion and degranulation of proenzymes that are usually directed toward extracellular targets, the oxidative species produced by the iNOS pathway (e.g., NO) and the NADPH oxidase pathway (hydrogen peroxide) are usually directed intracellularly against phagocytosed bacteria or particles contained within a phagosome. However, it has recently been proposed (49) that adherent neutrophils could release such reactive species into small pockets of synovial fluid, leading to inappropriate activation of proenzymes such as elastase or metallothionein proteases, and damage of the synovial fluid hyaluronan or cartilage. In several model systems of immunopathologic disease, inhibition of either NADPH or iNOS pathways or both together has yielded a reduction in the severity of inflammation or disease (29, 57, 58). Unexpectedly, we found that mice deficient for either gp91phox or iNOS2 activity presented similar disease phenotypes as wild-type control mice. There was no significant reduction in the severity of disease induced by K/BxN serum transfer, nor was there any significant alteration in the time of disease onset for these mutant strains of mice. Interestingly, iNOS2 knockout mice demonstrated enhanced swelling relative to B6 mice in two of three experiments. This suggests that neither of these two pathways are obligatory for immune complex-triggered joint inflammation in the K/BxN serum transfer model, although one might expect that they are likely to be involved in tissue damage once a joint becomes inflamed. Indeed, other studies have shown that overproduction of NO and its reaction product, peroxynitrate, contributes to the pathophysiology of RA and joint inflammation (59, 60).
To summarize, it has been hypothesized, but not directly shown, that neutrophils are an important component of inflammatory responses to immune complex deposition in the joints because they are found there in high numbers. This study convincingly demonstrates that neutrophils are an essential component of the K/BxN autoreactive IgG transfer model of rheumatoid-like arthritis, and that an induced state of neutropenia confers protection from joint-specific inflammation. These results are important because they demonstrate for the first time that neutrophils play an essential inductive role in the generation of joint-specific inflammation in the K/BxN serum transfer model (e.g., one or more of the properties of neutrophils are responsible for early stages of inflammation in the K/BxN). The mechanism by which neutrophils are recruited specifically to the joint in the K/BxN model, and which neutrophil characteristics are important in this location, are questions that bear further consideration and will be the subject of future experiments. Further studies to elucidate the exact operative mechanisms exerted by neutrophils may point to potential approaches for pharmacological intervention in other inflammatory diseases such as human RA, to help ameliorate or limit the severity and scope of joint disease.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Paul M. Allen, Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8118, St. Louis, MO 63110. E-mail address: allen{at}immunology.wustl.edu
3 Abbreviations used in this paper: RA, rheumatoid arthritis; CIA, collagen-induced arthritis; GPI, glucose-6-phosphate isomerase; IL-1ra, IL-1 receptor antagonist; iNOS, inducible NO synthase; NOD, nonobese diabetic.
Received for publication January 10, 2001. Accepted for publication May 18, 2001.
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References |
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receptors. J. Exp. Med. 191:1611. activity in vivo with a monoclonal antibody alleviates collagen-induced arthritis in DBA/1 mice and prevents the associated acute-phase response. Clin. Exp. Rheumatol. 11:515.[Medline]
and transforming growth factor during induction of collagen type II arthritis in mice. Proc. Natl. Acad. Sci. USA 89:7375.R expression on macrophages is related to severity and chronicity of synovial inflammation and cartilage destruction during experimental immune-complex-mediated arthritis (ICA). Arthritis Res. 2:489.[Medline]
and platelet-activating factor in the pathogenesis of acute immune complex alveolitis in the rat. Am. J. Pathol. 141:551.[Abstract]
1 (TGF-1) induced neutrophil recruitment to synovial tissues: implications for TGF--driven synovial inflammation and hyperplasia. J. Exp. Med. 173:1121. transgene develop a severe, erosive arthritis: characterization of the cytokine cascade and cellular composition. J. Immunol. 159:2867.[Abstract]
and IL-1 in rheumatoid synovium. J. Immunol. 145:2514.[Abstract]
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H. Seno, H. Miyoshi, S. L. Brown, M. J. Geske, M. Colonna, and T. S. Stappenbeck Efficient colonic mucosal wound repair requires Trem2 signaling PNAS, January 6, 2009; 106(1): 256 - 261. [Abstract] [Full Text] [PDF]
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K. Shin, P. A. Nigrovic, J. Crish, E. Boilard, H. P. McNeil, K. S. Larabee, R. Adachi, M. F. Gurish, R. Gobezie, R. L. Stevens, et al. Mast Cells Contribute to Autoimmune Inflammatory Arthritis via Their Tryptase/Heparin Complexes J. Immunol., January 1, 2009; 182(1): 647 - 656. [Abstract] [Full Text] [PDF]
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P. Boross, P. L. van Lent, J. Martin-Ramirez, J. van der Kaa, M. H. C. M. Mulder, J. W. C. Claassens, W. B. van den Berg, V. L. Arandhara, and J. S. Verbeek Destructive Arthritis in the Absence of Both Fc{gamma}RI and Fc{gamma}RIII J. Immunol., April 1, 2008; 180(7): 5083 - 5091. [Abstract] [Full Text] [PDF]
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Z. Jakus, T. Nemeth, J. S. Verbeek, and A. Mocsai Critical but Overlapping Role of Fc{gamma}RIII and Fc{gamma}RIV in Activation of Murine Neutrophils by Immobilized Immune Complexes J. Immunol., January 1, 2008; 180(1): 618 - 629. [Abstract] [Full Text] [PDF]
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J. S. Zhou, W. Xing, D. S. Friend, K. F. Austen, and H. R. Katz Mast cell deficiency in KitW-sh mice does not impair antibody-mediated arthritis J. Exp. Med., November 26, 2007; 204(12): 2797 - 2802. [Abstract] [Full Text] [PDF]
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D. Spitzer, L. M. Mitchell, J. P. Atkinson, and D. E. Hourcade Properdin Can Initiate Complement Activation by Binding Specific Target Surfaces and Providing a Platform for De Novo Convertase Assembly J. Immunol., August 15, 2007; 179(4): 2600 - 2608. [Abstract] [Full Text] [PDF]
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S. Faubel, E. C. Lewis, L. Reznikov, D. Ljubanovic, T. S. Hoke, H. Somerset, D.-J. Oh, L. Lu, C. L. Klein, C. A. Dinarello, et al. Cisplatin-Induced Acute Renal Failure Is Associated with an Increase in the Cytokines Interleukin (IL)-1beta, IL-18, IL-6, and Neutrophil Infiltration in the Kidney J. Pharmacol. Exp. Ther., July 1, 2007; 322(1): 8 - 15. [Abstract] [Full Text] [PDF]
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J. J. Yu, M. J. Ruddy, G. C. Wong, C. Sfintescu, P. J. Baker, J. B. Smith, R. T. Evans, and S. L. Gaffen An essential role for IL-17 in preventing pathogen-initiated bone destruction: recruitment of neutrophils to inflamed bone requires IL-17 receptor-dependent signals Blood, May 1, 2007; 109(9): 3794 - 3802. [Abstract] [Full Text] [PDF]
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R. A. Clemens, L. E. Lenox, T. Kambayashi, N. Bezman, J. S. Maltzman, K. E. Nichols, and G. A. Koretzky Loss of SLP-76 Expression within Myeloid Cells Confers Resistance to Neutrophil-Mediated Tissue Damage while Maintaining Effective Bacterial Killing J. Immunol., April 1, 2007; 178(7): 4606 - 4614. [Abstract] [Full Text] [PDF]
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T. Laragione, N. C. Yarlett, M. Brenner, A. Mello, B. Sherry, E. J. Miller, C. N. Metz, and P. S. Gulko The Arthritis Severity Quantitative Trait Loci Cia4 and Cia6 Regulate Neutrophil Migration into Inflammatory Sites and Levels of TNF-{alpha} and Nitric Oxide J. Immunol., February 15, 2007; 178(4): 2344 - 2351. [Abstract] [Full Text] [PDF]
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P. A. Nigrovic, B. A. Binstadt, P. A. Monach, A. Johnsen, M. Gurish, Y. Iwakura, C. Benoist, D. Mathis, and D. M. Lee Mast cells contribute to initiation of autoantibody-mediated arthritis via IL-1 PNAS, February 13, 2007; 104(7): 2325 - 2330. [Abstract] [Full Text] [PDF]
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A. M. Fusello, L. Mandik-Nayak, F. Shih, R. E. Lewis, P. M. Allen, and A. S. Shaw The MAPK Scaffold Kinase Suppressor of Ras Is Involved in ERK Activation by Stress and Proinflammatory Cytokines and Induction of Arthritis J. Immunol., November 1, 2006; 177(9): 6152 - 6158. [Abstract] [Full Text] [PDF]
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B. A. Maletto, A. S. Ropolo, D. O. Alignani, M. V. Liscovsky, R. P. Ranocchia, V. G. Moron, and M. C. Pistoresi-Palencia Presence of neutrophil-bearing antigen in lymphoid organs of immune mice Blood, November 1, 2006; 108(9): 3094 - 3102. [Abstract] [Full Text] [PDF]
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D. Zhu, H. Hattori, H. Jo, Y. Jia, K. K. Subramanian, F. Loison, J. You, Y. Le, M. Honczarenko, L. Silberstein, et al. Deactivation of phosphatidylinositol 3,4,5-trisphosphate/Akt signaling mediates neutrophil spontaneous death PNAS, October 3, 2006; 103(40): 14836 - 14841. [Abstract] [Full Text] [PDF]
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N. K. Banda, J. M. Thurman, D. Kraus, A. Wood, M. C. Carroll, W. P. Arend, and V. M. Holers Alternative Complement Pathway Activation Is Essential for Inflammation and Joint Destruction in the Passive Transfer Model of Collagen-Induced Arthritis J. Immunol., August 1, 2006; 177(3): 1904 - 1912. [Abstract] [Full Text] [PDF]
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B. Sarraj, K. Ludanyi, T. T. Glant, A. Finnegan, and K. Mikecz Expression of CD44 and L-Selectin in the Innate Immune System Is Required for Severe Joint Inflammation in the Proteoglycan-Induced Murine Model of Rheumatoid Arthritis J. Immunol., August 1, 2006; 177(3): 1932 - 1940. [Abstract] [Full Text] [PDF]
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J. C. Scatizzi, J. Hutcheson, E. Bickel, J. M. Woods, K. Klosowska, T. L. Moore, G. K. Haines III, and H. Perlman p21Cip1 Is Required for the Development of Monocytes and Their Response to Serum Transfer-induced Arthritis Am. J. Pathol., May 1, 2006; 168(5): 1531 - 1541. [Abstract] [Full Text] [PDF]
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N. D. Kim, R. C. Chou, E. Seung, A. M. Tager, and A. D. Luster A unique requirement for the leukotriene B4 receptor BLT1 for neutrophil recruitment in inflammatory arthritis J. Exp. Med., April 17, 2006; 203(4): 829 - 835. [Abstract] [Full Text] [PDF]
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M. Chen, B. K. Lam, Y. Kanaoka, P. A. Nigrovic, L. P. Audoly, K. F. Austen, and D. M. Lee Neutrophil-derived leukotriene B4 is required for inflammatory arthritis J. Exp. Med., April 17, 2006; 203(4): 837 - 842. [Abstract] [Full Text] [PDF]
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C Iking-Konert, B Ostendorf, O Sander, M Jost, C Wagner, L Joosten, M Schneider, and G M Hansch Transdifferentiation of polymorphonuclear neutrophils to dendritic-like cells at the site of inflammation in rheumatoid arthritis: evidence for activation by T cells Ann Rheum Dis, October 1, 2005; 64(10): 1436 - 1442. [Abstract] [Full Text] [PDF]
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H. Crandall, Y. Ma, D. M. Dunn, R. S. Sundsbak, J. F. Zachary, P. Olofsson, R. Holmdahl, J. H. Weis, R. B. Weiss, C. Teuscher, et al. Bb2Bb3 Regulation of Murine Lyme Arthritis Is Distinct from Ncf1 and Independent of the Phagocyte Nicotinamide Adenine Dinucleotide Phosphate Oxidase Am. J. Pathol., September 1, 2005; 167(3): 775 - 785. [Abstract] [Full Text] [PDF]
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D. J. Allendorf, J. Yan, G. D. Ross, R. D. Hansen, J. T. Baran, K. Subbarao, L. Wang, and B. Haribabu C5a-Mediated Leukotriene B4-Amplified Neutrophil Chemotaxis Is Essential in Tumor Immunotherapy Facilitated by Anti-Tumor Monoclonal Antibody and {beta}-Glucan J. Immunol., June 1, 2005; 174(11): 7050 - 7056. [Abstract] [Full Text] [PDF]
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G. M. Watts, F. J. M. Beurskens, I. Martin-Padura, C. M. Ballantyne, L. B. Klickstein, M. B. Brenner, and D. M. Lee Manifestations of Inflammatory Arthritis Are Critically Dependent on LFA-1 J. Immunol., March 15, 2005; 174(6): 3668 - 3675. [Abstract] [Full Text] [PDF]
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S. L. Pull, J. M. Doherty, J. C. Mills, J. I. Gordon, and T. S. Stappenbeck Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury PNAS, January 4, 2005; 102(1): 99 - 104. [Abstract] [Full Text] [PDF]
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 R. A. Clemens, S. A. Newbrough, E. Y. Chung, S. Gheith, A. L. Singer, G. A. Koretzky, and E. J. Peterson PRAM-1 Is Required for Optimal Integrin-Dependent Neutrophil Function Mol. Cell. Biol., December 15, 2004; 24(24): 10923 - 10932. [Abstract] [Full Text] [PDF]
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S. D. Swain, T. W. Wright, P. M. Degel, F. Gigliotti, and A. G. Harmsen Neither Neutrophils nor Reactive Oxygen Species Contribute to Tissue Damage during Pneumocystis Pneumonia in Mice Infect. Immun., October 1, 2004; 72(10): 5722 - 5732. [Abstract] [Full Text] [PDF]
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C. R. Brown, V. A. Blaho, and C. M. Loiacono Treatment of Mice with the Neutrophil-Depleting Antibody RB6-8C5 Results in Early Development of Experimental Lyme Arthritis via the Recruitment of Gr-1- Polymorphonuclear Leukocyte-Like Cells Infect. Immun., September 1, 2004; 72(9): 4956 - 4965. [Abstract] [Full Text] [PDF]
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P. Anderson, K. Phillips, G. Stoecklin, and N. Kedersha Post-transcriptional regulation of proinflammatory proteins J. Leukoc. Biol., July 1, 2004; 76(1): 42 - 47. [Abstract] [Full Text] [PDF]
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B. T. Wipke, Z. Wang, W. Nagengast, D. E. Reichert, and P. M. Allen Staging the Initiation of Autoantibody-Induced Arthritis: A Critical Role for Immune Complexes J. Immunol., June 15, 2004; 172(12): 7694 - 7702. [Abstract] [Full Text] [PDF]
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S. Szanto, I. Gal, A. Gonda, T. T. Glant, and K. Mikecz Expression of L-Selectin, but Not CD44, Is Required for Early Neutrophil Extravasation in Antigen-Induced Arthritis J. Immunol., June 1, 2004; 172(11): 6723 - 6734. [Abstract] [Full Text] [PDF]
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K. Phillips, N. Kedersha, L. Shen, P. J. Blackshear, and P. Anderson Arthritis suppressor genes TIA-1 and TTP dampen the expression of tumor necrosis factor {alpha}, cyclooxygenase 2, and inflammatory arthritis PNAS, February 17, 2004; 101(7): 2011 - 2016. [Abstract] [Full Text] [PDF]
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F. F. Shih, L. Mandik-Nayak, B. T. Wipke, and P. M. Allen Massive Thymic Deletion Results in Systemic Autoimmunity through Elimination of CD4+ CD25+ T Regulatory Cells J. Exp. Med., February 2, 2004; 199(3): 323 - 335. [Abstract] [Full Text] [PDF]
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F. Hong, R. D. Hansen, J. Yan, D. J. Allendorf, J. T. Baran, G. R. Ostroff, and G. D. Ross {beta}-Glucan Functions as an Adjuvant for Monoclonal Antibody Immunotherapy by Recruiting Tumoricidal Granulocytes as Killer Cells Cancer Res., December 15, 2003; 63(24): 9023 - 9031. [Abstract] [Full Text] [PDF]
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J. C. Clohisy, B. C. Roy, C. Biondo, E. Frazier, D. Willis, S. L. Teitelbaum, and Y. Abu-Amer Direct Inhibition of NF-{kappa}B Blocks Bone Erosion Associated with Inflammatory Arthritis J. Immunol., November 15, 2003; 171(10): 5547 - 5553. [Abstract] [Full Text] [PDF]
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K. S. Nandakumar, L. Svensson, and R. Holmdahl Collagen Type II-Specific Monoclonal Antibody-Induced Arthritis in Mice: Description of the Disease and the Influence of Age, Sex, and Genes Am. J. Pathol., November 1, 2003; 163(5): 1827 - 1837. [Abstract] [Full Text] [PDF]
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J. S. Zhou, D. S. Friend, A. M. Feldweg, M. Daheshia, L. Li, K. F. Austen, and H. R. Katz Prevention of Lipopolysaccharide-induced Microangiopathy by gp49B1: Evidence for an Important Role for gp49B1 Expression on Neutrophils J. Exp. Med., October 20, 2003; 198(8): 1243 - 1251. [Abstract] [Full Text] [PDF]
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G. J. Wright, H. Cherwinski, M. Foster-Cuevas, G. Brooke, M. J. Puklavec, M. Bigler, Y. Song, M. Jenmalm, D. Gorman, T. McClanahan, et al. Characterization of the CD200 Receptor Family in Mice and Humans and Their Interactions with CD200 J. Immunol., September 15, 2003; 171(6): 3034 - 3046. [Abstract] [Full Text] [PDF]
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J.-Y. Choe, B. Crain, S. R. Wu, and M. Corr Interleukin 1 Receptor Dependence of Serum Transferred Arthritis Can be Circumvented by Toll-like Receptor 4 Signaling J. Exp. Med., February 17, 2003; 197(4): 537 - 542. [Abstract] [Full Text] [PDF]
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E. P. Grant, D. Picarella, T. Burwell, T. Delaney, A. Croci, N. Avitahl, A. A. Humbles, J.-C. Gutierrez-Ramos, M. Briskin, C. Gerard, et al. Essential Role for the C5a Receptor in Regulating the Effector Phase of Synovial Infiltration and Joint Destruction in Experimental Arthritis J. Exp. Med., December 2, 2002; 196(11): 1461 - 1471. [Abstract] [Full Text] [PDF]
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M. Corr and B. Crain The Role of Fc{gamma}R Signaling in the K/B x N Serum Transfer Model of Arthritis J. Immunol., December 1, 2002; 169(11): 6604 - 6609. [Abstract] [Full Text] [PDF]
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L. Mandik-Nayak, B. T. Wipke, F. F. Shih, E. R. Unanue, and P. M. Allen Despite ubiquitous autoantigen expression, arthritogenic autoantibody response initiates in the local lymph node PNAS, October 29, 2002; 99(22): 14368 - 14373. [Abstract] [Full Text] [PDF]
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M. Corr and G. S. Firestein Innate Immunity as a Hired Gun: But Is It Rheumatoid Arthritis? J. Exp. Med., April 15, 2002; 195(8): F33 - F35. [Full Text] [PDF]
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, p < 0.013). Ab depletion of neutrophils
becomes progressively less effective at reversing disease after
sustained joint inflammation.