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*
Alexion Pharmaceuticals, Inc., New Haven, CT 06511; and
Department of Pathology, Yale University School of Medicine, New Haven, CT 06520
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-producing T cells in the periphery and
substantial intra-articular deposition of complement-fixing IgG Abs.
Nevertheless, these C5-deficient mice are highly resistant to the
induction of CIA. These data provide evidence for an important role of
complement in Ab-triggered inflammation and in the pathogenesis of
autoimmune arthritis. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In CIA, both T and B cell responses play a role in disease pathogenesis after immunization with type II collagen. The role of T cells in CIA has been illustrated by the resistance to disease induction of various mouse strains with germline deletions of TCR genes (9) as well as by the ability of anti-T cell reagents such as anti-CD4 mAbs to block disease onset (10, 11). However, T cells appear to play their predominant role in the initiation of disease because anti-CD4 mAb treatment has only marginal effects on the progression of established arthritis (12, 13).
Several lines of evidence demonstrate that B cells are also critical for the development of CIA. For instance, B cell-deficient mice on an otherwise genetically susceptible background do not develop arthritis (14). Further, transfer studies have shown that autoantibodies are directly pathogenic and can provoke at least some of the manifestations of joint inflammation (15, 16).
Abs, particularly as constituents of Ab/Ag immune complexes, play a central role in triggering inflammation in a number of autoimmune diseases (17). It has been proposed that immune complexes initiate inflammatory responses either via activation of the complement system (18) or, alternatively, by the direct engagement and activation of FcR-bearing inflammatory cells (19). Although the concept of immune complex-triggered inflammation via activation of the complement cascade is well established, recent studies in FcR-deficient mutant mice have promoted an opposing view that immune complexes induce inflammation predominantly through FcR engagement, with complement proteins subserving primarily immunoregulatory functions (19).
Studies to evaluate the role of complement in CIA, in particular the proinflammatory byproducts generated by activation of the C5 component, have led to conflicting conclusions, ranging from an essential role to virtually no role of C5 in disease progression (20, 21, 22, 23). Most of these studies have utilized F2 backcross analyses between CIA-susceptible and -resistant mouse strains to examine the contribution of various genetic loci to arthritis pathogenesis. As such studies have provided evidence for at least five to six disease-predisposing loci influencing severity and susceptibility to CIA (20, 21, 22, 23, 24), the conflicting conclusions regarding the role of complement in CIA pathogenesis may have reflected variable expression of distinct CIA susceptibility loci in individual F2 progeny.
To examine the role of C5 in arthritis pathogenesis on a constant genetic background strongly associated with CIA susceptibility, we have generated inbred DBA/1LacJ mice congenic for a mutant C5 allele. After collagen immunization, these C5-deficient animals were almost totally resistant to the development of CIA, despite generating unimpaired collagen-specific T cell and Ab responses. The results provide clear evidence that complement activation can play a major role in initiating immune complex-triggered inflammation and joint destruction.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Generation of C5-deficient DBA/1 mice (C5D-DBA/1) was accomplished as follows. C5D B10.D2/oSn mice (The Jackson Laboratory, Bar Harbor, ME) were crossed with DBA/1LacJ mice (The Jackson Laboratory). F1 and subsequent offspring heterozygous for the mutant C5 allele were backcrossed to DBA/1LacJ for six generations and then intercrossed to produce homozygous C5D-DBA/1 and C5-sufficient DBA/1 (C5S-DBA/1) lines. The C5 genotype was determined by PCR performed on tail DNA using a pair of primers (5'-CAC GAT AAT GGG AGT CAT CTG CG-3' and 5'- AAG TTG GAG TGT GGT CTT TGG GCC-3') that amplify a 280-bp DNA fragment from both wild-type and C5 mutant DNA. This fragment encodes a HindIII site that is selectively destroyed by the mutation in the C5 gene, such that HindIII (New England BioLabs, Beverly, MA) digestion (37°C overnight before resolution on a 3% agarose gel (FMC BioProducts, Rockland, ME)) selectively cleaves the wild type but not the C5 mutant PCR product into 150- and 130-bp fragments. Wild-type DBA/1LacJ mice were purchased from The Jackson Laboratory. Because the C5S-DBA/1 mice demonstrated a 100% incidence of CIA after type II collagen (CII) challenge (see below), these animals were used interchangeably with wild-type DBA/1LacJ mice in some experiments.
Induction and clinical evaluation of CIA
Bovine type II collagen (BCII) or mouse type II collagen (MCII) (Elastin Products, Owensville, MO) was dissolved in 0.01 M acetic acid by stirring overnight at 4°C at a concentration of 4 mg/ml. CFA was prepared by the addition of desiccated Mycobacterium tuberculosis H37RA (Difco, Detroit, MI) to IFA (Difco) at a concentration of 2 mg/ml. The solution of CII (4 mg/ml) was emulsified in an equal volume of CFA, and mice were immunized with 200 µg CII and 100 µg mycobacteria injected intradermally at the base of the tail in a volume of 100 µl. After 21 days, all mice were reimmunized using the identical protocol with either heterologous BCII or autologous MCII. Animals were examined daily beginning on the day of reimmunization for the appearance of arthritis. The presence of arthritis was determined by examining, measuring, and scoring each of the forepaws and hindpaws. The severity of arthritis in each affected paw was graded according to an established scoring system as: 0, normal joint; 1, mild/moderate visible erythema and swelling; 2, severe erythema and swelling affecting an entire paw or joint; and 3, deformed paw or joint with ankylosis. The sum of the scores for all four paws in each mouse was used as an arthritis index (maximum score/animal = 12) to represent overall disease severity and progression in an animal. Mice were sacrificed 6 wk after the initial immunization, at which time the joints were prepared for histologic evaluation.
T cell stimulation assays
Lymph node cells taken from animals 7–10 days after reimmunization with BCII were analyzed for specific T cell responses to BCII or MCII. T cells (5 x 105/well) were incubated with 20 µg/ml of BCII, MCII, OVA, or BSA in flat-bottom 96-well plates. The culture medium was HL-1 (BioWhittaker, Walkersville, MD) supplemented with 10% medium 199 (Cellgro Mediatech, Herndon, VA), 5 x 10-5 M 2-ME, 10 mM HEPES buffer, 1% L-glutamine, 1% sodium pyruvate, and 1% penstrep. The cultures were incubated at 37°C in 5% CO2 for 5–6 days. Eighteen hours before harvesting, 1 µCi of [3H]thymidine was added to each well. Results are expressed as stimulation index, which was calculated as the fold increase in the cpm of T cells cultured with BCII, MCII, or OVA relative to cpm of T cells cultured with medium alone.
Analysis of BCII-induced production of TNF-
Lymph node cells prepared from animals 12 days after
reimmunization with BCII were analyzed for BCII-specific TNF-
production. Cells (6–8 x 106/well) were
incubated with 20 µg/ml of BCII or OVA in individual wells of a
24-well plate. The cultures were incubated overnight at 37°C. Five
hours before harvesting the cells, 1 µg/ml of brefeldin A (GolgiPlug;
PharMingen, San Diego, CA) was added to each well. Cells were washed
with staining buffer (HBSS with 5% FCS and 0.02% sodium azide) and
incubated with FITC-conjugated rat anti-mouse CD4 (clone RM4-5) and
anti-mouse CD8 (clone 57.62) (PharMingen) before fixation and
permeabilization with 4% paraformaldehyde and 1% saponin
(Cytofix/Cytoperm Kit; PharMingen). After washing two times with
saponin solution, cells were incubated with PE-labeled anti-TNF-
mAb (clone MP6-XT22; PharMingen) or with a PE-labeled control rat IgG1
Ab (clone R3-34; PharMingen) at 4°C for 30 min. Cells were analyzed
by flow cytometry on a FACScan flow cytometer (Becton Dickinson,
Mountain View, CA) with logarithmic scales. CellQuest software (Becton
Dickinson) was used for the analysis of the data. Analyses of the
percentage of TNF--producing cells were performed on lymphoid
populations gated by forward and side scatter.
Quantification of anti-BCII Abs
Mice were bled 35 days after initial immunization with BCII. Standard ELISA assays were preformed to measure the serum levels, specificity, and subtype of anti-CII Abs. Briefly, 96-well flat-bottom ELISA plates (VWR, Philadelphia, PA) were coated with BCII or MCII (Elastin Products) at 8 µg/ml in TBS at 37°C for 1 h and were then blocked with BSA before incubation with the serum samples (1:20 dilution) obtained from C5S- or C5D-DBA/1 mice. The plates were washed and then incubated with HRP-coupled Abs to mouse IgG, IgG1, IgG2a, IgG2b, or IgG3 obtained from a murine Ig isotype subtyping kit (Boehringer Mannheim, Mannheim Germany). Anti-CII Ab titer was reported as the increase in the number of O.D. units of CII-specific Ab measured in the immunized C5S- or C5D-DBA/1 mice compared with those measured in unimmunized control DBA/1LacJ mice.
Histopathology
Mice from each group were sacrificed, and their limbs were fixed
in 10% buffered formalin and decalcified in diluted rapid bone
decalcification (Darlco, Oradell, NJ) solution for 1–3 days. The
tissue was then processed and embedded in paraffin with a VIP tissue
processor (Miles, Elkhart, IN). Five-micrometer tissue sections were
stained with hematoxylin and eosin (H&E) using standard methodology. To
detect intra-articular IgG and complement deposition, the limbs were
decalcified in a 0.1 M Tris solution containing 10% EDTA and 7.5%
polyvinyl pyrrolidone for 14 days and frozen in OCT at -80°C.
Five-micrometer sections were then prepared and stained with
FITC-labeled goat anti-mouse IgG, IgM, IgA (H+L) Ab (Zymed, San
Francisco, CA) or with FITC-conjugated sheep anti-mouse C3
(Biodesign, Kennebunk, ME) at a dilution of 1 to 50. FITC-conjugated
goat anti-human IgG 
-chain Ab (Sigma, St. Louis, MO) and
FITC-conjugated goat anti-human C3 (Cappel, West Chester, PA) were
used as negative controls on samples from the CII-immunized
animals.
Arthus reactions
Direct Arthus reactions were performed on C5D- and C5S-DBA/1 mice 45 days after initial BCII immunization. The mice were shaved and injected intradermally with 200 µg BCII in 50 µl PBS or with 200 µg BSA in 50 µl PBS. Intradermal injections of BCII or BSA were also performed in animals that had not been previously immunized with CII. After 24 h, animals were sacrificed. Skin biopsies were taken through the perimeter of the lesions; the areas of the macroscopic skin lesions as indicated by hemorrhagic responses from the inside of the skin were determined by multiplying the maximal transverse widths (in mm) in two perpendicular directions. Skin samples were either fixed in 10% buffered formalin for histological examination as previously described (25) or processed for myeloperoxidase (MPO) activity (26).
Hemolytic assay
After initial screening with PCR and analysis of serum C5-mediated hemolytic activity from each C5S and C5D littermate, animals were then grouped randomly and immunized with BCII. Serum samples were again harvested from representative C5D- and C5S-DBA/1 mice 35 days after initial immunization with BCII and were reassayed for hemolytic activity. Sera were prepared, and the serum hemolytic activity was measured as previously reported (25).
Statistical analysis
Student’s t tests assuming two samples with unequal variance were performed with the Microsoft Excel 97 data analysis program. The two-tail p value is represented. Contingency table analysis was performed with Statview statistical analysis program (Brain Power, Calabasas, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To examine the role of complement activation in the pathogenesis
of joint inflammation on a highly susceptible genetic background,
DBA/1LacJ mice were bred to C5D B10.D2.oSn animals. The
F1 offspring were backcrossed to parental
DBA/1LacJ mice; F2 and subsequent progeny
heterozygous for C5 deficiency were successively backcrossed to
DBA/1LacJ for six generations and were then intercrossed to produce
homozygous C5D- and C5S-DBA/1 lines. The mutant C5 genotype and
functional complement deficiency of the C5D-DBA/1 mice were confirmed,
respectively, by PCR and by demonstrating an absence of hemolytic
activity in the sera of these animals compared with their C5S-DBA/1
counterparts (Fig. 1
).
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To assess the effect of C5 deficiency on the induction of collagen
arthritis in the DBA/1 background, C5D-DBA/1, C5S-DBA/1, and wild-type
DBA/1LacJ mice were immunized with heterologous CII in CFA and then
boosted 3 wk later with either heterologous BCII or autologous MCII.
Mice were evaluated clinically for the presence of arthritis, and the
disease severity was quantitated by measurement of the arthritis index.
Among mice immunized and then boosted with heterologous CII, clinically
severe arthritis, characterized by redness and swelling and involving
multiple limbs, was observed by 4 wk after initial disease induction in
90% of wild-type DBA/1LacJ mice and in 100% of C5S-DBA/1 mice (Table I and Fig. 2). Thus, the penetrance of arthritis in
the C5S-DBA/1 mouse line was complete, with an incidence and severity
of disease equivalent to that of DBA/1LacJ animals. In marked contrast,
clinically significant arthritis was observed in only three of 20
immunized C5D-DBA/1 mice (Table I and Fig. 2). In particular, the three
C5D animals with arthritis had disease clinically and pathologically
(Fig. 5) similar to that observed in the C5S-DBA/1 mice (unpublished
observations). Hemolytic activity was reassessed in both C5S and C5D
mice at day 35 postimmunization to confirm the level of functional
complement activity (Fig. 1
). C5 deficiency was reconfirmed in all
three arthritic C5D animals as shown by their low-level serum
C5-mediated hemolytic activity (average, 9.43%) during the course of
joint inflammation, which was similar to the level found in the
arthritis-free C5D littermates (average, 8.2%; p =
0.88).
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and Fig. 2). Normal cellular and humoral immune responses in C5D-DBA/1 mice
To determine the potential influence of C5 deficiency on immune
responses to heterologous and autologous CII, representative C5D-DBA/1
mice were immunized and boosted with native bovine collagen in CFA, and
their CII-specific cellular and humoral immune responses were assessed
in comparison with those of DBA/1LacJ animals. The C5D-DBA/1 mice
manifested significant T cell proliferative responses to both the
heterologous bovine as well as autologous mouse collagens, both roughly
equivalent in magnitude to those of the wild-type DBA/1LacJ mice (Fig. 3A). Furthermore, examination
of cytokine production via intracellular immunofluorescence
demonstrated collagen-specific induction of the proinflammatory
cytokine TNF- in CD4+ T cells from C5D-DBA/1
mice, which again is equivalent to that observed in wild-type mice
(Fig. 3B). Finally, comparable levels of heterologous and
autologous collagen-specific IgG, with similar isotype distribution,
were elicited in primed arthritis-free C5D-DBA/1 and arthritic
C5S-DBA/1 mice (Fig. 3C). Interestingly, preliminary
evidence suggested that higher levels of antiautologous murine collagen
Ab may be present in arthritic C5D-DBA/1 mice, with increased
distribution toward IgG1 and IgG2a subclasses (data not shown).
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Histologic analysis was performed to confirm the clinical
observations. Significant synovial cell proliferation accompanied by
neutrophil, lymphocytic, and plasma cell infiltrates, invasive pannus
formation, and cartilage and bone erosion were observed in both
arthritic C5S-DBA/1 and C5D-DBA/1 mice (Figs. 4B and
5). Thus, the arthritis in the few C5D
animals that developed disease was histologically similar to that of
C5S littermates. In contrast, the joints of the majority of C5D-DBA/1
mice that had no clinical signs of arthritis were free of inflammatory
synovial infiltrates, pannus, and evidence of cartilage and bone damage
(Fig. 4C), which made them indistinguishable from joints of
normal nonimmunized animals (Fig. 4A). Importantly,
immunohistochemical analysis revealed equivalent intra-articular
deposition of IgG (Fig. 4, E and F) and C3 (Fig. 4, H and I) on the cartilaginous surfaces of
primed C5D-DBA/1 and C5S-DBA/1 animals.
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-producing T
cells in peripheral lymphoid tissue as well as intra-articular IgG and
C3 deposition, C5D-DBA/1 animals were highly resistant to the induction
of inflammatory arthritis. Relative contribution of C5 to Ab-driven inflammation may depend on tissue site
Previous reports have indicated that Ab/Ag immune complex-driven
inflammation in the murine reverse-passive Arthus reaction is
relatively complement-independent and rather appears to be
initiated predominantly by direct Ig binding and activation of
FcR-bearing inflammatory cells (29). We evaluated this
issue by eliciting direct Arthus reactions in collagen-primed
arthritis-free C5D-DBA/1 and arthritic C5S-DBA/1 mice, respectively.
After confirming the presence of circulating anti-collagen Abs, we
injected collagen intradermally and then quantitated the resulting
cutaneous inflammatory responses. Intradermal injection of CII elicited
roughly equivalent Arthus reactions in C5D and C5S animals when
evaluated with respect to edema and hemorrhage (Fig. 6A) as
well as neutrophil infiltration (Fig. 6B). The specificity
of the reactions was ascertained by the absence of measurable
inflammatory responses after intradermal injection with BSA (Fig. 6) or
after intradermal injection of BCII to DBA/1 mice that had not been
immunized with BCII (data not shown). Histologically, the Arthus
reactions in both C5S and C5D animals were characterized by edema and
intense inflammatory cell infiltrates comprised predominantly of
neutrophils (Fig. 7). Thus, in
actively immunized C5D-DBA/1 animals, pathologic
inflammatory responses were elicited after Ag binding and deposition of
collagen-specific Abs in the skin but not in the joint.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The results of this study provide clear evidence that activation of complement may play a critical role in the inflammatory process triggered by Ab and immune complex deposition. Thus, despite abundant Ig and C3 deposition within the joints of C5D-DBA/1 animals, virtually no inflammation ensued.
The paradigm of complement as an important mediator of humoral inflammation has been recently challenged by studies performed in FcR-deficient mouse models, which have shown an apparent predominant role for direct FcR engagement in the initiation of immune complex-triggered inflammatory responses (19, 29). These studies have led to the proposal that the role of the complement system is largely immunoregulatory and only minimally inflammatory, notwithstanding the well-documented proinflammatory activities of activated complement byproducts in multiple models of inflammation (30).
There are several factors that could influence the relative
contributions of complement vs FcR inflammatory pathways to a
particular immune complex-triggered inflammatory response. These
include Ab isotype and titer as well as the site of immune complex
deposition. With respect to Ig isotype, FcR mechanisms could
predominate with immune complexes comprised of
non-complement-fixing Abs or after deposition in sites with abundant
resident FcR-bearing inflammatory cells. Conversely, complement-driven
inflammation may dominate when immune complexes contain Ig-constant
regions poorly bound by FcR or when leukocytes must be attracted to an
inflammatory site. Indeed, the joints of the majority of
collagen-immunized C5D-DBA/1 mice in the current study were free of
inflammatory cells, despite the presence of activated collagen-specific
T cells as well as TNF--expressing CD11b+
mononuclear cells (data not shown) in the periphery of these animals.
Presumably, inflammatory cell recruitment to the joint by C5a or by
other complement-induced chemotactic factors is required for disease
initiation in this model. The recent demonstration of C5a receptors on
activated T cells is consistent with this interpretation
(31). In addition, Ab titer may influence humoral pathways
of inflammation. For example, it has been shown that the complement
dependence of Ab-mediated renal inflammation is lost at higher Ab doses
(32). This effect is observed even in the presence of
upstream complement inhibition, ruling out an enhanced role of
C3-dependent mechanisms (C3a and C3b) under these conditions
(32). Consistent with this, it is of interest that our
preliminary evidence suggests that the arthritic C5D animals in this
study had higher anti-murine CII autoantibody titers than their
nonarthritic counterparts. Further studies will be performed to
confirm this and to explore the pathogenesis of the articular
inflammation that occurs infrequently in C5D animals.
Finally, complement and FcR could act in concert in many inflammatory
responses, with complement both attracting and activating FcR-bearing
cells at sites of inflammation. Indeed, a role for FcR in the
pathogenesis of collagen-induced arthritis was suggested by the recent
observation that genetic deficiency of the inhibitory FcR
RIIB
rendered resistant H-2b mice susceptible to this disease
(33).
A role for humoral immunity in arthritis pathogenesis is suggested by evidence derived from preclinical animal models as well as patients with RA. A requirement for collagen-specific Ab generation in the progression of collagen-induced arthritis is well documented (5, 6, 8). Moreover, a recently described TCR transgenic mouse model of spontaneously arising polyarthritis, with many of the characteristics of human RA, was found to require the production of arthritogenic Igs for disease development (34). In this model, arthritis arose serendipitously by crossing a C57BL/6 TCR transgenic mouse line onto the nonobese diabetic genetic background (35). As is the case for collagen-induced arthritis and human RA, systemic T cell reactivity in this model was required predominantly for disease initiation rather than for the progression of established joint inflammation (34).
Considerable evidence also exists for the participation of humoral immune mechanisms in the inflammatory process in human RA (36, 37, 38). Thus, besides the accumulation of T cells, rheumatoid synovitis is also characterized by the infiltration of B cells that differentiate locally into Ab-producing plasma cells (39, 40, 41). The infiltrating plasma cells produce both polyclonal Ig and the autoantibody rheumatoid factors. The overall importance of humoral immunity in the disease process is suggested by the observation that RA disease severity is correlated with the degree of rheumatoid factor seropositivity (42, 43). As a consequence of the substantial local Ig production, Ig levels are markedly elevated in RA synovium. The local Ig production leads to abundant immune complex deposition throughout the joint and consequent complement activation through both the classical and alternative pathways (44). Immune complexes in RA have been proposed to play a role in the generation of invasive pannus and in irreversible cartilage matrix degeneration. Indeed, B cells and immune complexes are often located adjacent to and within sites of tissue destruction in RA joints.
Ab and immune complex deposition within RA joints trigger complement activation. A significant role for complement in the pathologic inflammatory process in RA is supported by a variety of molecular and pathologic evidence (45, 46, 47, 48, 49, 50, 51, 52, 53). First, extensive local complement activation has been clearly demonstrated in synovial tissue and the synovial fluid of affected joints of patients with RA. As a result, total hemolytic complement, C3, and C4 are markedly diminished in synovial fluid relative to total protein concentration. Measurement of the activated proinflammatory complement byproducts that are generated after C5 cleavage, C5a and C5b-9, has also shown significant elevations in RA joints (45, 46, 47, 48, 49, 50, 51, 52, 53). C5a and C5b-9 can mediate multiple proinflammatory activities, including leukocyte chemotaxis, adhesion molecule up-regulation, cellular activation with consequent release of additional mediators, and cell lysis (30). Studies have shown elevated levels of C5a in synovial fluid and have further correlated the levels of C5a with the number of synovial fluid neutrophils, the predominant cell type in inflammatory synovial fluid exudates in RA (48). These results have implicated C5a as a critical chemotactic factor responsible for neutrophil accumulation within the RA joint. Extensive deposition of the C5b-9 complex has also been documented throughout inflamed joint tissues in RA (45, 46, 47, 49, 50, 51, 52, 53). Further, the C5b-9 deposits in synovial tissue, both in the synovial cell layer and on stromal mononuclear cells, have been shown to correlate well with the extent of inflammatory synovitis (49). It has also been shown that abundant deposition of complement-containing immune complexes occurs within and adjacent to cartilage surfaces in RA (50). Coupled with the demonstrated toxicity of terminal complement for human chondrocytes (50), this finding implicates complement as a possible mediator of cartilage degradation in RA.
The critical role of complement in the pathogenesis of arthritis in the
congenic C5D-DBA/1 mouse strain demonstrated in this report, together
with evidence for humoral autoimmunity and complement activation in RA
joints, provides a rationale for the therapeutic inhibition of the
complement system in this disease. Clinical trials are ongoing to test
this hypothesis. Further, the recent proposal (34) that
joint lesions in RA may be precipitated by Ab and amplified by
cytokines such as TNF- raises the interesting possibility that
additive clinical benefit could be derived from concurrent complement
and cytokine blockade. In fact, synergism between TNF and complement C5
has been demonstrated in several preclinical models of inflammation
(54, 55, 56, 57).
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: CIA, collagen-induced arthritis; RA, rheumatoid arthritis; C5D-DBA/1, C5-deficient DBA/1LacJ mice; C5S-DBA/1, C5-sufficient DBA/1LacJ mice; CII, type II collagen; BCII, bovine type II collagen; MCII, mouse type II collagen; H&E, hematoxylin and eosin; MPO, myeloperoxidase.
Received for publication July 15, 1999. Accepted for publication February 9, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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X. Yu, K. Bauer, P. Wernhoff, D. Koczan, S. Moller, H.-J. Thiesen, and S. M. Ibrahim Fine Mapping of Collagen-Induced Arthritis Quantitative Trait Loci in an Advanced Intercross Line J. Immunol., November 15, 2006; 177(10): 7042 - 7049. [Abstract] [Full Text] [PDF]
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A.-K. B. Lindqvist, M. Johannesson, A. C. M. Johansson, K. S. Nandakumar, A. M. Blom, and R. Holmdahl Backcross and Partial Advanced Intercross Analysis of Nonobese Diabetic Gene-Mediated Effects on Collagen-Induced Arthritis Reveals an Interactive Effect by Two Major Loci J. Immunol., September 15, 2006; 177(6): 3952 - 3959. [Abstract] [Full Text] [PDF]
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 T. Honda, E. Segi-Nishida, Y. Miyachi, and S. Narumiya Prostacyclin-IP signaling and prostaglandin E2-EP2/EP4 signaling both mediate joint inflammation in mouse collagen-induced arthritis J. Exp. Med., February 21, 2006; 203(2): 325 - 335. [Abstract] [Full Text] [PDF]
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 A. Sjoberg, P. Onnerfjord, M. Morgelin, D. Heinegard, and A. M. Blom The Extracellular Matrix and Inflammation: FIBROMODULIN ACTIVATES THE CLASSICAL PATHWAY OF COMPLEMENT BY DIRECTLY BINDING C1q J. Biol. Chem., September 16, 2005; 280(37): 32301 - 32308. [Abstract] [Full Text] [PDF]
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 E.-K. Lee, S.-M. Kang, D.-J. Paik, J. M. Kim, and J. Youn Essential roles of Toll-like receptor-4 signaling in arthritis induced by type II collagen antibody and LPS Int. Immunol., March 1, 2005; 17(3): 325 - 333. [Abstract] [Full Text] [PDF]
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 M. O. Judex and B. M. Mueller Plasminogen Activation/Plasmin in Rheumatoid Arthritis: Matrix Degradation and More Am. J. Pathol., March 1, 2005; 166(3): 645 - 647. [Abstract] [Full Text] [PDF]
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J. Li, A. Ny, G. Leonardsson, K. S. Nandakumar, R. Holmdahl, and T. Ny The Plasminogen Activator/Plasmin System Is Essential for Development of the Joint Inflammatory Phase of Collagen Type II-Induced Arthritis Am. J. Pathol., March 1, 2005; 166(3): 783 - 792. [Abstract] [Full Text] [PDF]
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A.-S. Hansson, M. Johannesson, L. Svensson, K. S. Nandakumar, D. Heinegard, and R. Holmdahl Relapsing Polychondritis, Induced in Mice with Matrilin 1, Is an Antibody- and Complement-Dependent Disease Am. J. Pathol., March 1, 2004; 164(3): 959 - 966. [Abstract] [Full Text] [PDF]
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K. A. Latham, A. Zamora, H. Drought, S. Subramanian, A. Matejuk, H. Offner, and E. F. Rosloniec Estradiol Treatment Redirects the Isotype of the Autoantibody Response and Prevents the Development of Autoimmune Arthritis J. Immunol., December 1, 2003; 171(11): 5820 - 5827. [Abstract] [Full Text] [PDF]
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M. Szczepanik, M. Akahira-Azuma, K. Bryniarski, R. F. Tsuji, I. Kawikova, W. Ptak, C. Kiener, R. A. Campos, and P. W. Askenase B-1 B Cells Mediate Required Early T Cell Recruitment to Elicit Protein-Induced Delayed-Type Hypersensitivity J. Immunol., December 1, 2003; 171(11): 6225 - 6235. [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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P. W. Askenase Mast Cells and the Mediation of T-Cell Recruitment in Arthritis N. Engl. J. Med., September 25, 2003; 349(13): 1294 - 1294. [Full Text] [PDF]
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N. K. Banda, D. M. Kraus, M. Muggli, A. Bendele, V. M. Holers, and W. P. Arend Prevention of Collagen-Induced Arthritis in Mice Transgenic for the Complement Inhibitor Complement Receptor 1-Related Gene/Protein y J. Immunol., August 15, 2003; 171(4): 2109 - 2115. [Abstract] [Full Text] [PDF]
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R. A. Fava, E. Notidis, J. Hunt, V. Szanya, N. Ratcliffe, A. Ngam-ek, A. R. de Fougerolles, A. Sprague, and J. L. Browning A Role for the Lymphotoxin/LIGHT Axis in the Pathogenesis of Murine Collagen-Induced Arthritis J. Immunol., July 1, 2003; 171(1): 115 - 126. [Abstract] [Full Text] [PDF]
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T. Kagari, D. Tanaka, H. Doi, and T. Shimozato Essential Role of Fc{gamma} Receptors in Anti-Type II Collagen Antibody-Induced Arthritis J. Immunol., April 15, 2003; 170(8): 4318 - 4324. [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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R. F. Tsuji, M. Szczepanik, I. Kawikova, V. Paliwal, R. A. Campos, A. Itakura, M. Akahira-Azuma, N. Baumgarth, L. A. Herzenberg, and P. W. Askenase B Cell-dependent T Cell Responses: IgM Antibodies Are Required to Elicit Contact Sensitivity J. Exp. Med., November 18, 2002; 196(10): 1277 - 1290. [Abstract] [Full Text] [PDF]
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C. D. Kaplan, S. K. O'Neill, T. Koreny, M. Czipri, and A. Finnegan Development of Inflammation in Proteoglycan-Induced Arthritis Is Dependent on Fc{gamma}R Regulation of the Cytokine/Chemokine Environment J. Immunol., November 15, 2002; 169(10): 5851 - 5859. [Abstract] [Full Text] [PDF]
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 C. H. Nielsen and R. G. Q. Leslie Complement's participation in acquired immunity J. Leukoc. Biol., August 1, 2002; 72(2): 249 - 261. [Abstract] [Full Text] [PDF]
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M. A. Hietala, I.-M. Jonsson, A. Tarkowski, S. Kleinau, and M. Pekna Complement Deficiency Ameliorates Collagen-Induced Arthritis in Mice J. Immunol., July 1, 2002; 169(1): 454 - 459. [Abstract] [Full Text] [PDF]
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H. Ji, D. Gauguier, K. Ohmura, A. Gonzalez, V. Duchatelle, P. Danoy, H.-J. Garchon, C. Degott, M. Lathrop, C. Benoist, et al. Genetic Influences on the End-Stage Effector Phase of Arthritis J. Exp. Med., August 6, 2001; 194(3): 321 - 330. [Abstract] [Full Text] [PDF]
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