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Departments of
* Medical Biochemistry and
Rheumatology, Göteborg University, Göteborg, Sweden; and
Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
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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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Complement activation has previously been implicated in the pathogenesis of RA (8, 9). Complement components and activation products have been demonstrated both in the synovial fluid and in the synovial membrane of the affected joints (10, 11). Animals depleted of complement by cobra venom factor were found to be refractory to arthritis until their complement levels were recovered (12). However, as this depletion is achieved through an enormous activation of the complement system, the effects of which are both unknown and difficult to control, this approach has obvious drawbacks. Systemic administration of anti-C5 Ab prevented the onset of CIA and ameliorated established disease in this animal model (13). C5-deficient mice were partly resistant to CIA despite normal cellular and Ab responses to immunization with CII and substantial intra-articular deposition of complement-fixing Abs (14). These experiments could not elucidate the role of the earlier components of the complement activation cascade. Soluble complement receptor 1, a potent inhibitor of the classical and alternative complement pathways, prevented the progression of arthritis in both rats (15) and mice (16).
In this study, we have investigated the role of some of the early components of the complement cascade, C3 and factor B (FB), respectively, in the pathogenesis of CIA. The mice deficient for C3 or FB, previously generated in our laboratory (17, 18), were immunized with bovine CII and arthritis was evaluated both clinically and histopathologically. We show that the Ab response in C3-/- and FB-/- mice is impaired but can be boosted by repeated immunization. Regardless of the specific anti-CII Ab levels, the complement-deficient mice display reduction or almost complete absence of clinically or histologically verifiable arthritis. These results show that the classical pathway and possibly also the alternative pathway are involved in the pathogenesis of CIA.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mice carrying the C3 (17) or FB null allele (18), respectively, were backcrossed to the CIA-susceptible DBA/1J genetic background (Bomholtgaard, Ry, Denmark) for six generations. Animals heterozygous for the respective null mutation were intercrossed to generate homozygous C3-deficient (C3-/-), FB-deficient (FB-/-), and control lines. Mice were maintained at the transgenic core facility at Göteborg University under specific pathogen-free conditions. Routine screening of the mice for murine pathogens according to the recommendations of the Federation of European Laboratory Animal Science Associations was negative.
Collagen preparation
Bovine type II collagen (BCII) was prepared from nasal cartilage by pepsin digestion and subsequent purification as described previously (19). BCII was solubilized to a concentration of 2 mg/ml in 0.01 M acetic acid at 4°C with constant mixing overnight. For induction of CIA, BCII was emulsified with an equal volume (1:1) of CFA (Difco, Detroit, MI).
Induction and clinical evaluation of CIA
Male C3-/-, FB-/-, and control mice at the age of 8–12 wk were injected intradermally at the base of the tail with 50 µl of the BCII/CFA emulsion under light isofluorane anesthesia. In the booster group, the injection was repeated after 21 days.
Arthritis development was assessed by inspection three times a week by a blinded examiner. Clinical severity of arthritis was quantified according to a graded scale from 0 to 3 as follows: 0, normal; 1, detectable swelling in one joint; 2, swelling in more than one but not in all joints; and 3, severe swelling of the entire paw and/or ankylosis. Each paw was graded, and each mouse could achieve a maximum score of 12. A mean arthritic score value was calculated.
Quantification of anti-BCII Abs
Mice were bled from the tails at different time points after immunization, and individual sera were analyzed for CII-specific IgG, IgG1, and IgG2a Abs by ELISA. Microtiter plates (Maxisorp; Nunc, Roskilde, Denmark) were coated overnight at 4°C with 10 µg of native BCII in PBS. Plates were washed with PBS containing 0.05% Tween 20 (PBS/Tween), and serum samples were added in serial dilution with PBS/Tween and incubated for 2 h at room temperature. The plates were then washed and incubated for 2 h at room temperature with 50 µl of sheep anti-mouse IgG conjugated to HRP peroxidase (DAKO, Glostrup, Denmark) diluted 1/1000, anti-mouse IgG1, or anti-mouse IgG2a (Southern Biotechnology Associates, Birmingham, AL) diluted 1/2000 in PBS/Tween. After additional washings, the enzyme reaction was started by the addition of chromogen (20 mg of 1,2-phenylenediamine dihydrochloride (Sigma-Aldrich, St. Louis, MO)) and 10 µl of H2O2 in 75 ml of 0.1 M citrate/phosphate buffer, pH 5). The reaction was stopped by addition of 1 M H2SO4 after 4 min. The staining was quantified spectrophotometrically at 490 nm. A polyclonal anti-BCII standard with known Ab concentration was included on every microtiter plate to allow calculation of the Ab content using Softmax software (Molecular Devices, Menlo Park, CA). The standard was purified by affinity chromatography from pooled sera obtained from BCII-hyperimmunized mice.
Histopathology
All mice were killed on day 72, hind paws were fixed in 4% phosphate-buffered formaldehyde solution, and decalcified in Parengy’s decalcification solution overnight. The tissue was then processed and embedded in paraffin. Tissue sections (4 µm) were stained with H&E using standard methodology. The joints were studied by two blinded examiners (M.A.H. and I.-M.J.). Synovial hypertrophy was defined as a synovial membrane thickness of more than two cell layers (20). Pannus formation as well as cartilage and bone erosion were registered in the knee, ankle, talar, and toe joints. Each parameter was given a score of 0–3.
PCR and RFLP genotyping at the H-2 locus
DNA samples were collected from tail biopsies and purified by phenol-chisam extraction. The primers for H2-specific amplification were derived from Eb gene sequences (21): the forward primer 5'-CGACTGTAGAACCTTAGCCTG-3' and the reverse primer 5'-GTGGACACAATTCCTGTTTT-3'. The PCR amplification was conducted using 50–100 ng of purified DNA in the presence of 1.9 mM MgCl2 0.1% Tween 20, 10 mM of each dNTP, 12.5 pmol/µl each primer, 2 U Taq DNA polymerase including 10x PCR Buffer (Lifetech/InVitrogen, Carlsbad, CA), in a final volume of 40 µl. The PCR scheme was as follows: initial denaturation step at 94°C for 3 min, 35 cycles including a denaturation step at 93°C for 1 min, annealing at 58°C for 2 min, extension at 72°C for 2 min followed by a final extension at 72°C for 4 min in a thermal cycler (PerkinElmer, Norwalk, CT).
Following amplification, the DNA was precipitated with 99.5% ethanol and resuspended in 25 µl of water. Twenty microliters was treated with 2 U of Fnu4HI (New England Biolabs, Beverly, MA) overnight at 37°C in the buffer supplied by the manufacturer. The DNA were electrophoresed through a 2% agarose gel. The H2b allele gave fragments of 85 and 208 bp, respectively, while the H2q allele yielded two fragments of 186 and 115 bp, respectively.
Statistical analysis
Data were analyzed using the SPSS 10.0 and Statview 5.0 software. Repeated measure ANOVA was used for statistical analysis of the clinical arthritic score and anti-BCII Ab response. For histological scores, the Mann-Whitney U two-sample rank test was used. Values of p < 0.05 were considered to be significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Single immunization of C3-/- mice with
BCII did not trigger development of arthritis. Indeed, their arthritic
score reached a maximum of 0.25 ± 0.13 (mean ± SEM) on day
39 and declined thereafter. In contrast, control mice developed
progressive arthritis with the arthritic score of 10.0 ± 0.71
(mean ± SEM) by the end of the experiment. (Fig. 1
a). The
C3-/- mice reached 25% incidence of arthritis
on day 42 and 12.5% at the termination of the experiment (Fig. 2a). Both the control and
FB-/- animals developed CIA with 100%
incidence within 28 days after the BCII injection. However, at
termination of the experiment, the FB-/- mice
did not show any clinical signs of arthritis.
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Booster immunization with BCII elicited rapid development of
arthritis both in the control and in the FB-/-
mice. However, despite the booster immunization, the
C3-/- animals displayed only mild arthritis
with a delayed onset (Fig. 1
b). At the end of the
experiment, the arthritic score was 11.1 ± 0.40 in the control
group vs 7.17 ± 0.98 in the FB-/- group
and 1.63 ± 1.49 in the C3-/- group
(mean ± SEM). Only one animal of the nine mice in the
C3-/- group developed arthritis of the same
severity as the control mice (arthritic score of 12 at the end of the
experiment). The incidence for both the control and
FB-/- mice was 100% already 23 days after
immunization and remained unchanged for the rest of the experiment. The
C3-/- mice showed a peak incidence of
88% at day 46 but by the end of the experiment the incidence was
reduced to 25% (Fig. 2b).
Complement-deficient mice show only mild morphological changes in the joints, while the control mice exhibit severe cartilage and bone erosion
The control mice injected with a single dose of BCII exhibited
substantial pannus formation and
thickening of the synovium. Booster
immunization led to severe erosion of both
cartilage and bone and massive
infiltration of the joints with inflammatory cells. The
FB-/- mice showed no pathological signs in the
joint after single-dose immunization, whereas the booster immunization
of FB-/- mice triggered a slight thickening of
the synovium. Irrespective of the immunization protocol, the
C3-/- mice did not show any signs of
inflammation or destruction of the joints (Figs. 3 and 4 and Table I).
The affected joints of the single C3-/- mouse
that displayed severe arthritis when evaluated by clinical scoring
exhibited morphological changes that were similar to those of the
control mice.
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Single immunization with 50 µg of BCII triggered low
CII-specific IgG response in the C3-/- and
FB-/-mice while the corresponding response in
the control mice was strong (Fig. 5a). The Ab levels reached
the peak on day 56 after immunization in all groups: 12,028 ±
2,678 µg/ml in the control mice, 4,190 ± 937 µg/ml in the
C3-/- mice, and 4,716 ± 622 µg/ml in
the FB-/- mice (mean ± SEM). Repeated
immunization of the C3-/- and
FB-/- mice with BCII 3 wk later led to
increased production of CII-specific IgG, fully comparable to that of
control animals that received only single doses of BCII (9,946 ±
2,275 µg/ml in the C3-/- mice and 14,004
± 1,899 µg/ml in the FB-/- mice on day 35
after the initial dose (mean ± SEM; Fig. 5b). To
assess the IgG subclass composition of the Ab response, we measured the
levels of the CII-specific IgG1 and IgG2a isotypes in sera on day 35
after the first immunization. The ratio of the CII-specific IgG1 and
IgG2a subclasses (IgG1:IgG2a) revealed that to single BCII
immunization, the C3-/- mice responded
predominantly by IgG1 production while the control and
FB-/- mice responded predominantly by IgG2a
production (IgG1:IgG2a ratio, 1.84 vs 0.57 and 0.14, respectively).
There were no differences in the IgG isotype pattern between the
C3-/- and control mice after repeated
immunization (IgG1:IgG2a ratio 0.91 vs 1.00), while the response of
FB-/- still contained a predominant IgG2a
component (IgG1:IgG2a ratio 0.25).
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Murine C3 and FB are both encoded by genes located on chromosome 17 at a distance of 13 and <1 cM, respectively (22) from H-2, a major CIA susceptibility locus (23). To rule out the possibility that the differences in the response to CII immunization between the control and C3-/- mice are due to differences in the H-2 alleles, the mice were genotyped at the H-2 locus. Although all the control and C3-/- mice were found to carry only the H-2q allele, the FB-/- mice still carried the H-2b allele from the original C57BL/6 x 129Ola strain (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Both humoral and cell-mediated immunity are required for active induction of CIA (2). T as well as B cells have been implicated in the pathogenesis of arthritis with self-reactive T cells indirectly provoking the disease via B lymphocytes and Igs (reviewed in Ref. 24). The severity of murine arthritis is positively correlated with the IgG autoantibody response to CII (3) and the predominance of autoreactive IgG2a Abs (25). Complement has been shown to enhance the immunogenicity of both T cell-independent (26) and T cell-dependent Ags (27, 28, 29, 30). It was suggested that the requirement for complement activation products and receptors for the Ab response may be partly reversed by an increased dose of Ag (27). Here, we show that both pathways of complement activation are required for a normal Ab response to immunization with BCII since a single dose of BCII triggered deficient Ab response in both mice lacking C3 and FB. The singly immunized C3-/- mice were found to respond by an aberrant CII-specific IgG1:IgG2a isotype ratio which may point to a role of the C3 activation products in the Th1- and Th2-induced switch from IgM to IgG2a/b and IgG1, respectively, in activated B lymphocytes. We have also found that the impaired Ab response, including the IgG1:IgG2a isotype ratio, is reversed in complement-deficient mice by repeated immunization with BCII. Thus, complement plays a role in the induction phase of CIA by controlling both the quantity and the isotypic pattern of the specific Ab production but the requirement for complement activation in the production of CII-specific Abs can be overcome by repeated immunization.
The importance of anti-CII Abs and Fc receptors for IgG in the regulation of CIA was recently demonstrated by Kleinau et al. (31). The mild arthritic response of complement-deficient mice cannot be solely explained by the impaired B cell response leading to low levels of BCII Abs with an aberrant IgG isotype pattern, since the C3-/- mice exhibited very low mean arthritic scores also after repeated immunization, despite high titers of the CII-specific IgG and IgG1:IgG2a isotype ratio comparable to that of the control mice. Thus, complement activation seems to play a critical role in the inflammatory reaction triggered by the Abs reactive with CII. The fact that the FB-/- mice exhibited reduced arthritic scores compared with the control mice after both single and booster immunization indicates that the alternative pathway of complement activation plays a role in the pathogenesis of CIA. The classical pathway of complement activation is therefore most plausibly triggered by the anti-CII Abs and the activation and generation of inflammatory molecules is further amplified by the alternative pathway. Indeed, in a passive Ab transfer model of arthritis, Ji et al. (32) have recently shown that the alternative pathway is critical for the recruitment and/or activation of polymorphonuclear leukocytes and development of arthritis while components of the classical pathway are entirely dispensable for the effector phase of arthritis. Altogether our results indicate that complement deficiency affects both the induction and the effector phases of CIA.
It has earlier been shown that the H-2 MHC locus on
chromosome 17 is important for the total IgG autoantibody response
(25) and that it determines the susceptibility of mice to
CIA (23) but not the isotypic pattern of the autoantibody
response (25). Although the C3-/-
mice in our study carried the H-2q allele, the
FB-/- mice carried the H-2b allele
of the C57BL/6 x 129Ola strain on which the null mutation was
originally generated. Although C57BL/6 mice
(H-2b) do not develop CIA even after repeated
immunization (data not shown) and six generations of backcrossing to
DBA/1J strain imply that 
97% of loci in the
FB-/- mice are homozygous for the DBA/1J
allele, we cannot exclude that the differences at the H-2
and perhaps even additional loci could have contributed to the impaired
specific autoantibody and inflammatory response in the singly immunized
FB-/- mice but presumably not to the relative
resistance of the FB-/- mice to CIA after
repeated immunization. Although rather demanding, the reconstitution of
the FB-/- mice with FB would clearly provide
the most appropriate control group to allow the assessment of the
alternative pathway contribution to both the induction and effector
phases of CIA. Because passive anti-collagen Ab transfer induction
of arthritis is independent of the H-2 haplotype
(4), this approach or induction of arthritis by monoclonal
anti-CII Ab transfer would resolve the question of the involvement
of the alternative pathway in the effector phase and generation of
tissue damage. Recently, C3-/- as well as
FB-/- mice but not
C4-/- mice were found to be highly resistant to
arthritis induced by transfer of serum containing anti-GPI Abs
(32). Although this model differs from CIA, the results
from both studies implicate the alternative pathway as an important
player in the pathogenesis of arthritis.
Although the mean arthritic score of the C3-/- mice was substantially lower compared with both the FB-/- and control mice, after booster immunization the incidence of arthritis in the C3-/- mice was comparable to that of the FB-/- and control mice. Thus, the C3 deficiency ameliorates CIA but does not fully protect against its development. Our observation that one of nine C3-/- mice (i.e., 11%) developed severe arthritis suggests that the inhibition of complement activation increases the threshold for the development of CIA. Our findings are in line with the recent observations of Wang et al. (14), reporting that C5-deficient mice are highly resistant to CIA. Interestingly, 15% of the C5-/- mice in that study developed arthritis clinically and pathologically indistinguishable from that seen in the control mice.
In summary, the C3-/- and FB-/- mice respond by a low specific Ab production to single doses of BCII but this impaired Ab response can be overcome by repeated immunization. Complement deficiency ameliorates CIA in mice. Complement inhibition at the level of C3 activation thus appears to be a rational therapeutic approach in patients with RA.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Marcela Pekna, Department of Medical Biochemistry, Göteborg University, Box 440, SE-405 30, Göteborg, Sweden. E-mail address: marcela.pekna{at}medkem.gu.se
3 Abbreviations used in this paper: RA, rheumatoid arthritis; CIA, collagen-induced arthritis; CII, type II collagen; FB, factor B; BCII, bovine type II collagen.
Received for publication January 22, 2002. Accepted for publication April 25, 2002.
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