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Native Type II Collagen-Induced Arthritis in the Rat.

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1356
NATIVE TYPE I1 COLLAGEN-INDUCED ARTHRITIS
I N THE RAT
The Effect of Complement Depletion by Cobra Venom Factor
KEITH MORGAN, ROY B. CLAGUE, MARY J . SHAW, STEPHEN A . FIRTH, TREVOR M. TWOSE,
and P. J . LENNOX HOLT
Antibodies to native bovine type I t collagen may
be important in initiating arthritis in rats immunized
with this antigen. The cross-reactivity of these antibodies with native rat type I1 collagen was higher in rats
that developed arthritis than in those that did not.
Depletion of serum C3 levels by cobra venom factor
delayed the onset of arthritis until C3 levels were
returning to normal; therefore, complement may he
involved in initiation of the arthritis, and this arthritis
may be an example of an immune complex-mediated
disease.
An inflammatory polyarthritis can he induced in
rats (1-3) and mice (4) after the intradermal injection of
heterologous or homologous native type 11 collagen
emulsified in complete or incomplete Freund's adjuvant. In view of the onset of arthritis at least 10 days
after primary immunization of rats, the presence of
From the Department of Kheumatology, University of
Manchester Medical School, Oxford Road. Manchester. England
and Imperial Chemical Industries Ltd. Mereside. Alderley kirk.
Macclesfield, Cheshire.
Supported by grants from the Arthritis and Rheumatism
Council, Medical Research Council. and the North Western Kegional Hospital Board.
Keith Morgan. BSc. PhD: Senior Scientific Officer; R o y 13.
Clague. MD, MRCP (UK): Consultant Kheumatologisl: Mar; J .
Shaw, BSc: Research Technician; Stephen A . Firth, HSc: Research
Technician, Department of Rheumatology. University of Miinchester Medical School; Trevor M. Twose. HSc. Phl): Research I3ioScientist, Imperial Chemical Industries. Lld. Cheshire; P. J. I.ennox Holt, MD, FRCP: Consultant Rheumatologist, Department of
Rheumatology, University of Manchester Medical School.
Address reprint requests to Dr. K. Morgan, Department of
Rheumatology, University of Manchester Medicid School. Oxford
Road, Manchester MI3 9PT, England.
Submitted for publication Octoher 24. 1980: accepted in
revised form March 19, 1981.
Arthritis and Rheumatism, Vol. 24, Nn. 1 1 (November 1981)
high serum antibody levels to native type I1 collagen
before the onset of arthritis in rats (9,and the finding
of higher serum antibody levels to native type I1
collagen in arthritic than in nonarthritic rats (3,6,7),
we suggest that these antibodies may have a role in the
induction of the arthritis.
Previous investigators (8) have noted a lack of
species specificity of the antibodies produced by immunization with collagen. There have been no previous studies in this model to determine the crossreactivity of the serum antibodies produced by
heterologous collagen with native rat type I1 collagen.
We now present further evidence of the importance of
humoral immunity to native type I1 collagen in the
induction of this arthritis. First, we show that serum
antibodies to native bovine type 11 collagen cross-react
with native rat type I1 collagen to a greater extent in
arthritic than in nonarthritic rats. Second, we show
that rats treated with cobra venom factor (CVF) have a
delayed onset of arthritis associated with depleted
levels of complement ( C 3 ) . A possible pathogenetic
mechanism for native type I1 collagen-induced arthritis is discussed.
MATERIALS AND METHODS
Rats. Outbred, female Sprague Dawley rats (150-250
gm) from the Manchester Medical School Closed Colony
were used. They were given food and water ad libitum.
Collagens. Native bovine type I1 collagen was extracted from articular or nasal cartilage by pepsin solubilization after previous treatment wth 2M magnesium chloride
(9). Native pepsin-soluble rat type I1 collagen was extracted
from a transplanted rat chondrosarcoma (10) by the same
method. The collagens appeared pure for type by polyacrylamide gel electrophoresis and were negative for uronic acid,
so there seemed to be no proteoglycan contamination (1 1).
NATIVE TYPE I1 COLLAGEN-INDUCED ARTHRITIS
The collagens were stored in a lyophilized state and
dissolved in 0.45M NaCII0.02M Tris buffer (pH 7.5) at a
concentration of 1 mg/ml before use. Native bovine type I1
collagen was emulsified at a ratio of 1:1 with Freund’s
incomplete adjuvant (ICFA, Miles Laboratories Ltd).
Cobra venom factor. Cobra venom factor (CVF) was
prepared by DEAE-cellulose chromatography followed by
Sephacryl S200 chromatography from the lyophilized venom
of Nuju naju (Thailand Cobra, Sigma Cat. No. V9125) by the
method described by Ballow and Cochrane (12). On polyacrylamide gradient gels (Pharmacia), the protein migrated
as a single band (MW 190,000 daltons). This is the low
molecular weight anticomplementary factor, not the high
molecular weight factor described by Ballow and Cochrane
(12), which has a molecular weight of almost lo6 daltons.
Injection of the purified CVF into a rat caused rapid depletion of complement to levels that were not detectable in a
standard hemolytic assay.
To inactivate any phospholipase A2 activity, the
cobra venom factor was incubated with 0.2 mM p-bromophenacylbromide (PBPB) at pH 8.0 for 30 minutes at 37°C
(13) and the PBPB was subsequently removed by chromatography on Sephadex G25 (PD 10 mini-column, Pharmacia).
This CVF was used for the rats in group 4.
Treatment of rats. Experiment I: cross-reuctivity.
Rats were injected intradermally on the back at several sites
with a total of 1 ml of emulsion that contained 500 pg of
native bovine type I1 collagen (day 0) followed by a booster
dose of 500 pg of the antigen alone intraperitoneally on day
21. The rats were bled (= 1 ml) by cardiac puncture under
light ether anesthesia on days 14, 21, 28,42, 56, and 70 after
primary immunization. The blood was allowed to clot for 1
hour at room temperature, was centrifuged at 1500g for 7
minutes, and the serum was removed for storage at -70°C.
Class-specific antibodies to native type I1 collagen (rat or
bovine) were detected in sera by radioimmunoassay as
described below. Rats were observed daily for the onset of
arthritis and nonarticular lesions.
Experiment 2: treatment with CVF. Rats were immunized as in experiment 1 and bled on day 0 (day of immunization) and various days thereafter until day 28. Immunized
rats were injected intraperitoneally with either 5 units (250
111) of CVF or 250 p1phosphate-buffered saline (PBS; control
group) in the morning and 6 hours later on days 9 and 12.
Rats were examined daily for the onset of arthritis.
Radioimmunoassay. Class-specific IgM and IgG serum antibodies to native bovine or rat type I1 collagen were
measured by a solid-phase double-antibody radioimmunoassay as previously described (3). For the crossreactivity experiment, sera were measured for antibodies to
both antigens in one assay. The results were expressed as
milligrams of antigen-specific IgM and IgG antibody per liter
of serum.
Measurement of C3 levels. Serum C3 levels were
measured by single radial immunodiffusion (14). The test
sera were diluted 1 to 5 with PBS and allowed to diffuse into
1.5% agarose in PBS containing a 1 to 20 dilution of anti-rat
BIC/BIA (C3) (Nordic Immunochemicals Ltd). The C3 levels were expressed as a percentage of the day 0 levels for
each rat.
Statistics. Experiment I: cross-reactivity. The anti-
1357
body levels to native rat type 11 collagen were plotted against
the antibody levels to native bovine type I1 collagen in the
same serum samples. Because the standard deviation of the
anti-rat antibody levels increased in the samples that had
higher anti-bovine antibody levels, a weighted linear regression was performed on the data to give an estimate of the
slope (15). The slopes for arthritic rats were compared to the
slopes for nonarthritic rats at each sample time by the
Student’s t-test (16).
Experiment 2: CVF. Antibody levels to native bovine
type I1 collagen of CVF-treated and PBS-treated groups
were compared after logarithmic transformation by a twoway analysis of variance in repeated measures (across
times). When there were unequal numbers of rats in the two
groups, an “unweighted means” analysis was used (17). The
Student’s t-test was used to compare the groups at each time
separately if the analysis of variance indicated a significant
interaction with time and at later times if the numbers were
reduced because rats had died under anesthesia.
RESULTS
Experiment 1: cross-reactivity. In a group of 34
rats immunized by native bovine type I1 collagen
emulsified in ICFA, 22 (65%) developed an inflammatory polyarthritis in one or more hind limbs (onset:
median day 12, range 10-18). Five rats developed
swellings related to the cartilaginous endplates in the
distal region of the tail, and the ears of 5 rats became
erythematous and swollen, but none of these lesions
were observed before day 30.
When the levels of antibodies to native rat type
I1 collagen were plotted against the levels of antibodies
to native bovine type I1 collagen in the same sera, a
straight line through the origin was produced (e.g., day
14 samples, Figure 1). Thus, the levels of antibodies to
native rat type I1 collagen were a fixed proportion of
the antibody levels to native bovine type I1 collagen,
and the slope of this line estimates this proportion.
Therefore, a proportion of the antibodies raised to
native bovine type I1 collagen may cross-react with
native rat type 11 collagen.
For each sample date, the levels of IgM and IgG
antibodies to rat collagen were plotted against the
antibody levels to bovine collagen in the same samples
for arthritic and nonarthritic rats separately, and the
slopes were compared. For IgM antibodies at days 14
and 21, the slope was greater in arthritic rats than in
nonarthritic rats, but this difference was not statistically significant (Table 1). In regard to the IgG antibodies,
the slopes plotted for arthritic rats were greater than
those for nonarthritic rats (except for days 56 and 70).
These differences were statistically significant on day
14, P < 0.05; day 21, P < 0.001; and day 28, P < 0.02
MORGAN ET AL
1358
Table 2. Serum C3 levels in rats after treatment by cobra venom
factor*
C3 levels (96 of initial values)
0
Normal rats
I
2
3
Rats immunized 9 days
previously by type 11
collagen ICFA
I
2
3
4
5
f
**:
**
100
100
Hours after first CVF
3
6
24
loo
25.4
21.4
57.1
3.1
3.8
9.2
3.8
4.6
100
100
100
loo
100
17.9
15.7
60.8
22.5
36.9
12.5
5.7
40.5
5.4
3.1
5.4
4.3
3.8
I .6
2.3
4.1
* Five units given after initial bleed followed by 5 units after 6
hours.
30
60
120
90
150
IgG to native bovine type I I collagen (rng.1-l
1
Figure 1. Levels of serum IgG antibodies to native rat type I1
collagen plotted against IgG antibodies to native bovine type II
collagen in the same sera (day 14 after immiiniration).
(Table I ) . Thus, arthritic rats had serum antibodies,
raised by immunization to native bovine type 11 collagen, that had greater cross-reactivity to rat type I1
collagen than did nonarthritic rats.
Experiment 2: treatment with CVF. Cobra venom factor given intraperitoneally to 3 rats caused a
reduction in serum C3 levels 3 hours after injection
(Table 2). At 6 hours, the levels had fallen to less than
10% of their original values, and at 24 hours, they were
less than 5% of their original values. Similar results
were found in a group of 5 rats injected with native
bovine type 11 collagen 9 days before. Arthritis has
never been observed before day i0 in these SpragueDawley rats (personal observations); therefore, we
decided to inject CVF on day 9 in order to deplete
serum C3 levels before the expected onset of arthritis.
Effect of CVF on the onset of native type I1
collagen-induced arthritis. Table 3 shows the number
of rats that developed arthritis and the time of onset of
the arthritis, after primary immunization with native
type 11 collagen in rats treated with CVF or PBS.
In all four groups, treatment with CVF caused a
Table 3. Effect of cobra venom factor on incidence and onset of
native type I1 collagen-induced arthritis
Table 1. Comparison of slopes for arthritic and nonarthritic rats*
Day
IgM
14
21
IgG
14
21
28
42
56
70
Nonarthritic
(n = 12)t
Arthritic
(n = 22)
0.89 2 0.02
0.77 ? 0.02
0.91 2 0.02
0.83 ? 0.03
0.81 2 0.04
0.80 5 0.04
0.68 f 0.05
0.63 2 0.06
0.61 5 0.07
0.66 5 0.08
Treatment
0.91 2 0.02
0.96 f 0.02
0.85 t 0.04
0.68 ? 0.04
0.61 2 0.04
0.55 2 0.04
Slope
comparison$
i =: -0.6
f
z:
-1.38
f =: -2.35
i == -3.66
f =: - 71.65
f =:
f =
f =:
-0.80
0.1 I
- I .47
NS
NS
P < 0.05
P < 0.001
P < 0.02
NS
NS
NS
* Slopes generated by plotting levels of antibodies to rat type I1
collagen against those to bovine type 11 collagen in the same
samples.
t Slope f standard error.
$ N S = not significant.
Group 1
PBS
CV F
Group 2
PBS
CVF
Group 3
PBS
CV F
Group 4
PHS
CVF*
Total
PHS
CVF
No.
of rats
No. with
arthritis
Time of
onset after
immunization
(days)
12
9
7
2
12-14
22
5
S
3
5
10-13
17-22
5
6
3
2
11-18
20
16
21
9
12
11-14
19-22
38
22
41
21
10-18
17-22
* Group 4: this CVF had phospholipase-A2 activity removed as
described.
NATIVE TYPE I1 COLLAGEN-INDUCED ARTHRITIS
1359
treated and PBS-treated rats, and there was no statistically significant difference between these groups. The
IgM and IgG antibody levels to bovine type I1 collagen
were measured less frequently in the other groups of
rats, but again there was no difference between the
levels in CVF-treated and PBS-treated rats.
Relationship between C3 levels and the onset of
arthritis. The onset of arthritis was delayed in CVFtreated rats (median, day 21) compared with PBStreated rats (median, day 12). Serum C3 levels were
depleted in CVF-treated rats from day 9 and returned
to normal between days 17 and 21. Thus, the onset of
arthritis in the CVF-treated rats occurred only when
the serum C3 levels had started to return to normal.
Ua", alter lmmvnlralan
Figure 2. Levels of serum 1gM and IgG antibodies to native bovine
=
type 11 collagen and serum C3 levels in PHS-treated rats. ~e
IgM; a= IgG: C - -O = C3.
delay in the onset of arthritis in comparison with PBStreated rats. The delay varied between groups. but
there was no overlap of onset between PBS-treated
and CVF-treated rats in any one group.
The overall incidence of arthritis was similar in
PBS-treated (22 of 38) and in CVF-treated rats (21 of
41).
Effect of CVF on serum C3 levels and the levels of
serum antibody to native type I1 collagen. The rats from
group I (Table 3) were bled at frequent intervals after
primary immunization with native type I1 collagen.
Serum IgM and IgG antibody levels to this antigen and
serum C3 levels were measured in these animals
(Figures 2 and 3).
There was no significant reduction in serum C3
levels of PBS-treated rats (Figure 2). However, serum
C3 levels in CVF-treated rats were greatly reduced
after CVF injection on day 9 and remained low for
several days (Figure 3). By day 17. the C3 levels had
returned to 75-95% of their initial values in 4 rats.
although the levels remained low for longer in the
others (mean 36.9% ? 12.4% on day 17). By day 19,
the levels were high in all rats (mean 89.6% ? 5.3%),
and by day 21, normal levels had been restored. The
serum C3 levels in all the other groups of rats were
similar; all CVF-treated rats showed a marked reduction in C3 levels with subsequent recovery, but no
PBS-treated rats showed significant reductions in C3
levels.
The 1gM and 1gG antibody levels to native
bovine type I1 collagen were very similar in both CVF-
DISCUSSION
An inflammatory polyarthritis can be induced in
some rats after immunization by heterologous (bovine,
human, or chick) or homologous native type I1 collagen (1-3). Previous studies (3,6,7) have demonstrated
that serum antibody levels to the native type I1 collagen used in the immunization procedure are higher in
arthritic than in nonarthritic rats. N o previous studies
on the cross-reactivity of these antibodies with rat
native type I1 collagen have been reported. We have
extracted native collagen from a transplanted rat chondrosarcoma, and this collagen has previously been
CVF
-
CVF
nay, alle.
Imm""tZdll0"
Figure 3. Levels of serum IgM and IgG antibodies to native bovine type 11 collagen and serum C3 levels in CVF-treated rats.
= IgM; "
4 = IgG; c - a= C3.
1360
biochemically identified as cartilage type 11 collagen
(10).
We have shown that antibodies raised in rats to
native bovine type I1 collagen cross-react to a large
extent with rat native type I1 collagen. The extent of
this cross-reactivity varied; it was greatest soon after
immunization. More importantly, we have shown that
the cross-reactivity of these antibodies with native rat
type I1 collagen was greater in arthritic than nonarthritic rats. Further evidence that this experimental arthritis is induced by an autoimmune response to a component of rat articular cartilage is supplied by: I ) the
demonstration that serum antibodies from rats with
arthritis induced with native type I1 collagen react with
homologous native type I1 collagen, and 2) the previous demonstration ( I ) that arthritis can be induced by
immunization with homologous native type I1 collagen.
Injection of CVF, given at least 24 hours before
the expected onset of arthritis and followed by further
injections 3 days later, delayed the onset of native type
I1 collagen-induced arthritis by about 9 days in comparison to PBS-treated rats, but had no apparent effect
on the eventual incidence of arthritis (Table 3). This
effect was demonstrated in several groups of rats and
was independent of any possible phospholipase A?
activity (Table 3).
Although an immunosuppressive effect has
been shown to occur if CVF is administered at the time
of immunization (18,19), no significant reduction in the
humordl immune response to native type 11 collagen
occurred when CVF was injected on days 9 and 12
after immunization. Since there was no apparent suppression of antibody formation in the rats treated with
CVF, the CVF may not have produced a nonspecific
suppression of arthritis by toxic action on cells or by
alteration of cellular responses to external stimuli (20)
via phospholipase A2 activity.
CVF is known to activate the complement
cascade and subsequently deplete complement components (21). Serum C3 levels were depleted in the
CVF-treated rats between days 9 and 17 and showed a
temporal relationship to the delayed onset of the
arthritis. Therefore, complement may be directly involved in the induction of this arthritis.
Cell-mediated immunity to native type I1 collagen was not measured in CVF-treated rats, but this
work is in progress. Treatment with CVF, however,
has been shown to have no effect on T cell function in
mice according to several in vivo and in vitro tests
(22). The role of T lymphocytes in this arthritis is
MORGAN ET AL
unclear at present, but a T cell response may be
required to sustain the synovitis (23).
In preliminary histologic studies investigators
have shown the predominant infiltration of neutrophils
and mast cells within 24 hours of the onset of the
arthritis (personal observations). The infiltration of
neutrophils in the synovium early in the arthritis has
been described in both the rat (7) and mouse (4)
models. Thus, neutrophils appear to be an important
cellular component early in the genesis of the arthritic
lesion.
These findings could be explained as follows.
The binding of IgM and IgG antibodies to the rat native
type 11 collagen in the articular cartilage would form
intraarticular immune complexes and subsequently
activate the complement cascade (24). The action of
the activated complement components, especially
C5a, would lead to infiltration of neutrophils (25). mast
cells, and other components of the inflammatory response from the blood vessels in the periarticular and
articular tissues (e.g., synovium), because the articular
cartilage is avascular. Phagocytosis of immune complexes by neutrophils would be accompanied by degranulation of lysosomes and release of hydrolytic
enzymes and collagenase accompanied by break-down
of the cartilage matrix and collagen (26,27). Thus, the
arthritic lesion would be initiated by immune complex
formation and would persist until total destruction of
the cartilage occurred.
Thus, the finding of high levels of serum antibody to native type I1 collagen before the onset of
arthritis ( 9 ,the occurrence of higher levels in arthritic
than nonarthritic rats (3,6,7), the greater cross-reactivity of these antibodies with homologous native type 11
collagen in arthritic and nonarthritic rats, the predominant early infiltration of neutrophils and mast cells,
and the apparent dependence of the induction of the
arthritis on the presence of complement components
may be evidence of an immune complex-mediated
disease. Some of the previous experimental models of
inflammatory arthritis (28,29) may be examples of
immune complex-mediated diseases (23,30), although
in these instances, the antigen must be injected
intraarticularly about 14 days after systematic immunization by the antigen in complete Freund's adjuvant.
The foreign antigen is trapped in the articular cartilage
in these models, whereas in native type I1 collageninduced arthritis, the antigen presumably forms an
integral part of the articular cartilage.
In these studies, further evidence is provided
for the possible importance of the formation of intraar-
NATIVE TYPE I1 COLLAGEN-INDUCED ARTHRITIS
ticular immune complexes in the induction of arthritis.
In addition, we may suggest that humoral immunity to
native type I1 collagen in humans (31,32) may be
important as a component in the destruction of articular cartilage in some patients with rheumatoid arthritis.
ACKNOWLEDGMENTS
We are grateful to Ms Jacqueline Weiss and Dr. R.
Brown for analysis of the collagen types and for advice on
their preparation. We would like to thank Drs. M. Billingham and M. Smith for the gift of the rat chondrosarcoma.
We would also like to thank Miss Linda Hunt (Faculty of
Medicine Computational Group) for statistical advice. Mrs.
Doreen Ward for typing the manuscript, and the Department
of Medical Illustration for preparing the figures.
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A 8, R Symposia Issues
Beginning in 1983 Arthritis and Rheumatism will no longer publish conference proceedings.
However, a conference series to be issued jointly by the American Rheumatism Association and a
private publisher is tentatively planned.
Planners of future symposia who wish to have their proceedings published should contact Alan
Myers, MD, Chair of the ARA General Publications Committee.
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