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Rat cytomegalovirus infection enhances type II collagen arthritis in rats.

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1263
RAT CYTOMEGALOVIRUS INFECTION ENHANCES
TYPE 11 COLLAGEN ARTHRITIS IN RATS
CHARLES B. SMITH, MARIE M. GRIFFITHS. and LIAN S. WE1
The effect of rat cytomegalovirus (RCMV) infection on type I1 collagen-induced arthritis was studied in
DA rats. Rats were infected with RCMV 5 days before,
simultaneously with, or 5 days after immunization with
calf type 11collagen. Control rats were either given type
II collagen alone or were injected with normal rat
salivary gland (NRSG) simultaneously with collagen
immunization. Severity of arthritis in each limb was
graded on a scale of 1 4 (maximum score 16). In 5
experiments, peak arthritis scores in the RCMV groups
were twice those of the control groups which received
NRSG or collagen only (8-9 versus 4-6). Radiographs of
involved joints showed greater destruction of cartilage
and articular bone in the RCMV rats than in the NRSG
control group. Repeated attempts to culture RCMV
from joint tissues were unsuccessful. Our results indicate that RCMV infection enhances the arthritic process
in this experimental model of an autoimmune arthritis.
Among the many hypotheses which have been
proposed to explain the pathogenesis of rheumatoid
arthritis, we have been interested in the possibility that
viral infection may exacerbate an underlying, diseaserelated autoimmune process in genetically predisposed
individuals (1,2). To test this hypothesis, we have
From the Veterans Administration Medical Center and the
Department of Medicine, University of Utah College of Medicine,
Salt Lake City.
Supported by The Veterans Administration and by NIH
grant no. AM-30763.
Charles B. Smith, MD; Marie M. Griffiths, PhD; Lian S.
Wei, MS.
Address reprint requests to Charles B. Smith, MD, Medical
Service, Veterans Administration Medical Center, 500 Foothill
Drive, Salt Lake City, UT 84148.
Submitted for publication January 6, 1986; accepted in
revised form May 30, 1986.
Arthritis and Rheumatism, Vol. 29, No. 10 (October 1986)
studied the effect of experimental rat cytomegalovirus
(RCMV) infection on the course of type I1 collageninduced arthritis in laboratory rats. Cytomegalovirus
was chosen for study because of its ubiquitousness
and its ability to alter the immune system in human
subjects and laboratory animals (3). Type I1 collagen-induced arthritis was selected because it has
many similarities to human rheumatoid arthritis and to
the seronegative polyarthritides (43). This animal
model of autoimmune arthritis is also desirable to
study because the target of the autoimmune process
(type I1 collagen) is well-defined biochemically and
immunochemically (6,7), because it is possible to
measure the contributions of humoral and T cell-mediated aspects of the immune system (5,8-lo), and
because susceptibility to the autoimmune process is
genetically determined in rats ($1 1,12). Our studies
indicated that RCMV infection of DA laboratory rats
is associated with increased severity of type I1 collagen-induced arthritis.
MATERIALS AND METHODS
Animals. DA (RTlaV1)
strain rats were obtained from
our breeding colonies at the VA Hospital, Salt Lake City.
Periodic testing for antibodies to common rat pathogens
(Microbiological Associates, Bethesda, MD) indicated that
the colony has been free of the following specific pathogens:
rat parvoviruses H1 and Kilham, reovirus 3, GDV-11,
Sendai, LCM virus, and mouse adenovirus. Some animals in
our breeding colony had antibodies to pneumonia virus of
mice and to sialodacryoadenitis virus, and sera were therefore tested at the end of experiments for antibodies to these
viruses. Acute respiratory tract illness was not evident
during any of these experiments.
Virus. The rat cytomegalovirus used in these studies
was obtained from PK Priscott, Nedlands, Australia. The
1264
virus was originally isolated from a wild rat in London, UK
(13), and had been passaged 4 times by intracerebral inoculation into SPF Sprague-Dawley rats, followed by harvest of
the salivary glands. In our laboratory the original pool was
inoculated intraperitoneally (IP) into weanling (3-week-old)
DA strain rats, and salivary glands were harvested and
pooled 3 weeks later. Rat cytomegalovirus was characterized based on observation of a cytopathic effect on rat
embryo fibroblast (REF) cell cultures which was typical for
cytomegaloviruses. Cross-antibody neutralization studies
using the Smith strain of mouse cytomegalovirus (MCMV)
and antisera from animals infected with MCMV and RCMV
indicated no cross-reactivity between the 2 viruses, confirming the original findings of Priscott and Tyrrell (13).
The RCMV inoculum represented the sixth passage
of salivary gland material, and had a titer of approximately
lo6 plaque-forming units per ml when assayed on REFS.
Rats were injected IP with 0.2 ml of a 1:lO dilution of the
salivary gland pool. RCMV infection was usually initiated at
the same time as immunization with type I1 collagen (experiments 8, 11, and 13), while in experiment 14, additional
groups of 10 animals received RCMV 5 days before and 5
days after collagen immunization. Control rats either received collagen only or they received an IP injection of
normal rat salivary gland (NRSG) from DA rats, prepared in
a manner similar to that described above. These NRSG
injections were given simultaneously with collagen immunization.
Type I1 collagen arthritis. Methods for preparation of
type I1 calf collagen and for induction of arthritis have been
previously described (8,11,14) and have been used in our
laboratory for the past 6 years. Native calf type I1 collagen
was prepared, from articular cartilage, by pepsin digestion
and was purified to apparent homogeneity by sodium
dodecyl sulfate-polyacrylamide gel electrophoresis, sequential salt precipitation, DEAE chromatography, and repeated
dialysis versus low ionic strength buffer, pH 7.5. The immunogen consisted of type I1 collagen dissolved in 0.1N
acetic acid (1 mg/ml) and emulsified with an equal volume of
Freund’s incomplete adjuvant (Difco, Detroit, MI). DA rats
of both sexes, 6-8 weeks of age, were injected intradermally
at 4-6 sites on the back. In each experiment, virus-infected
and control groups were closely matched according to age
and sex. The total dose of collagen was 2 mg/kg body weight
in 4 experiments and 0.5 mg/kg in 1 experiment.
Arthritis was graded subjectively (M+)for each
appendage, at daily intervals for 2 weeks after the onset of
disease and at alternate-day intervals thereafter, until the
termination of the experiment. According to this grading
system, the maximum total daily severity score for an animal
after summation of scores of the individual appendages was
16+. Objective measurements of ankle thickness were also
made biweekly, using constant-tension calipers.
Radiographic assessments of chronic arthritic
changes in hind feet and ankles were made by a modification
of the method of Clark et al(l5). Radiographs were taken in
a Ftixitron model 805 unit (Hewlett-Packard, McMinnville,
OR). Exposures were with 30 kilovolts (peak), 3 mA, and
3040-second exposures. The focus-film distance was 60 cm
and the object film distance was approximately 5 mm. Kodak
(Rochester, NY) X-Omat T L film was used. The degree of
SMITH ET AL
ARTHRITIS
SCORE
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
34
36
38
DAY
Figure 1. Results of experiment 14. Mean collagen arthritis scores
of groups of 10 rats infected with rat cytomegalovirus (RCMV) 5
days before collagen immunization (5D PRE), simultaneously with
collagen immunization (SIMUL), and 5 days after collagen immu-
nization (5DPOST). Control groups received collagen (COLL)only
(4 rats) or were injected with normal rat salivary gland (NRSG)
simultaneously with collagen immunization (10 rats). Differences
between RCMV and control groups were significant (P < 0.05)
beginning at day 20 for the RCMV 5D PRE and the RCMV SIMUL
groups, and beginning at day 26 for the RCMV 5D POST group.
radiologic involvement was assessed “blindly,” on a scale of
1 4 + , for erosions, periostitis and new bone formation,
cartilage space changes including ankylosis, and alignment,
according to the criteria of Clark et al (15). The maximum
total severity score by this method was 16+.
RESULTS
General effects of RCMV infection. RCMV infection of collagen-injected rats was not associated
with clinically detectable illness during the first 2
weeks after initiation of the viral infection. After 14
days, the RCMV-infected animals developed more
severe arthritis than the NRSG group, and consequently appeared to be less active and healthy. The
greater degree of illness in RCMV-infected animals
was best illustrated by the greater sensitivity of
RCMV-infected animals to the C 0 2 anesthesia used
for examinations: 5 of 53 (9.4%) of RCMV-infected
animals died during C 0 2 anesthesia induction, while
none of the NRSG control animals died. The mean day
of death was day 28, which was within the period of
greatest severity of arthritis (Figure 1).
All rats which received IP injections of RCMV
became infected, as judged by the development of
virus-neutralizing antibodies at titers of 2 1:32. No
such antibodies developed in animals which received
NRSG. Infection was also documented by the isola-
CMV AND TYPE I1 COLLAGEN ARTHRITIS
1265
Tnble 1. Severity of type I1 collagen-induced arthritis in rat cytomegalovirus (RCMVtinfected rats and control rats injected with normal rat
salivary gland (NRSG) or with collagen only
Experiment 8*
n
Mean day of arthritis onset
Mean arthritis score
Day 20
Day 21
Day 22
Day 23
Day 24
Day 25
Day 26
Day 27
Day 28
Day 29
Day 31
Day 33
Day 34
Day 36
Ankle size (mm)
Day 14
Day 17
Day 24
Day 29
Day 31
Experiment 1 lA*
Collagen
Experiment 1 lB*
Experiment 13*
NRSG
RCMV
only
NRSG
RCMV
NRSG
RCMV
NRSG
RCMV
10
19.9
10
17.9
4
10
18.9
10
17.4
10
19.6
10
18.7
20
18.5
20
18.6
4.4
7.1
5.1
5.1
5.3
6.3
7.8t
7.6t
7.8t
2.6
3.5
3.0
3.4
4.4
4.2
4.1
3.3
2.3
1.7
5 .O
7.1
7.7t
7.9t
8.7t
8.4t
7.6t
8.2t
7.2t
4.3
4.3
9.0t
5.1
5.8
6.8
6.5
5.5
4.3
4.3
3.2
3.1
8.9t
9.4t
8.3t
7.4t
5.9
6.8
6.6
5.6
4.7
2.8
7 .Ot
4.9
9.0t
4.9
7.2t
4.0
2.7
2.7
2.0
6.6t
5.5t
4.3
3.8
7.6t
6.3t
3.9
3.4
6.4t
6.lt
3.0
2.0
1.8
0.8
5.lt
3.4
1.4
5.8t
4.3t
2.5
4.9t
4.5t
11.0
13.8
13.7
11.4
13.0
13.0
12.2
16.lt
15.5t
11.3
15.2
14.8
11.9
16.4
16.0t
12.5
14.1
12.4
15.4t
13.6
15.H
6.1
5.0
8.5
9.8t
1o.ot
8.7t
4.3t
10.6
10.8
12.4
12.0
14.4
13.5t
* RCMV inoculum and collagen dose were as follows: 1.0 x lo6 plaque-formingunits (PFU) and 2 mg/kg, respectively, in experiment 8; 1.2 x
lo5 PFU and 2 mg/kg, respectively, in experiment 1 I A ; 1.2 x lo5 PFU and 0.5 mg/kg, respectively, in experiment 1 IB; and 1.4 x 10' PFU and 2
mg/kg, respectively, in experiment 13.
t P < 0.05 versus control group or groups, by Student's t-test.
tion of RCMV from salivary glands cultured at the end
of the experiments (days 42-45) in 35 of 35 rats.
RCMV could not be cultured from synovial tissues of
involved knee joints which were harvested from 5 rats
that died during anesthesia, nor from knee joints of 1 1
rats that were studied at the end of the experiments
(days 4245).
Infections with other indigenous rat viruses. Sera
collected from animals at the termination of experiments 8, 1 1 , and 13 were assayed for antibodies to
pneumonia virus of mice (PVM) and sialodacryoadenitis virus (SDA). Half the animals had antibodies to
PVM and 20% of the animals had antibodies to SDA.
The frequency of PVM positivity and SDA antibody
positivity and the mean antibody titers were similar in
the RCMV and NRSG groups.
Severity of arthritis. Rats infected with RCMV
and immunized with type I1 collagen developed arthritis that was approximately twice as severe as that seen
in control animals injected with NRSG and similarly
immunized with type I1 collagen or in animals which
received only collagen (Figure 1 and Table 1). Onset of
arthritis occurred 1-2 days earlier in the virus-infected
group, in 4 of the 5 separate experiments. Onset was
earliest in animals which were infected with RCMV 5
days before collagen immunization, and it was delayed
by 1-2 days in those that received RCMV 5 days after
collagen immunization; however, peak arthritis scores
were not affected by the timing of RCMV infection
(Figure 1). Significant differences in arthritis scores
between the RCMV and NSRG groups were generally
first evident by day 19 or 20 and were greatest at days
22-24, when peak arthritis scores were observed (Table 1). There were no significant differences in the
severity of arthritis seen in the NRSG and collagenonly control groups (Figure 1 and Table 1).
Some degree of arthritis occurred in all the
animals in both groups. The mean day of occurrence of
arthritis was day 22 in virus-infected animals and day
23 in controls. The greater total arthritis scores in the
RCMV group were due to greater severity of arthritis
in the hind limbs, which were always involved, and to
more frequent occurrence of arthritis in the front limbs
1266
SMITH ET AL
Figure 2. Residual swelling and deformity of the foot of a rat 45
days after immunization with type I1 collagen and infection with rat
cytomegalovirus (top right), compared with the minor residual
swelling and no deformity of the foot of a rat which received type I1
collagen and normal rat salivary gland (top left), and with the foot of
a normal, untreated rat (bottom). Rats were studied in experiment 8.
(91% involved in the RCMV versus 65% involved in
the NRSG group; P < 0.01 by chi-square).
Measurement of ankle swelling with spring calipers provided a more objective indication of the
degree of acute arthritis. In each experiment, ankle
swelling was significantly greater in the RCMV group
(Table 1).
The acute arthritis stage, as indicated by
erythema and swelling, was mostly gone by day 3542
after type I1 collagen immunization. After this time,
joints in RCMV-infected animals appeared to become
more deformed than did joints in the control group
(Figure 2). The degree of bone deformity was assessed
radiographically (Figure 3). There was a greater degree
of bone erosions, new bone formation, ankylosis, and
deformity in the RCMV group (Table 2).
DISCUSSION
Rat cytomegalovirus infection significantly enhanced the severity of type I1 collagen-induced arthritis in DA rats. The enhanced arthritis was detected by
a number of measurements: gross observation, direct
measurements of swelling, and radiographic assessment of bone involvement. The severity of type I1
collagen-induced arthritis in the rat can be influenced
by a variety of experimental parameters, including rat
strain (11,12,14), age (8,16), sex (under certain conditions of test cross-breedings) (12,14), dose and quality
of the collagen-adjuvant emulsion (17), and animal
Figure 3. Radiographs showing extensive erosions and periosteal
new bone formation in the phalangeal, metatarsal, and tarsal bones
of a rat 45 days after receiving rat cytomegalovirus plus type I1
collagen (right), versus minimal erosions and periostitis seen in the
foot of a control rat which received normal rat salivary gland and
type I1 collagen (left). Rats were studied in experiment 11A.
stress (18,19). Only one other study has questioned the
effect of infectious agents on collagen-induced arthritis: Taurog et a1 (20) showed that simultaneous infection of specific pathogen-free Lewis rats with Mycoplasma pulmonis and immunization with type I1
collagen led to a decrease in the incidence and severity
of joint disease.
Table 2. Radiographic assessment of type I1 collagen-induced
arthritis in rat cytomegalovirus (RCMVkinfected rats and control
rats treated with normal rat salivary gland
Radiographic score (mean 2 SD)
Experiment 11A
Experiment 11B
RCMV
group
12.1 2 1.88*
9.7 f 1.73*
* P < 0.01 versus controls, by
Student’s t-test.
5.9 2 0.99
5.5 f 1.31
CMV AND TYPE I1 COLLAGEN ARTHRITIS
In an attempt to reduce the effect of these
variables, we allocated littermates to virus and control
groups with sex and age matching, immunized virus
and control groups with the same type I1 collagen
emulsion in an alternating protocol, subjected both
groups to similar stresses of examination and bleeding,
and isolated both virus and control groups in the same
room to reduce the likelihood of introduction of new
infectious agents such as Mycoplasma. Although some
animals in our study groups had antibodies to indigenous infectious agents such as PVM and SDA, the
occurrence of infections and the levels of antibody
titers were the same in RCMV and control animals; it
is therefore unlikely that these viruses influenced the
outcome. The results were consistently reproduced in
5 separate experiments, which leads us to believe that
RCMV infection was probably the single variable that
was most responsible for the enhanced severity of the
arthritis.
Similar approaches to studying the effect of
viral infections in experimental models of autoimmunity have been reported in animal models of experimental allergic encephalomyelitis (EAE). Hochberg (2 1)
induced EAE in Lewis rats after they had recovered
from herpes simplex virus (HSV) encephalitis. After
recovery from EAE, rechallenge with HSV caused a
recrudescence of neurologic symptoms and pathologic
changes indicative of reactivated EAE. Massanari (22)
reported that the incidence and severity of EAE in
hamsters could be greatly accentuated if the animals
had been “primed” by the prior induction of measles
encephalitis. The only study we found on the effect of
viral infection on an animal model of arthritis is by
Garlinghouse and van Hoosier (23). They found that
Sendai virus infection initiated 7 days before immunization with Freund’s complete adjuvant had an inhibitory effect on the development of adjuvant arthritis in
rats. In none of these models was it possible to
elucidate the mechanism for the effect of the viral
infection on the experimental autoimmune disease.
There are several possible explanations for
the enhanced effect of RCMV infection on type I1
collagen-induced arthritis which was observed in our
study. Viral infection of synovial tissues could have
accentuated the severity of the arthritis. In humans,
cytomegalovirus can cause viremia and involvement
of many different body organs, particularly in immunosuppressed individuals (3). Of particular relevance to this study are 2 reports of the isolation of
human CMV from joint tissues or fluid of 2 patients
with rheumatoid arthritis (24,25). The relative rarity of
1267
such reports, compared with the relatively large number of studies that have sought evidence of viral
infections in rheumatoid arthritis (26), and the lack of
a particular tropism of cytomegaloviruses for synovial
tissues in animal models, lead us to suspect that
cytomegaloviruses are occasionally and incidentally
found in synovial tissues, rather than being common
arthritogenic agents.
In our experimental model, RCMV infection
alone did not produce clinical evidence of arthritis. In
addition, we were unable to isolate RCMV from
synovial tissues that were cultured when rats died at
the peak of arthritis (3-4 weeks after the onset of the
disease). It is possible that more vigorous culture of
synovial tissues earlier in the course of the arthritis
and the use of in situ hybridization probes for latent
CMV in synovial tissues may yield evidence of synovial virus infection, and we are currently pursuing
studies to investigate this.
Cytomegaloviruses are known to cause a variety of alterations in the immune system in humans and
in experimental infections in laboratory animals (3).
Often the effect of CMV infection has been described
as immunosuppressive (3). In some reports, however,
an early stimulating effect of CMV on some lymphocyte functions has been described (27). We have
recently shown that in the first 7 days after infection of laboratory rats with mouse CMV (28) and rat
CMV (unpublished observations), there is a transient
period when lymphocytes are hyperresponsive to
mitogens. These observations and the enhanced type
I1 collagen arthritis seen following RCMV infection
suggest that the enhanced arthritis is due to enhancement of an autoimmune process. It is possible, however, that the enhanced arthritis could be due to a
general enhancement of inflammation unrelated to
autoimmune processes.
Studies to assess the effects of RCMV infection
on specific measures of cellular and humoral immunity
to type 11 collagen are currently under way in our
laboratory. Because the relative roles of antibodyversus cell-mediated immunity to type I1 collagen in
the pathogenesis of this experimental arthritis are still
a subject of controversy (3,our studies of the mechanism of the RCMV-enhancing effect may help to
clarify the mechanisms of pathogenesis of the arthritis. This animal model system for study of the mechanism of virus enhancement of a pathologic autoimmune rheumatic process may also have relevance for
improving our understanding of rheumatoid arthritis
in humans.
1268
SMITH ET AL
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