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Lentivirus infection augments concurrent antigen-induced arthritis.

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LENTIVIRUS INFECTION AUGMENTS CONCURRENT
ANTIGEN-INDUCED ARTHRITIS
KEITH L. BANKS, CINDY A. JACOBS, FRANK H. MICHAELS, and WILLIAM P. CHEEVERS
Experimental antigen-induced arthritis was
compared in normal goats and goats infected with
caprine arthritis-encephalitis virus. Although acute arthritis was the same in infected and uninfected animals,
the disease lasted 16 weeks longer in the caprine arthritis-encephalitis virus-infected goats. Our findings suggest that the arthritis caused by this virus is due to
events other than, or in addition to, the immune reaction to viral antigens.
Caprine arthritis-encephalitis virus (CAEV) is a
retrovirus of the lentivirus subtype (1). There is a
marked variation in the expression of arthritis resulting from CAEV infection; it ranges from no demonstrable disease to severe crippling disease (2). The
arthritis is usually episodic, and goes through stages of
progression and remission from unknown causes. The
lesions that occur are accumulations of lymphocytes,
macrophages, and a few plasma cells within the
synovial membranes that are morphologically similar
to rheumatoid arthritis of humans (3-9). Our knowledge of the pathogenesis of these lesions is incomplete. Antiviral immune responses, including the reaction of virus-specific lymphocytes (10,ll) and antibody
(8,10,12), have led to the suggestion that the lesions
From the Department of Veterinary Microbiology and
Pathology, Washington State University, Pullman.
Supported by PHS grant AM-27680 from the NIADDK and
by USDA Agricultural Research Cooperative Agreement 58-YAHZ2-679.
Keith L. Banks, DVM, PhD; Cindy A. Jacobs, PhD; Frank
H. Michaels, MS; William P. Cheevers, PhD.
Address reprint requests to Keith L. Banks, DVM, PhD,
Department of Veterinary Microbiology and Pathology, Washington
State University, Pullman, WA 99164.
Submitted for publication October 24, 1986; accepted in
revised form March 9. 1987.
Arthritis and Rheumatism, Vol. 30, No. 9 (September 1987)
are induced primarily by the interactions between viral
antigens and these host immune responses (13-16).
However, this explanation is based on correlative data
and does not rule out the possible contribution of other
events in the development of the inflammatory lesions.
Macrophages are the major, if not the only, cell
type infected by the CAEV (3,17-21) and the maedil
visna virus (14,19,22-25), a closely related lentivirus.
Recent studies have shown that infection by these
viruses is associated with increased expression of
class I1 histocompatibility antigens (26), the production by infected macrophages of a factor that stimulates T lymphocytes to secrete a unique interferon
(1 9), and an increase in macrophage participation in
the proliferation of lymphocytes stimulated with
mitogens (27). Because of the role of macrophages in
inflammation and arthritis and these recent findings
that indicate enhanced macrophage capacity during
lentivirus infection, we suggest that CAEV infection of
macrophages may alter inflammatory events, such that
infected animals have enhanced reactions to nonviral,
as well as viral, inciting events. From this hypothesis
we predicted that antigen-induced arthritis will be
more severe in CAEV-infected animals. We report
here our findings that CAEV infection and antigeninduced arthritis result in a progressive arthritis, whereas
antigen-induced arthritis alone results in only acute
arthritis.
MATERIALS AND METHODS
Experimental design and animals. Similar studies
were conducted approximately 1 year apart using 9, groups of
animals.
Experiment 1 was conducted with 12 2-month-old
Saanen goats. The goats were immunized subcutaneously in
LENTIVIRUS AUGMENTATION OF ARTHRITIS
the first week with 1 mg of methylated human serum albumin
(mHSA) emulsified in 1 ml of Freund’s complete adjuvant,
and in the second week with 1 mg of mHSA suspended in
saline. Human serum albumin (Sigma, St. Louis, MO) was
methylated as described by Crowle et a1 (28). In the second
week, at the same time as immunization, 6 of the goats were
given 1 x lo7 tissue culture infective dose 5O%/ml
(TCIDSdml) of CAEV intravenously and fed 5 x lo6
TCIDSdml of CAEV in milk. The remaining 6 goats were
given control medium intravenously and in milk. Virus
inoculum was prepared from tissue culture-infected synovial
membrane cells, as previously described (29) and control
medium was prepared from similar cells that were not
infected with CAEV. During the sixth week, all goats
received an intraarticular injection of 200 pg of mHSA in
saline in the left carpal joint, and an intraarticular injection of
saline in the right carpal joint.
Experiment 2 was conducted with 10 Saanen goats
from the same herd as the goats in experiment 1. The goats
were 5 months old at the first immunization. These goats
were immunized, infected, and injected intraarticularly by
the same procedure and at the same time intervals as the
goats in experiment 1, except that infected goats did not
receive CAEV orally. The goats in experiment 2 were only
studied for the first week after intraarticular injection of
mHSA.
Infection of virus-inoculated goats was confirmed by
the use of established techniques to demonstrate anti-CAEV
antibody (2) and/or the presence of CAEV; likewise,
noninfected goats lacked antibody to CAEV.
Measurement of clinical arthritis. After hair was
removed from the forelegs, the circumference of each carpus
was measured in a transverse plane at the level of the
accessory carpal bone when the leg was extended. At the
same time, the circumference of the metacarpus was measured at midshaft. A carpal:metacarpal (c:m) ratio was
calculated by dividing the carpal joint circumference by the
circumference of the metacarpal joint. This ratio is a quantitative measure of carpal joint swelling that is independent
of the growth of the joint as the animal ages. Noninoculated
joints have a relatively constant c:m ratio as the goats grow.
Carpal and metacarpal measurements were taken before
immunization and CAEV infection, daily for 1 week after
intraarticular injection, and 1 or 2 times each week for the
remainder of the experiment. Statistical differences in joint
swelling among the goats were analyzed by Wilcoxon rank
sum analysis and differences in the right and left carpal joints
of the same goat were analyzed by the Wilcoxon sign rank
test. The c:m ratios of groups of animals are expressed as the
mean k SEM.
Synovial fluid analysis. Synovial fluid (SF) samples
were collected during weeks 19 and 24 of experiment 1.
These samples were aspirated from left and right carpal
joints, diluted 1:5 in RPMI 1640 medium, and centrifuged at
450g for 30 minutes at 4°C to isolate the S F cells. The cells
were washed in calcium- and magnesium-free Hanks’ balanced salt solution, counted, and characterized morphologically by nonspecific esterase and Wright’s-stained cytosmears (30). Lymphoblastogenesis assays were performed
only on SF cells from infected goats (only these goats had
enough cells for this analysis), using the same technique
1047
described previously for peripheral blood mononuclear cells
(1 1). These cells were stimulated with 6 pg of mHSA or 6 pg
of purified protein derivative (PPD). In addition, SF cells
were incubated with heat-killed CAEV, isolated from
synovial membrane cell cultures as previously described
(ll), and added to the cultures at a concentration equivalent
to 0.5 infectious virus units per SF lymphocyte in culture.
Synovial fluid was analyzed for CAEV at weeks 19
and 24 of experiment 1 and during week 1 of experiment 2.
As described previously (131, concentrations of CAEV were
determined by adding twofold dilutions of SF to cultures of
caprine synovial membrane cells and then observing these
indicator cells for 2 weeks for the cytopathic effect characteristic of CAEV infection. These titrations were expressed
as those cultures with 50% of the replicates infected, or the
TCIDSo. When the samples collected at week 24 failed to
show the cytopathic effect by the end of the first 2 weeks of
testing, they were cultured for an additional 2 weeks and
were then reported as “virus detectable” or “undetectable.”
Gross and microscopic pathology. At the end of the
experiment, the goats were euthanized. The synovial membranes of the radiocarpal sac and tarsal joint, and sections of
the liver, lung, spleen, kidney, and thymus were formalinfixed, stained, and mounted for microscopic examination.
RESULTS
Dynamics of joint swelling after induction of
antigen-induced arthritis. The goats used in experiment 1 were examined for all the parameters described
below. In the goats used in experiment 2, only the
concentration of CAEV and the number and types of
cells present were determined, 5-6 days after mHSA
injection into the left carpus.
Carpal joint swelling was compared in CAEVinfected and noninfected goats after intraarticular injection of mHSA into the left joints and saline into the
right joints (Figure 1). Before injection, the c:m ratios
were the same in the 2 groups of goats (1.73 2 0.005).
Within 24 hours of the injection of mHSA, the left
j o i n t s became swollen, reaching c:m ratios of
1.94 t 0.04 and 1.94 & 0.05 for infected and noninfected goats, respectively. At 24 hours, the joints were
erythematous and warm and the goats were unable to
bear weight on their left legs. These signs continued
for 48 hours in all goats, but began to disappear in
some goats 3 days postinjection. During this acute
reaction to the injected antigen, there were no differences between infected and noninfected goats in the
degree of swelling or loss of function. There was no
swelling or loss of function in the right joints that
received an injection of saline.
By 1 week after injection of mHSA, the swelling in the left carpus of the noninfected goats began to
subside (c:m ratio 1.81 k 0.04), while the left joints of
1048
BANKS ET AL
2 05
-
2.00
-
u Right
1.95
-
0----0 L e f t Infected
MRight Infected
1.90
-
1.85
-
o----Q
0
.m
a
(11
P
m
+.
:
1.80
1.75
m
-+
1.70
-
1.65
-
1.60
joints.
Left Uninfected
Uninfected
1
1
I
1
I
I
1
1
1
1
..
1
1
I
I
I
I
I
+ = baseline.
the infected goats remained swollen (c:m ratio
1.92 :
0.04). All animals walked normally 2 weeks
after injection. By 3% weeks after intraarticular injection of the antigen, the swelling in the noninfected
goats had returned to the preinoculation range (c:m
ratio 1.73 0.03), whereas in CAEV-infected goats
the joints were persistently swollen (c:m ratio
1.89I! 0.04). The mHSA-injected joints of infected
goats continued to be swollen throughout the remaining 19 weeks of the study, while the joints of the
noninfected goats that were similarly treated showed
no diflerence from the saline-injected joints for the rest
of the experiment. The joint swelling of the left,
antigen-injected joint of CAEV-infected goats was
significantly greater than that in the noninfected goats
( P < 0.001) 1 week postinjection of mHSA and remained significantly different for 16 weeks (Figure 1).
Beginning at week 12 (11 weeks after CAEV
infection), 4 of the 6 CAEV-infected goats had swelling of the right carpus (c:m ratio 1.82 0.02). This
swelling of the right carpus of all the infected goats
was significantly greater (P < 0.02) than that in the
*
*
right joints of noninfected goats for the remainder of
the experiment. For example, the mean c:m ratio at 14
weeks was 1.81 -+ 0.04 for the infected goats and
1.71 + 0.02 for uninfected goats (Figure 1). However,
the swelling of the antigen-injected joints in the infected goats was always significantly ( P < 0.02)
greater than the swelling of the contralateral right
joints, as illustrated by the c:m ratios given in Table 1.
Analysis of synovial fluid. Synovial fluid was
obtained by arthrocentesis at week 19 (14 weeks after
intraarticular injection), and directly from the open
carpus when the goats were killed at week 24. These
specimens were examined for the number and type of
cells present, the presence of CAEV, and the SF cell
blastogenic reactivity to antigens. The number of cells
in the joints of each goat at week 19 is displayed in
Table 1 . The antigen-injected left joint of the infected
goats contained 50-3,853 X lo4 cellslml, while the
same joint of the noninfected goats contained 6-26 x
lo4 cells/ml. This difference was pronounced in 5 of the
6 CAEV-infected goats; the 1 remaining CAEVinfected goat had only a small number of cells in the
LENTIVIRUS AUGMENTATION OF ARTHRITIS
1049
Table 1. Joint swelling (carpa1:metacarpal [c:m] ratio), synovial fluid cell number, and synovial
fluid virus titer 19 weeks after the beginning of immunization and 14 weeks after the injection of
antigen into the left carpal joint and saline into the right carpal joint of caprine arthritis-encephalitis
virus (CAEV)-infected and noninfected goats
Synovial cells
( x 104/mi)
c:m ratio
Virus titer*
Goat
Left
Right
Left
Right
CAEV-infected
156
159
164
I65
I67
I74
Mean ? SD
Noninfected
1.93
2.15
2.26
2.10
1.92
1.92
2.05 t 0.14
1.85
1.99
1.86
1.96
1.88
1.78
1.88 5 0.08
450
1,967
3,853
73 1
1,200
50
4
3
261
11
1,632
1.709
1.82
1.73
I .83
I .78
1.86
1.78
1.80 t 0.05
1.79
I .76
1.76
1.75
1.79
1.79
1.77 t 0.02
8
9
17
6
26
7
1
4
7
6
3
I
151
157
161
168
169
171
Mean t SD
* The tissue culture infective dose 50%/ml of CAEV in synovial fluid. +
=
Left
+
+
3,162
Right
0
0
0
0
0
630
0
660
0
0
0
0
0
0
0
0
0
0
0
0
+
detectable but not titratable;
0 = undetectable.
left joint. The saline-injected right joint of noninfected
goats contained slightly fewer cells (1-7 x lo4 cells/ml)
than the left, while the right joint of 3 infected goats at
week 19, and 4 infected goats at week 24 contained
2100 x lo4 or more cells.
The cells in the SF of both infected and
noninfected goats from experiment 1 were predominantly lymphocytes and macrophages; <3% of the
cells were neutrophils. Seventy percent or more of the
cells from the left and right joints of noninfected goats
were macrophages. In 4 of the CAEV-infected goats,
the number of macrophages was greater than than the
number of lymphocytes; in the other 2 infected goats,
the number of lymphocytes was greater than or equal
to the number of macrophages. The types of cells were
similar at week 19 and week 24. In contrast, during the
acute stage of arthritis in experiment 2 , the cells were
>95% neutrophils.
To determine if there was a difference in the
amount of CAEV in the left and the right joints of
infected goats, titrations for CAEV were performed at
week 19 (Table 1) and week 24 (data not shown) of
experiment 1 . At week 19, 4 goats had detectable
CAEV in the left carpus (2joints were titratable) and 2
had detectable virus in the right carpus (1 was titratable). Findings on other samples were negative. At
week 24, 3 left carpi had titratable virus, and none of
the right carpi had titratable CAEV. By these criteria,
5 of 6 goats had CAEV in the left carpus, while 2 had
virus detectable in the right carpus. Noninfected goats
lacked detectable CAEV infection. There was no
correlation between the degree of swelling of the
joints, number of cells in the joints, and the amount of
virus present.
Studies on experiment 2 goats were performed
to determine if CAEV was present earlier than 19
weeks into the course of the antigen-induced arthritis.
Within 24 hours of mHSA injection, these goats had
severely swollen joints and were lame in their left legs.
The c:m ratio of mHSA-injected joints of infected
goats was 2.03 ? 0.08, while that of the noninfected
goats was 1.94 +- 0.06. Saline-injected right joints had
no swelling, with c:m ratios of 1.78 ? 0.04 and
1.69 '-+ 0.04 for infected and noninfected goats, respectively. Synovial fluid was collected by arthrocentesis from the right and left carpal joints 5 or 6 days
after the injection of mHSA. CAEV was not detected
in any of the synovial samples.
Synovial fluid cells were cultured with mHSA,
inactivated CAEV, and PPD. Because sufficient numbers of cells were not available from noninfected
goats, the lymphoblastogensis assay was performed
only with samples from CAEV-infected goats that had
r l x lo6 SF cells. The S F cells from mHSA-injected
joints reacted positively to mHSA in 6 of 8 tests (Table
2). When S F cells from the saline-injected right joints
1050
BANKS ET AL
Lymphoblastogenesis of synovial fluid cells from caprine arthritis-encephalitis virusinfected goats in the presence of medium and methylated human serum albumin (mHSA) at weeks
19 and 24 of the experiment*
Table 2.
Week 24
Week 19
Goat
156
RPMI
mHSA
159
RPMI
mHSA
164
RPMI
mHSA
165
RPMI
mHSA
167
RPMI
mHSA
174
RPMI
mHSA
Left
carpal
joint
Right
carpal
joint
Left
carpal
joint
Right
carpal
joint
8,488 f 523
9,691 f 391
ND
ND
ND
ND
ND
ND
4,566 t 844
25,549 2 6,402
ND
ND
1,739 t 259
16,011 k 666
ND
ND
10,896 f 376
20,181 f 1,027
9,860 t 1,512
12,913 k 628
ND
ND
ND
ND
5,744 t 89
21,993 2 2,437
ND
ND
1,629 t 158
11,947 f 941
2,959 f 242
12,130 t 555
8,624 f 428
37,992 f 1,098
3,588 f 361
33,799 2 2,010
ND
ND
7,991 f 646
28,685 -+ 2,375
4,353
7,407
f
310
1,198 f 358
4,721 2 123
f 634
ND
ND
3,100 f 178
8,424 f 343
* Synovial fluid cells were collected at weeks 19 and 24 of the experiment, cultured with 6 pg of mHSA
or RPMI 1640for 5 days, and assayed for 3H-thymidineincorporation. Values are the mean cpm SEM
of 5 replicate assays. ND = not done because of insufficient cell numbers.
*
were assayed, results of all 6 tests were positive. The
SF cells from the left joints of 3 of 4 goats responded
to CAEV, while cells from 2 of 4 of the right joints had
similar reactions (Table 3). There were sufficient
synovial cells available from 3 goats to test for the
blastogenic reaction to PPD. Cells of the left carpal
joints of 2 goats had proliferation 8- and 77-fold greater
than the nonstimulated cultures, while SF cells of
another goat had less than twofold stimulation by PPD
(data not shown).
Gross and microscopic pathologic examination.
The right carpal joints of noninfected goats were
normal, having neither gross nor microscopic lesions.
The right carpal joints of all 6 infected goats had
inflamed synovial membranes. In 4 infected goats,
these lesions ranged from mild focal to mild diffuse
infiltration of mononuclear cells, while the other 2
infected goats had more extensive infiltration of lymphocytes and macrophages, forming nodules of
lymphoid tissue. In the left carpal joints of noninfected
goats, which had received mHSA 19 weeks previously, the adipose tissue beneath the cells of the
synovial lining was replaced by immature collagen
Table 3. Lymphoblastogenesis of synovial fluid cells from
caprine arthritis-encephalitis virus (CAEVbinfected goats in the
presence of medium and CAEV at week 24 of the experiment*
Goat
Left carpal
joint
Right carpal
joint
~
156
RPMI
CAEV
159
RPMI
CAEV
164
RPMI
CAEV
165
RPMI
CAEV
167
RPMI
CAEV
174
RPMI
CAEV
~_____
806 t 224
10,749 f 546
ND
ND
1,739 f 259
3,744 f 273
ND
ND
ND
ND
5,395 2 225
4,487 f 1,350
1,629 f 158
4,561 2 1,017
4,353
5,553
f
f
ND
ND
310
643
2,959 f 242
8,082 2 520
1,198 2 358
5,215 f 181
3,199 f 178
2,199 2 563
* Synovial fluid cells were collected at week 24 of the experiment,
cultured with RPMI 1640 or inactivated CAEV for 6 days, and
assayed for 3H-thymidineincorporation. Values are the mean cpm f
SEM of 5 replicate assays. ND = not done because of insufficient cell
numbers.
LENTIVIRUS AUGMENTATION OF ARTHRITIS
fibers mixed with rare tissue macrophages. In contrast, 5 of 6 CAEV-infected goats had marked
synovitis in the left carpal joints. The synovial membrane was grey-red, soft, villous tissue extending into
the synovial space from several locations on the joint
lining. No cartilaginous changes were noted, but fibrin
occasionally attached the excess synovium to adjacent
structures. The synovium always contained subsynovial accumulations of lymphocytes and macrophages.
The extent of this infiltration of mononuclear inflammatory cells varied. The left joints of 2 infected goats
had patchy to confluent areas of inflammation, while 3
other joints had massive infiltration that extended into
adjacent collagenous tissues, and necrosis and fibrin at
the tips of the most affected synovial villi. The left
joint of 1 infected goat had few areas of infiltration. In
summary, the noninfected goats had very little arthritis in any of the carpal joints, while 4 of 6 of the
CAEV-infected goats had more severe arthritis in the
left joint than in the right.
Only 1 CAEV-infected goat had lesions in the
synovium of the tarsal joints, and they were typical of
virus-induced synovitis. No gross or histologic differences were noted in the liver, spleen, thymus, kidney,
or lungs of CAEV-infected and noninfected goats, and
no differences in total body weight or in the weights of
the spleen or thymus were observed.
DISCUSSION
The arthritic inflammation that was induced by
intraarticular injection of antigen in sensitized goats
remained for approximately 16 weeks longer in the
CAEV-infected goats than in the noninfected goats.
This difference was demonstrated by the presence of
greater joint swelling, more lymphocytes and macrophages in the SF, and more severe histopathologic
lesions. At least 5 mechanisms may explain the increased severity of the antigen-induced arthritis in
CAEV-infected goats.
First, injection of mHSA may have caused
greater CAEV antigen expression, possibly through
CAEV replication in inflammatory macrophages, and
the combined immune response to the viral antigens
and mHSA resulted in arthritis of greater severity. To
address this possibility, we examined the joints of
goats for infectious CAEV. In experiment 1, joints
were cultured twice late in the experiment; the joints
of the goats in experiment 2 were cultured within 5 or
6 days of mHSA injection. Only slightly more virus
was detected in the antigen-inoculated joints of the
1051
goats in experiment 1 . These amounts were very
similar to those previously observed in goats that were
not subjected t o antigen-induced arthritis (13). There
was no correlation between the amount of virus and
the degree of joint swelling, and the differences between virus titer in the right and left joints were small.
There was no difference in the amount of virus detected in the left and right joints of the goats in
experiment 2.
It is possible that we did not test at the appropriate times or that viral antigen was produced but
infectious virus was not. Howe.c:er, if the arthritis was
caused by a greater immune response to CAEV, we
would have expected immune reactivity to CAEV
antigens by synovial fluid lymphocytes to be greater in
cells of the left joints than in the right joints, and this
was not observed. In addition, the magnitude of the
reaction of CAEV antigen was no greater than that to
mHSA or PPD, which indicated that there were no
more SF cells reactive to CAEV than to those other 2
antigens. Therefore, it is unlikely that the prolongation
of arthritis in those joints of CAEV-infected goats
receiving antigen is due solely to greater virus expression and subsequent immune response to the newly
expressed viral antigens.
The remaining 4 mechanisms that could account for the greater antigen-induced arthritis in
CAEV-infected animals stem from the ways CAEV
infection of macrophages influences the events involved in antigen-induced arthritis. Findings from this
study and from others provide some indication of
which of these mechanisms may be involved in this
process. The infected macrophages may have decreased or increased functions. For example, the
macrophages of the infected goats may not degrade the
mHSA as well as the macrophages of uninfected
animals. This may allow the mHSA to persist longer in
the infected joint and, thus, the immune reactivity may
proceed for longer periods. Alternatively, CAEV infection of macrophages may enhance functions of
infected macrophages, so that Stimulation of the immunized synovial environment by mHSA has a greater
inflammatory reaction and an increased immune response. Either of these 2 possibilities would be expected to induce differences in amounts of antibody
and delayed hypersensitivity to mHSA in infected and
uninfected animals, but when we examined these
parameters in the 2 groups of goats, we found no
differences (data not shown).
Another reaction of macrophages that may be
altered by CAEV infection is their rate of division. We
1052
BANKS ET AL
examined this possibility previously, and we found
that indeed, synovial macrophages of infected animals
divide 3-6 times more than do macrophages from
uninfected animals (31). The greater division can account for the increased number of macrophages in the
synovial fluid, and there is a positive correlation
between the degree of division and the amount of
arthritis. The increased division is associated with
increased response of macrophages from infected animals to soluble factors produced by phytolectinstimulated lymphocytes (31). These findings support
the notion that the larger number of macrophages in
the lesions provoked by antigen-induced arthritis was
due to the release of mitogenic factors from lymphocytes stimulated by the injection of mHSA, followed
by a greater proliferation of macrophages from CAEVinfected animals to these growth factors.
A fifth explanation of how CAEV produces
more severe antigen-induced arthritis may involve
how lymphocytes and monocytes localize at sites of
inflammation. Activated macrophages induce neovascularization (32-34). An overreaction of this macrophage function could lead to more vessels with receptors for mononuclear cells (35,36) in infected goats,
thereby providing a means for localization of the
inflammatory cells in the synovial membrane. The net
result would be more severe arthritis in the stimulated
joint of infected animals, which was the result we
noted. Evidence that CAEV may increase the capacity
of macrophages to induce neovascularization and subsequent localization of lymphocytes in the joints is
being sought.
The findings reported here suggest that the
pathogenesis of the arthritis induced by CAEV may
involve accelerated inflammation to viral and/or
nonviral antigens. A detailed explanation of how stimulation of infected macrophages leads to progressive
arthritis requires further studies to document the
amount of viral antigen released and the functional
changes that occur in infected macrophages.
ACKNOWLEDGMENTS
We thank J. L. Carlson, Deta Stem, and Cheryl
Haugo for expert technical assistance, and Mark Jutila for
helpful discussions.
REFERENCES
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Chronic arthritis in goats caused by retrovirus. Science
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1981
3. Adams DS, Crawford TB, Klevjer-Anderson P: A
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4. Brassfield AL, Adams DS, Crawford TB, McGuire TC:
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virus infection. Infect Immun 41:805-815, 1983
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