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Ultrastructure of arthritis induced by a caprine retrovirus.

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930
ULTRASTRUCTURE OF ARTHRITIS INDUCED
BY A CAPRINE RETROVIRUS
ALBERTA L. BRASSFIELD, D. SCOTT ADAMS, TIMOTHY B. CRAWFORD,
and TRAVIS C. McGUIRE
nective tissue disease in adults is described primarily
as chronic, debilitating arthritis, bursitis, and tenosynovitis, with occasional inflammatory lesions seen in
other organs, such as the mammary gland and kidney,
and in skeletal muscle and blood vessels (I-3,8). The
prevalence of clinical disease is estimated to be between 0-25% in different goat herds; however, results
from an agar gel immunodiffusion test that detects
antibody to CAEV demonstrates that 80-90% of domestic goats that are tested are seropositive (1 1).
Connective tissue lesions in this induced disease begin as mild, multifocal synovitis with hypertrophic synovial lining cells and perivascular mononucleCaprine arthritis-encephalitis (CAE) is a virusar inflammatory cell accumulations (2,8). As these
induced disease of goats most commonly characterlesions progress, villi become hypertrophied because
ized by a chronic progressive arthritis in adult animals
of synovial lining cell hyperplasia and mononuclear
(1-4) and a chronic demyelinating leukoencephalocell infiltration. Lymphoid follicle and germinal center
myelitis in kids 2-4 months of age (5-8). The causative
formation is common later in infection. Blood and
agent, CAE virus (CAEV), is a newly described memfibrin are also deposited beneath the synovial member of the retrovirus family, closely related to visna
brane. Blood vessels are surrounded by heavy cuffs of
and progressive pneumonia viruses (1,8-10). The conmononuclear inflammatory cells, and vascular endoI
, thelial cells are hypertrophic and appear by light
From the Department of Veterinary Microbiology and
,-microscopy
to encroach on vascular lumina (2). CAE
Pathology, Washington State University, Pullman, WA.
Supported in part by a Research Initiation and Support
viral antigens detected by immunofluorescence are
Grant from the National Science Foundation, the Kroc Foundation,
present in cells from synovial fluid of infected goats 1
the National Institutes of Health Grant AM 27680, and the Agriculto 10 days after inoculation and in synovial membrane
tural Research Center of Washington State University, project no.
0432, paper no. SP 6047.
lining cells 6 and 9 days after inoculation (2). Although
Alberta L. Brassfield, MS: Research Technologist, Washviral antigens could not be demonstrated by immunoington State University; D. Scott Adams, DVM, PhD: Veterinary
fluorescence 10 days after inoculation, virus was isoMedical Officer, U.S. Department of Agriculture, Pullman, WA;
Timothy B. Crawford, DVM, PhD: Veterinarian, Sherburn, MN;
lated from all inoculated goats from which isolation
Travis C. McGuire, DVM, PhD: Professor, Washington State
was attempted up to 79 days after inoculation (2).
University.
Address reprint requests to Alberta L. Brassfield, MS,
Cell-mediated and humoral immune responses
Department of Veterinary Microbiology and Pathology, Washington
of CAEV-infected goats were monitored for 9 months
State University, Pullman, WA 99164.
after infection and compared with responses of control
Submitted for publication October 7, 1981; accepted in
goats (4). Proliferation of infected and control monorevised form January 6, 1982.
The ultrastructure of early retrovirus-induced
arthritis was studied sequentially in 20 goat kids inoculated with caprine arthritis-encephalitis virus. Synovial
lesions began as intercellular edema and collagen fragmentation and continued as progressive mononuclear
cell infiltration and lining cell hyperplasia, hypertrophy,
and necrosis. At 18 through 45 days after the inoculation, lining cells contained small accumulations of viruslike particles similar to virus seen in infected tissue
culture cells. No virus was seen budding from infected
lining cell membranes.
Arthritis and Rheumatism, Vol. 25, No. 8 (August 1982)
ULTRASTRUCTURE OF CAEV ARTHRITIS
nuclear cells in response to phytohemagglutinin and
lipopolysaccharide B were not significantly different,
indicating no immune suppression or potentiation
caused by the infection. W hen CAEV antigens were
tested, there was a significant increase in the response
of infected mononuclear cells as compared with control cells. Antibody to virus appeared from 21 to 35
days after infection and continued to be present for the
length of the monitoring period. In spite of these
vigorous cell-mediated and humoral immune reactions
mounted to CAEV infection, virus was isolated from
peripheral blood mononuclear cells (4).
The purpose of these studies was to characterize the fine structure of a well-defined virus-induced
arthritis, attempt location of the sites of viral replication in vivo, and correlate these data with results from
other pathogenetic studies. To evaluate the virus-like
particles found in vivo, it was necessary t o compare
their morphology with CAE virus particles in tissue
culture cells.
MATERIALS AND METHODS
Animals. Because of the high prevalence of CAEV in
the U.S. goat population, as indicated by the presence of
antibody (1 l), cesarean derivation of specific-pathogen-free
experimental kids was necessary. Colostrum was withheld
from these kids; however, they were given seronegative goat
serum to provide passive transfer of immunoglobulins ( 2 ) .
The kids were fed cow milk and isolated from all other goats.
Virus. The isolation and passage history of CAEV
used as inocula have been described ( 2 ) . Culture medium
from uninfected synovial membrane cultures was the control
inoculum.
Tissue culture. Synovial membranes for CAEV isolation were asceptically collected from a 4-year-old arthritic
goat and minced into 1x1-mm fragments. After being
washed with Dulbecco eagle’s modified medium (DMEM),
the fragments were planted into plastic flasks in DMEM with
20% inactivated fetal calf serum. Cells grew from these
explants, and characteristic cytopathic effect progressed
rapidly in scattered colonies of cells. Before being subcultured, a flask of cells was fixed for electron microscopic
examination.
Experimental design. Ten kids were injected both
intravenously (1 ml) and in the left radiocarpal joint (0.25 ml)
with an inoculum containing 106.2TCIDSO/ml infectious
virus. At 6, 13, 34, and 45 days after inoculation, two goats
were killed each day. At 18 and 20 days after inoculation, 1
goat was killed each day. In a later experiment, 10 kids were
injected both intravenously (1.75 ml) and in the left radiocarpal joint (0.25 ml) with an inoculum containing 106.5TCIDSOI
ml infectious virus. Three of these animals were killed at 3
days after inoculation, 2 at 6 days, 3 at 9 days, and 2 at 13
days. Five kids were inoculated similarly with control medium and killed at 6, 13, 27, 29, and 39 days after inoculation,
respectively. At necropsy, kids were examined for gross
lesions, and tissues were collected for morphologic and
93 1
virologic examinations. Results from light microscopic, immunofluorescent, and virus quantitation studies were reported previously (2).
Electron microscopy. Left radiocarpal synovia excised from the experimental goats were immersed in cacodylate-buffered (0. l M , pH 7.4) 2% glutaraldehyde containing
1% sucrose and 0.5% dimethylsulfoxide and minced into
1 x 1-mm pieces. CAEV-infected synovial membrane cells
grown in vitro were dispersed with trypsin, fixed in cacodylate-buffered glutaraldehyde, and centrifuged into 2% agar.
Tissues and agar-embedded cells were washed in cacodylate
buffer, postfixed in I% osmium tetroxide, and stained en
bloc with 1% aqueous uranyl acetate. After dehydration
through a graded series of ethanols and propylene oxide,
tissues and cells were embedded in Epon-DDSA-Araldite.
Thick sections were cut on an ultramicrotome and stained
with a polychrome stain for light microscopic examination.
Ultra-thin sections were cut, stained with uranyl acetate and
lead citrate, and examined with an electron microscope at 60
kV.
RESULTS
Morphology of joint tissue from control goats.
Since goat synovial membrane ultrastructurally resembled synovial membrane from human, rabbit, and
sheep (12-16), the nomenclature for synovial lining
cells in humans w a s used (12). To compare ultrastructure with light microscopic morphology, a light micrograph of synovial membrane from a control goat is
provided in Figure 1 . T ype A cells predominated at the
joint space and contained numerous membrane bound
vacuoles, vesicles, mitochondria, and prominent Golgi
systems. These cells also exhibited many surface
filopodia but had limited rough endoplasmic reticulum.
T h e preponderance of these organelles w as compatible
with the phagocytic function of type A synovial cells.
Figure 1. Light micrograph of synovium from control kid goat.
Note lining layer of 1-3 cells deep. (Original magnification x4SO.)
932
Some type A synovial cells had isolated debris with
filopodia and had engulfed amorphous membranous
structures within cytoplasmic vacuoles. Type B synovial cells were richly endowed with rough endoplasmic
reticulum but contained a paucity of vacuoles and
Golgi cisternae. These characteristics morphologically
confirmed the proposed synthetic activity of type B
lining cells. An intermediate cell, type C synovial
cells, that contained both Golgi structures and rough
endoplasmic reticulum was also observed. Subsynovial fibroblasts had scanty cytoplasm and organelles
and appeared to be inactive. Both lining cells and
fibroblasts contained vacuoles of varying size and
shape; a fibrillar coating was on the inside of portions
of these structures. Some vacuoles near the cell surface appeared to be fused filopodia or invaginations of
the plasma membrane (Figure 2).
The morphology of the numerous vessels found
in the subsynovium varied greatly. Some vessels were
patent and lined by flat endothelial cells. while others
Figure 2. Synovial membrane from goat kid inoculated with control
medium shows vacuolated type A lining cells with surface filopodia
(A), vacuolated fibroblasts (F), collagen bundles (Co), and partially
occluded vessels (V). (Original magnification ~ 4 , 3 2 0 . )
BRASSFIELD ET AL
were constricted by the intrusion of rounded endothelial cells into lumina. Patent and constricted vessels
appeared in groups with little mixing of the 2. All
endothelial cells were bounded by a basal lamina and
possessed many micropinocytotic vesicles on both
luminal and adventitial surfaces.
All the cells and vessels described were embedded in an amorphous, electron-dense matrix, containing long collagen bundles. Collagen was very prominent in the subsynovium and was found to a lesser
degree between lining cells. Lining cells and fibroblasts were dispersed throughout the matrix and
lacked cell-to-cell contact and junctions. No basal
lamina separated lining cells and the adjoining joint
space from underlying stroma (Figure 2).
Morphology of joint tissue from infected animals.
Synovia infected by CAEV for a short time-3 and 6
days after inoculation-varied little compared with
synovia from animals inoculated with control medium.
Fibroblasts and lining cells were vacuolated, and the
extremes of vascular patency or stenosis seen in
controls remained. However, there appeared to be an
increase in intercellular space, caused by edema in the
tissues. At 9 days after inoculation, easily discernible
changes were evident when compared with joint tissue
of controls. Vacuolated fibroblasts exhibited numerous surface filopodia and an increase in both rough
endoplasmic reticulum and Golgi complexes. The hyperplasia of these organelles contributed to fibroblast
hypertrophy, indicating that these cells were in a
metabolically active state. A few lymphocytes were
seen in the perivasculature of the subsynovium, and
lining cells were still separated, accentuating the
edematous appearance.
At 13 days after inoculation, collagen was disrupted into short, narrow pieces that lacked any
orientation (Figure 3) as compared with the long
bundles of perivascular collagen seen in controls.
Enlarged, vacuolated fibroblasts in areas of this fragmented collagen had many enlarged Golgi cisternae
and appeared very reactive. Synovial lining cells were
hyperplastic, hypertrophied, and spaced closely together. Some of these cells contained swollen mitochondria and degranulated rough endoplasmic reticulum, exhibited loss of cytoplasmic and nuclear
density, and lacked normal organelle architecture,
indicating cellular necrosis (Figure 3 ) . A few necrotic
lining cells appeared to be poorly attached to the
underlying matrix and extended into the joint space.
Inflammatory cells were seen in the perivascular
spaces. Micropinocytotic vesicles were reduced in
ULTRASTRUCTURE OF CAEV ARTHRITIS
Figure 3. Synovial membrane from inoculated joint at 13 days after
inoculation. Note perivascular fragmented collagen, increased intercellular space, and necrotic lining cells. (Original magnification
x 2,280.)
numbers and, instead of being aligned along the borders of the endothelial cells, were located intracellularly. All of the changes noted at 13 days after inoculation
increased in severity, and by 18 and 20 days after
inoculation the synovium was quite hyperplastic and
many mononuclear cells were present in the subsynovium.
By 34 days after inoculation, the synovial membrane was dramatically changed as compared with that
of controls. The subsynovium was heavily infiltrated
by lymphocytes and plasma cells. Lining cell hypertrophy resulted from distended, swollen, and hyperplastic intracellular organelles, notably rough endoplasmic
reticulum, Golgi structures, and vacuoles. The predominant lining cell was the synthetic type B synovial
cell. Lining cells from 1 goat were markedly vacuolated, with distended cytoplasmic organelles and large
amounts of membranous debris in the intercellular
matrix. At the joint space, necrotic lining cells appeared to be detached from underlying synovial cells,
and a few of the closely opposed lining cells were
joined by desmosomes. Fibroblasts were greatly vacuolated, but organelle proliferation had decreased, and
the cells appeared to be less active than previously
noted. Long bundles of morphologically normal collagen were again seen between cells, and there was an
increase in the amount of collagen as compared with
that seen in controls.
The lesions in the synovium at 45 days after
inoculation progressed in severity. Lining cells were
933
hypertrophied and hyperplastic, necrosis of some synovial cells occurred, and mononuclear inflammatory
cells continued to infiltrate the subsynovium (Figure
4). A light micrograph of synovial membrane at 45
days after inoculation (Figure 5 ) is provided to correlate the ultrastructural lesions with those at the light
microscope level. Deeper in the subsynovium, fibroblasts appeared similar to those from control joints.
At 18 through 45 days after inoculation, viruslike particles that consistently measured 90-1 10 nm
were observed in all 3 types of lining cells (Figure 6).
Five to 10 particles were grouped together in the
cytoplasm in close proximity to the Golgi structures.
In comparison, electron microscopic examination of
CAEV-infected tissue culture cells showed large accumulations of spike-covered virions, measuring 80-1 04
nm, free in the cytoplasm (Figure 7) and nucleus.
Mature virions budded from the tissue culture cell
membrane into cytoplasmic vacuoles and the extracellular space. No budding virus or nuclear particles were
seen in the joint tissues examined.
Ultrastructural changes seen in lining cells,
fibroblasts, and interstitia from infected goats are
summarized in Tables 1, 2 and 3. All 3 types of lining
cells were involved in the disease process (Table 1).
These cells were hypertrophied, hyperplastic, and
necrotic from 9 days after inoculation and throughout
the experiment. Virus-like particles were observed in
lining cells from 18-45 days after inoculation. In
contrast, the fibroblasts (Table 2) never exhibited any
Figure 4. Synovial lining cells from inoculated joint at 45 days after
inoculation. Lining cell organelles are hypertrophied and hyperplastic, resulting in marked cellular swelling. (Original magnification
x 2,650.)
BRASSFIELD ET AL
934
Figure 5. Light micrograph of synovium from inoculated joint at 45
days after inoculation shows lining cell hyperplasia, inflammatory
cell infiltration, and formation of lymphoid follicles and germinal
centers. (Original magnification x 100.)
hyperplasia or necrosis and were hypertrophied only
at 9-20 days. No virus-like particles were seen in any
fibroblasts. Interstitial lesions (Table 3) began as temporary edema and collagen fragmentation, then progressed to mononuclear inflammatory cell infiltration,
and finally to fibrosis.
DISCUSSION
The fine structure of joint lesions in CAEVinfected goats reflected the progression of mild synovitis to a chronic, inflamed, hyperplastic synovial mem-
Figure 7. Caprine arthritis+ncephalitis virus particles in tissue
culture cells. (Original magnification X 52,500.)
brane. Ultrastructural changes in CAEV-infected
joints were seen in 2 disparate cell types, synovial
lining cells (Table 1) and connective tissue fibroblasts
(Table 2), each of which responded differently. Fibroblasts were temporarily altered but eventually returned to an inactive state. In contrast, lining cells
were chronically involved in the disease process.
In vitro, CAEV grew in cells derived from
synovial membrane rather than cells from other organs
(1, lo). In vivo, virus-like particles morphologically
similar to virus seen in tissue culture were seen only in
infected synovial lining cells, not in fibroblasts, endoTable 1. Ultrastructural lesions in synovial membrane lining cells
from goat kids inoculated with caprine arthritis~ncephalitisvirus
DPI*
3
6
9
13
18
20
34
45
Number
of kids
3
4
3
4
1
1
2
2
Viruslike
particlest
Hypertrophy$
Hyperplash§
Necrosis7
-
-
+
+
++
+++
-
+
++
++
+++
+++
+
+
++
++
+++
+++
+
+
++
++
++
++
* DPI = days postinoculation.
t - = similar to controls; + = < 15% cells with particles; + + = 15-
Figure 6. Virus-like particles in synovial lining cell. Particles are
adjacent to hypertrophied Golgi. (Original magnification ~25,600.)
30% cells with particles; + + + = >30% cells with particles.
$ - = similar to controls; + = slight; ++ = moderate; +++ =
severe.
$ - = similar to controls; + = <10 cells thick; ++ = 10-20 cells
thick; +++ = >20 cells thick.
ll - = similar to controls; + = <5 necrotic cells per grid square; + +
= >5 necrotic cells per grid square.
ULTRASTRUCTURE OF CAEV ARTHRITIS
Table 2. Ultrastructural lesions in subsynovial fibroblasts from
goat kids inoculated with caprine arthritis-encephalitis virus
DPI*
Viruslike
particlest
Number
of kids
Hypertrophy$
-
3
6
9
Hyperplasia
Necrosis
moderate;
+++
-
+
++
+++
+++
+
13
18
20
34
-
4s
* DPI = days postinoculation.
t - = similar to controls.
$ - = similar to controls;
+
=
slight;
++
=
=
severe.
thelial cells, blood cells, or inflammatory cells. These
particles may not be virus; however, they are related
to virus infection, because they were seen only in cells
that were persistently involved in the disease process.
Although no virus was seen budding from cell surfaces
in vivo, as was noted in vitro, the inflammatory
reaction persisted throughout the experiment. This
inflammation may be directed toward virus-induced
cell-surface antigens, which have been reported in
another nononcogenic retrovirus infection, equine infectious anemia (17). Another possibility may be a
situation analogous to visna virus infection of sheep, in
which only a small proportion of infected cells actually
produce virus while the majority of cells harbor proviral DNA without replicating virus (18,19).
In later stages of CAE synovitis, the fine structure of lesions was similar to that seen in rheumatoid
Table 3.
virus
DPI*
3
6
9
13
18
20
34
45
935
arthritis and juvenile rheumatoid arthritis, with minor
differences. Like CAE, synovia in rheumatoid and
juvenile rheumatoid arthritis show marked villous hypertrophy, lining cell proliferation and necrosis, inflammatory cell infiltration, and fibrosis. Authors have
disagreed on which lining cell is hyperplastic in rheumatoid arthritis. Proposals include increased type A
synovial cells (12,20), increased intermediate and type
B lining cells (14), o r a proportional increase in both
lining cells (21).
In juvenile rheumatoid arthritis, type A cells
accounted for the increase in lining cell numbers (22).
In CAEV-infected goats, type B lining cells predominated in the sections examined. Vascular involvement
in rheumatoid arthritis varied from interendothelial
gaps (23), endothelial degeneration (231, and occlusions of vascular lumina (21). Endothelial proliferation
and adventitial hypertrophy occurred in juvenile rheumatoid arthritis (22). Other investigators have failed to
find vascular involvement in rheumatoid arthritis or
have seen similar changes in controls as we have noted
in CAE (24). The Golgi cisternae in rheumatoid arthritis lining cells are reduced (14,25) and appear quiescent; however, the Golgi structures in CAEV-infected
lining cells of this study were hyperplastic.
It is difficult to compare some aspects of ultrastructure of CAE and rheumatoid and juvenile rheumatoid arthritis because CAEV infection was studied
in a defined host, in the early stages of disease, before
clinical signs, and in the absence of pharmacological
treatments. Studies of rheumatoid and juvenile rheumatoid arthritis, however, vary markedly in patient
age, initial appearance and duration of clinical signs,
Ultrastructural interstitial lesions in goat kids inoculated with caprine arthritis-encephalitis
Number
of kids
Edema?
3
4
3
4
+
+
+
+
1
1
-
2
2
-
-
Mononuclear
inflammatory cells$
Collagen
fragmentation§
-
-
-
-
+
+
++
++
++
++
+
+
+
+
-
Fibrosis7
-
+
++
++
*DPI = days postinoculation.
- = similar to controls; + = space between cells increased.
$ - = similar to controls; + = <lo% inflammatory cells per grid square; ++ = >lo% inflammatory
cells per grid square.
5 - = similar to controls; + = fragmentation of fiber bundles.
T - = similar to controls; + = slight increase of collagen between cells; + + = moderate increase of
collagen between cells.
t
BRASSFIELD ET AL
drug treatment, and concomitant diseases. Another
comparison should be made between material from
patients with rheumatoid arthritis and material from
older, chronically arthritic goats.
CAE affords a valuable opportunity to study the
mechanisms of viral persistence and the pathogenesis
of a chronic arthritis. Because retroviruses have the
capacity to be integrated in the host genome unexpressed or with partial expression, it is feasible that
they may initiate and maintain immunologically mediated lesions in some diseases of unknown causes. As
the only mammalian model of virus-induced chronic
arthritis, CAE will hopefully provide information useful in evaluating the role of retroviruses in the cause of
arthritides in people.
ACKNOWLEDGMENTS
The authors gratefully acknowledge the excellent
technical assistance of Jan Carlson and Ruth Brown.
REFERENCES
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22. Wynne-Roberts CR, Anderson CH, Furano AM, Baron
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