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Journal of Virology, April 2000, p. 3338-3344, Vol. 74, No. 7
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Tumor Necrosis Factor Alpha-Deficient, but Not
Interleukin-6-Deficient, Mice Resist Peripheral Infection with
Scrapie
Neil A.
Mabbott,1,*
Alun
Williams,1,
Christine F.
Farquhar,1
Manolis
Pasparakis,2
Giorgos
Kollias,2 and
Moira E.
Bruce1
Neuropathogenesis Unit, Institute for Animal
Health, Edinburgh EH9 3JF, Scotland, United
Kingdom,1 and Hellenic Pasteur
Institute, 115 21 Athens, Greece2
Received 21 October 1999/Accepted 4 January 2000
 |
ABSTRACT |
In most peripheral infections of rodents and sheep with scrapie,
infectivity is found first in lymphoid tissues and later in the central
nervous system (CNS). Cells within the germinal centers (GCs) of the
spleen and lymph nodes are important sites of extraneural replication,
from which infection is likely to spread to the CNS along peripheral
nerves. Here, using immunodeficient mice, we investigate the identity
of the cells in the spleen that are important for disease propagation.
Despite possessing functional T and B lymphocytes, tumor necrosis
factor alpha-deficient (TNF-
/) mice lack GCs and
follicular dendritic cell (FDC) networks in lymphoid tissues. In
contrast, lymphoid tissues of interleukin-6-deficient (IL-6/) mice possess FDC networks but have impaired
GCs. When the CNSs of TNF-/, IL-6/,
and wild-type mice were directly challenged with the ME7 scrapie strain, 100% of the mice were susceptible, developing disease after
closely similar incubation periods. However, when challenged peripherally (intraperitoneally), most TNF-/ mice
failed to develop scrapie up to 503 days postinjection. All wild-type
and IL-6/ mice succumbed to disease approximately 300 days after the peripheral challenge. High levels of scrapie infection
and the disease-specific isomer of the prion protein,
PrPSc, were detectable in spleens from challenged wild-type
and IL-6/ mice but not from TNF-/
mice. Histopathological analysis of spleen tissue demonstrated heavy
PrP accumulations in direct association with FDCs in challenged wild-type and IL-6/ mice. No PrPSc
accumulation was detected in spleens from TNF-/
mice. We conclude that, for the ME7 scrapie strain, mature FDCs are
critical for replication in lymphoid tissues and that in their absence,
neuroinvasion following peripheral challenge is impaired.
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INTRODUCTION |
The transmissible spongiform
encephalopathies (TSEs), or prion diseases, comprise a closely related
group of neurodegenerative disorders that include Creutzfeldt-Jakob
disease (CJD) and kuru in humans, scrapie in sheep and goats,
transmissible mink encephalopathy, and bovine spongiform
encephalopathy in cattle. The TSEs are characterized by the
deposition within the brain of PrPSc (4),
an abnormal, detergent-insoluble, relatively protease-resistant isoform
of a normal host cellular protein, PrPc (37).
While the precise nature of the agent is still the subject of
controversy (11), PrPSc copurifies with
infectivity (40) and is considered to be a major component
of the infectious agent. Furthermore, mice deficient in the PrP gene
(PrP/ mice) do not develop TSE disease (7),
demonstrating that host cells must express PrP in order to propagate infection.
Natural TSE infections are most often acquired by peripheral routes of
infection. Disease may be established through the skin (by
scarification), orally (through foodstuffs or cannibalism), or, in some
instances of CJD in humans, iatrogenically through transplantation of
CJD-contaminated tissues or pituitary-derived hormones. In the United
Kingdom, the consumption of beef products contaminated with bovine
spongiform encephalopathy is the most likely cause of variant CJD
(vCJD) in humans (6).
Following peripheral infection of sheep or rodents with scrapie, high
titers of infectivity rapidly accumulate in the spleen. Lymphoid
tissues play an important role in pathogenesis, as genetic asplenia or
splenectomy of mice, prior to or shortly after a peripheral scrapie
challenge, significantly extends the incubation period of the disease
(15). From the lymphoid tissues, infectivity is considered
to gain access to the central nervous system (CNS) via its spread along
peripheral nerves (1, 35). Although it has been suggested
that TSE infection may enter the CNS by hematogenous spread
(22), there is no firm evidence to support this. Once
scrapie infection enters the CNS, the neurodegeneration it causes is
irreversible and death is inevitable.
Thymectomy does not affect the incubation period of the disease
following peripheral challenge (15) and neither does
ionizing irradiation (16), implying that scrapie
pathogenesis depends on radioresistant and mitotically inactive cells.
Ionizing irradiation eliminates T lymphocytes, their precursors, and
actively dividing B lymphocytes as potential sites of scrapie
replication. Follicular dendritic cells (FDCs) fulfil the above
criteria and also decorate strongly with anti-PrP antibodies, even in
uninfected mice (34, 43). In severe combined immunodeficient
(SCID) mice, the absence of mature B and T lymphocytes prevents the
maturation of FDCs (20). These mice resist peripheral
infection with the scrapie strain ME7 (13, 45) or the human
TSE strain Fukuoka-2 (21) and fail to accumulate infectivity
and PrPSc in their spleens. Maturation of FDCs and
germinal centers (GCs), along with susceptibility to scrapie, can
be induced by grafting SCID mice with bone marrow (13). As
FDC networks do not develop in the absence of lymphocytes
(20) and both FDCs (5, 34, 43) and lymphocytes
(31) appear to express PrPc, further experiments
using mice that expressed and did not express PrPc in their
FDCs and lymphocytes have been undertaken to determine the role of
these cells in scrapie pathogenesis (5).
Signalling between FDCs and lymphocytes through cytokines, including
tumor necrosis factor alpha (TNF-) and interleukin-6 (IL-6), plays
an important role in the organization of the GC. Mice deficient in
TNF- lack splenic primary B-cell follicles, FDC networks, and GCs
(38). Despite the absence of GC structure, B lymphocytes are
still able to respond to antigen stimulation and immunoglobulin
class-switching can still occur. The effects of TNF- on GC
architecture are mediated via signalling through TNF receptor 1 (TNF-R1) expressed on FDCs and/or its precursor (46). IL-6
production by FDCs has also been shown to be important for maintaining
GC reactions. In the lymphoid tissues of mice deficient for IL-6, FDC
complexes are able to form but GC development is diminished
(26). To determine if FDCs, GCs, and lymphocytes are
required for susceptibility to a peripherally routed infection, scrapie
pathogenesis was studied in mice which lack FDCs and GCs but possess
functional lymphocytes (TNF--deficient mice) and in mice in which
FDC networks are present but GC development is impaired (IL-6-deficient mice).
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MATERIALS AND METHODS |
Mice.
TNF- knockout (TNF-/
[38]) and IL-6 knockout (IL-6/
[25]) mice were bred on a mixed 129/Sv × C57BL/6
background. Wild-type (control) mice also shared the 129/Sv × C57BL/6 background.
Scrapie inoculation.
Mice were injected intracerebrally
(i.c.) or intraperitoneally (i.p.) with 20 µl of a 1.0% (wt/vol)
dilution of unspun brain homogenate from C57BL mice terminally affected
with scrapie strain ME7. Following challenge, animals were coded and
scored weekly to determine the clinical end point and incubation period
of neurological disease, according to previously established criteria
(14). Scrapie diagnosis was confirmed by histopathological
assessment of vacuolation and PrP immunostaining in the brain. Where
indicated, some mice were sacrificed 5 and 10 weeks postchallenge and
spleens were taken for further analysis. For bioassay of scrapie
infectivity, individual spleen halves were prepared as 10% homogenates
in physiological saline and injected i.c. into C57BL assay mice. The
scrapie titer in each spleen was determined from the mean incubation
period in the assay mice, by reference to established dose-incubation period response curves for scrapie-infected spleen tissue.
Immunoblot detection of PrPSc.
Tissues were
prepared by a modification of a method previously described
(10). Briefly, frozen tissues were weighed and pulverized in
precooled Potter homogenizers and then homogenized in 0.2 M potassium
chloride (2 ml) with 20 µl of each of the protease inhibitors, 100 mM
phenylmethylsulfonyl fluoride (PMSF) and 100 mM
N-ethylmaleimide (NEM), both in propan-1-ol. Suspensions
were then centrifuged at 500 × g for 10 min at 4°C.
The supernatants were decanted and centrifuged for 30 min at
100,000 × g at 4°C. The resultant pellets were
resuspended in 2 ml of 100 mM Tris-HCl at pH 7.4, and the suspension
was divided into two equal parts. To one fraction, 20 µl of 20-mg/ml
proteinase K (Sigma, Poole, United Kingdom) was added, and the contents
were incubated at 37°C in an orbital shaker for 60 min; the other
fraction was held at 4°C with 20 µl each of PMSF and NEM (100 mM).
Subsequently, 1 ml of Sarkosyl (2%, wt/vol), 20 µl each of PMSF and
NEM, and 2 µl of 2-mercaptoethanol were added to all tubes, which
were incubated at 37°C for a further 60 min. The contents of each
tube were then layered onto a cushion of 20% sucrose in 50 mM Tris-HCl (pH 7.4) and centrifuged at 100,000 × g for 2 h
at 4°C. Pellets were drained and stored at 
70°C before further analysis.
Samples were then electrophoresed through sodium dodecyl sulfate-12%
polyacrylamide gels and transferred to polyvinylidine difluoride
membranes (Bio-Rad, Hemel Hempstead, United Kingdom) by semidry
blotting. Membranes were blocked with 2% bovine serum albumin in 0.1 M
Tris-HCl (pH 7.6) and probed with the PrP-specific rabbit polyclonal
antiserum 1B3 (12). Following counter-staining with alkaline
phosphatase-conjugated goat anti-rabbit antiserum (Jackson
ImmunoResearch Laboratories, Inc., West Grove, Pa.), bound alkaline
phosphatase activity was detected with SigmaFast nitroblue
tetrazolium-BCIP (5-bromo-4-chloro-3-indolylphosphate) solution (Sigma).
Immunohistochemical analysis.
Spleens halves were
snap-frozen and maintained at the temperature of liquid nitrogen.
Serial 6-µm-thick sections were cut on a cryostat, air dried, and
fixed in acetone for 10 min. FDCs were visualized by staining first
with FDC-M1 monoclonal antiserum (28) and subsequently with
biotinylated murine anti-rat serum. To detect PrP, sections were
stained first with 1B3 polyclonal antiserum and subsequently with
biotinylated goat anti-rabbit serum (Jackson ImmunoResearch
Laboratories). To visualize GC B cells, sections were stained with
biotinylated peanut agglutinin (Vector Laboratories, Peterborough,
United Kingdom). Immunolabeling was carried out using alkaline
phosphatase coupled to the avidin-biotin complex (Vector Laboratories).
Vector Red (Vector Laboratories) was used as a substrate.
For the detection of PrP in brain tissue, brains were fixed in
periodate-lysine-paraformaldehyde and embedded in paraffin
wax.
Sections (thickness, 6 µm) were deparaffinized, and pretreated
to
enhance PrP immunostaining by hydrated autoclaving (15 min,
121°C,
hydration), and subsequent immersion in formic acid (98%)
for 5 min
(
34). Sections were then stained with the PrP-specific
antiserum 1B3 or normal rabbit serum as a control and
immunocytochemical
labeling was carried out using the
peroxidase-antiperoxidase technique
with diaminobenzidine as a
substrate. Sections were counterstained
with hematoxylin to distinguish
cell
nuclei.
Immunohistoblot analysis of PrPSc.
Spleen halves
were snap-frozen and maintained at the temperature of liquid nitrogen.
Serial 10-µm-thick sections were cut on a cryostat, applied directly
to polyvinylidine difluoride membranes, and thoroughly air dried. For
the detection of total PrP (PrPc and PrPSc) and
PrPSc alone, membranes were rehydrated and treated in the
absence and presence (respectively) of 20 µg of proteinase K per ml
for 60 min at 37°C, as previously described (44).
Following processing, membranes were probed with PrP-specific
polyclonal antiserum 1B3 and counter-stained with alkaline
phosphatase-conjugated goat anti-rabbit antiserum and bound alkaline
phosphatase activity was detected with SigmaFast nitroblue
tetrazolium-BCIP solution.
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RESULTS |
Susceptibility of TNF-/ and
IL-6/ mice to scrapie infection.
When mice were
challenged i.c. with scrapie strain ME7, no significant differences
between wild-type, TNF-/, and IL-6/
mice in the onset of clinical signs or incubation period of disease were observed (Fig. 1). All i.c. infected
mice succumbed to disease approximately 170 days postchallenge.
Histopathologic analysis of brain tissue from terminal i.c. infected
wild-type, IL-6/, and TNF-/ mice
showed the characteristic spongiform pathology and PrPSc
accumulation associated with ME7. Thus, if scrapie was delivered directly to the CNS, scrapie pathogenesis in the brain proceeded without any detectable influence of the immune status of the host.
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FIG. 1.
Incubation period of disease following i.c. or i.p.
challenge of wild-type (WT), IL-6/, and
TNF-/ (TNF/) mice with scrapie strain ME7. Each
bar represents the mean ± the standard error for 5 to 14 mice.
While most i.p. challenged TNF-/ mice remained free
of the clinical signs of scrapie 503 days postinfection, three mice did
succumb to disease (dots).
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When mice were challenged with scrapie peripherally via the i.p. route,
no significant difference was observed between wild-type
and
IL-6
/ mice in the incidence and incubation period of
disease. With
both of these mouse strains, all animals succumbed to
infection
following mean incubation periods of 303 ± 4 days
(wild-type mice;
n = 8) and 309 ± 4 days
(IL-6
/ mice;
n = 14) (Fig.
1).
Furthermore, spongiform pathology, gliosis,
and PrP
Sc
accumulation typical of an i.p. infection with scrapie strain
ME7 were
detected in the brains of wild-type and IL-6
/ i.p.
challenged mice (Fig.
2a and b,
respectively). In contrast,
following i.p. challenge of
TNF-
/ mice with scrapie, five of eight mice remained
free of signs
of disease up to 503 days postinfection, at which time
the experiment
was terminated (Fig.
1). No evidence of spongiform
change or PrP
Sc accumulation was detected in the brains of
any surviving i.p.
challenged TNF-
/ mice (Fig.
2c).
However, three of eight TNF-
/ mice did succumb to an
i.p. challenge with scrapie. In these,
disease developed after
individual incubation periods of 350,
441, and 475 days. These
incubations periods were beyond the range
seen in i.p. infected
wild-type and IL-6
/ mice (289 to 325 and 280 to 325 days, respectively).
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FIG. 2.
Immunocytochemical analysis of brain tissue from i.p.
challenged, terminally scrapie-affected wild-type (a) and
IL-6/ (b) mice detected large PrP accumulations (brown)
in the hippocampus. In contrast, no PrP accumulations were detected in
tissue derived from i.p. challenged TNF-/ mice that
remained free of the signs of scrapie 503 days postinfection (c). All
sections were counterstained with hematoxylin (blue). Magnification,
×200.
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Scrapie infectivity and PrPSc accumulation in the
spleen.
High levels of scrapie infectivity were detected in
spleens from wild-type mice collected 35, 70, and 310 days
postchallenge, by which time the mice were terminally affected with
scrapie (Table 1). Interestingly, no
infectivity has been detected so far in one of four spleens collected
35 days postchallenge, suggesting a titer less than 2.5-log-unit i.c.
50% infective doses (ID50)/g. However, by 70 days
postchallenge, high levels of infection were detected in all four
spleens assayed. In contrast, scrapie infectivity has so far been
undetectable in all of the spleens taken from scrapie-challenged
TNF-/ mice 35, 70, and 503 days postchallenge (Table
1). While most indicator mice injected with tissue from
infected-wild-type mice succumbed to TSE disease between 175 and 210 days postchallenge, all those injected with tissue from challenged
TNF-/ mice remained free of TSE disease up to at
least 400 days postchallenge. This represents an infectious titer, if
present, below 2.0-log-unit i.c. ID50/g (the limit of
detection of the assay), at least 1,000-fold less than the titer
measured in spleens from wild-type mice. High levels of scrapie
infectivity were detected in all spleens collected from
IL-6/ mice 35 and 70 days postchallenge (Table 1).
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TABLE 1.
Scrapie infectivity titers in spleens from wild-type,
IL-6/, and TNF-/ mice following i.p.
challenge with scrapie strain ME7
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Immunoblot analysis of tissue from i.p. challenged, terminally
scrapie-affected wild-type and IL-6
/ mice detected
large accumulations of detergent-insoluble, proteinase
K-resistant
PrP
Sc in the spleen (Fig.
3a). In contrast, no PrP
Sc
was detected in spleens derived from i.p. challenged
TNF-
/ mice, which remained free of the signs of
scrapie 503 days postinfection
(Fig.
3a), or from any of the three
TNF-
/ mice that succumbed to disease (Fig.
3b).
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FIG. 3.
Immunoblot analysis of spleen tissue from wild-type
(WT), TNF-/, and IL-6/ mice
following intraperitoneal challenge with the ME7 scrapie strain.
Samples were treated in the presence (+) or absence () of proteinase
K (PK) before electrophoresis. (a) Large PK-resistant accumulations of
PrPSc were detected in spleens derived from clinically
scrapie-affected WT and IL-6/ mice. No
PrPSc accumulations were detected in spleens derived from
scrapie-challenged TNF-/ mice that remained free of
disease 503 days postinfection. (b) Large PK-resistant accumulations of
PrPSc were detected in spleens derived from clinically
scrapie-affected WT mice but not in spleens derived from clinically
affected TNF-/ mice. Values given below lanes are
the individual incubation periods of disease or times postchallenge at
which the spleens were harvested. Lane M, molecular size markers.
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Large FDC networks and peanut agglutinin-positive GCs were detected by
immunohistochemistry in the spleens of wild-type mice
(Fig.
4a and
d, respectively). In spleens from
IL-6
/ mice, FDC networks were detected but GCs were
impaired and considerably
smaller than those from wild-type mice (Fig.
4b and e, respectively).
Neither mature FDCs nor GCs were detected in
tissues from TNF-
/ mice (Fig.
4c and f,
respectively). Analysis of adjacent sections
of spleen from both
wild-type and IL-6
/ mice demonstrated large PrP
accumulations (Fig.
4j and k, respectively)
in direct association with
FDCs (Fig.
4g and h, respectively)
in tissue taken 10 weeks
post-peripheral challenge with scrapie.
No FDCs or PrP accumulations
were detected immunocytochemically
in the spleens of
TNF-
/ mice (Fig.
4i and l, respectively). Further
analysis of adjacent
cryostat sections by immunohistoblotting
demonstrated that in
spleens from scrapie-challenged wild-type mice,
large proteinase
K-resistant PrP
Sc accumulations (Fig.
5g) occurred in direct association with
FDCs
(Fig.
5a). No PrP
Sc accumulations or FDCs were
detected in spleens from scrapie-challenged
TNF-
/
mice (Fig.
5b and h, respectively). In spleens from uninfected
wild-type mice, only the proteinase K-sensitive, cellular isomer
of the
prion protein, PrP
c, was detected in association with FDCs
(Fig.
5f, i, and c, respectively).
Taken together, these observations
demonstrate that following
peripheral challenge with scrapie strain
ME7, PrP
Sc accumulates in the spleen in direct association
with FDCs. Interestingly,
no PrP
c was detectable by
immunoblot analysis in spleens derived from
TNF-
/
mice (Fig.
3), although low levels were detected in spleens from
uninfected wild-type animals by immunoblot analysis (data not
shown)
and immunohistoblot analysis (Fig.
5f). This difference
is most likely
due to the lack of FDCs expressing high levels
of PrP
c in
the spleens of TNF-
/ mice.
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FIG. 4.
Immunocytochemical analysis of GC structure and PrP
accumulation in spleen tissue from ME7-challenged mice. (a to c)
Sections from wild-type (a), IL-6/ (b), and
TNF-/ (c) mice were stained with FDC-M1 antiserum to
detect FDCs (red). (d to f) Adjacent sections from wild-type (d),
IL-6/ (e), and TNF-/ (f) mice were
stained with peanut agglutinin to detect GCs (red). (g to i) Sections
from wild-type (g), IL-6/ (h), and
TNF-/ (i) mice were stained with FDC-M1 (red). (j to
l) Adjacent sections from wild-type (j), IL-6/ (k), and
TNF-/ (l) mice were stained with the PrP-specific
antiserum 1B3 (red). Magnification, ×100 (a to f) and ×400 (g to
l).
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FIG. 5.
Immunohistoblot analysis of PrP accumulation in the
spleen. (a to c) Sections from scrapie-challenged wild-type (WT) (a),
scrapie-challenged TNF-/ (b), and uninfected
wild-type (c) mice were stained with FDC-M1 antiserum to detect FDCs
(red). (d to i) Histoblots were prepared from adjacent sections for
specific staining of total PrP-PrPc and PrPSc.
(d to f) Immunodetection of total PrP-PrPc in samples from
scrapie-challenged wild-type (d), scrapie-challenged
TNF-/ (e), and uninfected wild-type (f) mice without
prior treatment with proteinase K (PK). (g to i) Immunodetection of
PrPSc in samples from scrapie-challenged wild-type (g),
scrapie-challenged TNF-/ (h), and uninfected
wild-type (i) mice with prior treatment with proteinase K (+PK).
Following treatment, histoblots were stained with the PrP-specific
antiserum 1B3. Magnification, ×40.
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DISCUSSION |
The susceptibility of TNF-/ mice to peripheral
challenge with scrapie in this study was greatly reduced in comparison
with that of immunocompetent wild-type mice. We also demonstrated that TNF-/ mice, unlike wild-type mice, failed to
accumulate scrapie infectivity in their spleens. However, following
peripheral challenge of IL-6/ mice with scrapie, no
significant differences in incubation period or incidence of disease
were observed between mutant and wild-type mice. Likewise, high levels
of scrapie infectivity were detected in the spleens of challenged
IL-6/ mice. The disease-specific isomer of the prion
protein, PrPSc, is associated with high levels of scrapie
infectivity (40) and provides a reliable indicator for the
presence of infection in this model (10). Large
PrPSc accumulations were detected in the spleens of
scrapie-challenged wild-type and IL-6/ mice but not in
the spleens of TNF-/ mice. This was true even for
the few TNF-/ mice that developed disease after
protracted incubation periods.
Overexpression of TNF- has been implicated as a key pathogenic
mediator in several human inflammatory, infectious, and autoimmune CNS
disorders (39), including bacterial meningitis
(30), multiple sclerosis (42), cerebral malaria
(17), and Alzheimer's disease (36). In rodents,
neutralization of TNF- prevents the formation of inflammatory
lesions and demyelination caused by experimental autoimmune
encephalomyelitis (24). Induction of IL-1, IL-1
, IL-6,
and TNF- synthesis has been reported to occur in the brains of mice
showing clinical signs of scrapie (47), suggesting that cytokines may be significant factors in determining the pathogenesis of
neurodegeneration in scrapie. Similarly, expression of TNF- and
IL-1 is increased in the brains of mice infected experimentally with
the Fujisaki strain of human TSE (27). Here, when the CNSs of TNF-/ and IL-6/ mice were
infected directly with scrapie, no significant differences were
observed between mutant and wild-type mice in either the onset of
clinical disease or CNS pathology. Although cytokine production by
activated glia precedes the apoptotic loss of hippocampal neurons in
brains from scrapie-infected mice (47), the experiments presented here suggest that TNF- and IL-6 alone do not play a critical role in the development of pathology in the CNS. Therefore, the apparent resistance of TNF-/ mice to i.p.
challenge with scrapie could not be attributed to a role of TNF- in
the development of pathology in the CNS. Our experiments strongly
suggest that the effects of TNF- operate at a peripheral stage,
prior to neuroinvasion.
How scrapie infectivity is delivered to the lymphoid tissues is not
known. As membrane lymphotoxin, instead of TNF-, regulates the
migration of dendritic cells in the spleen (48), it is
unlikely that the effects of TNF- deficiency on scrapie pathogenesis
are due to impaired cell trafficking from the site of scrapie challenge to the spleen. Gene deletion experiments with mice have shown that
signalling by both TNF- and lymphotoxin / is required for FDC
development (33, 38). The subsequent maintenance of FDCs in
a differentiated state requires the continual stimulation of FDCs by B
lymphocytes through lymphotoxin / and TNF- (32). Hence, lymphoid tissues from TNF-/ mice lack FDC
networks and GCs but possess functional lymphocytes (38). In
contrast, recent work suggests that IL-6 production by FDCs may act
directly on GC B lymphocytes via IL-6-sensitive transcription factors
and may also amplify local C3 synthesis by tingible body macrophages
(25). This leads to impaired GC formation and antibody
responses, but mice deficient in the production of IL-6 are able to
form FDC complexes. Our experiments suggest that deficiencies in GCs
alone do not affect scrapie pathogenesis, as peripherally challenged
IL-6/ mice developed disease at the same time as
wild-type mice and had high levels of scrapie infectivity and large
PrPSc accumulations in their spleens. It is also unlikely
that T and B lymphocytes are directly involved in disease pathogenesis,
as these cells are present and functional in lymphoid tissues of TNF-/ mice (38), which did not develop
disease or accumulate scrapie infectivity or PrPSc in the
spleen. Immunohistopathology demonstrated that the large PrPSc accumulations in the spleens of wild-type and
IL-6/ mice were directly associated with FDCs. FDCs
were completely absent in spleens from challenged
TNF-/ mice. We therefore conclude that scrapie
accumulation in the spleen depends on the presence of mature FDCs.
These findings are consistent with recent experiments that used mice
that expressed and mice that did not express PrPc in their
FDCs and lymphocytes. In these experiments, replication of scrapie
strain ME7 in the spleen was also dependent on
PrPc-expressing FDCs (5). From the spleen,
infectivity is most likely to spread to the CNS along peripheral nerves
(1, 34), as noradrenergic and peptidergic nerve fibers are
present in both primary and secondary lymphoid organs among cells of
the lymphoid follicles (2).
Interestingly, three TNF-/ mice did succumb to
scrapie following peripheral challenge, although with significantly
longer incubation periods than challenged wild-type and
IL-6/ mice. No PrPSc was detected in the
spleens of any clinically scrapie-positive TNF-/
mice, suggesting that due to a lack of FDCs, spleen tissue is not
involved in pathogenesis. Similarly, while SCID mice resist peripheral
challenge with moderate doses of scrapie strain ME7, high doses produce
CNS disease despite only trace levels of infection in the spleen
(13). How scrapie infection had spread to the CNS in both of
these instances is not known. Klein and colleagues (22)
suggested that peripheral blood lymphocytes may carry infection from
the periphery to the CNS. However, subsequent experiments have failed
to detect infectivity in peripheral blood lymphocytes, despite high
levels of infectivity in the spleen in this model (41). The
most likely explanation is that in the absence of a functional immune
system, neurological disease follows direct uptake of infection by
nerve endings in the periphery and spreads to the CNS along peripheral
nerves (1).
The pathogenesis of scrapie strain ME7 following peripheral challenge
appears to differ significantly from that of the scrapie isolate RML
studied elsewhere; in that study infection accumulated in the spleen in
the absence of PrPc expression on FDCs (3).
Further experiments using the RML scrapie isolate implicated B
lymphocytes in disease pathogenesis, as mice deficient in B lymphocytes
failed to accumulate infectivity in their spleens and were refractory
to disease (22). However, as outlined above, mice deficient
in B lymphocytes are also indirectly deficient in FDCs, as lymphocytes
provide important signals for their maturation and maintenance
(20, 32, 33). In order to distinguish between these two cell
populations in the pathogenesis of the RML scrapie isolate,
TNF-R1/ mice were used. Like TNF-/
mice, these mice lack mature FDCs but do possess functional lymphocytes (29, 33). Interestingly, TNF-R1/ mice were
as susceptible to peripheral challenge with the RML scrapie isolate as
wild-type mice (22), implying that in the presence of
PrP-expressing lymphocytes, FDCs are not critical for the pathogenesis
of RML. In a third study, PrP expression on B lymphocytes was not
critical for RML pathogenesis (23) in the presence of
PrP-expressing FDCs. These observations suggest that the RML scrapie
isolate, unlike the ME7 scrapie isolate, may utilize both FDCs and B
lymphocytes, but the exact roles of these two cell types are not clear.
However, direct comparisons of the peripheral pathogenesis of the RML
scrapie isolate and the ME7 scrapie strain are required to demonstrate
that the discrepancy between them is not due to different experimental practices.
The apparent differences in the pathogenesis of the ME7 and RML scrapie
isolates have important implications, as they suggest that different
scrapie strains may target different cell populations in lymphoid
tissues. Current evidence suggests a similar variation in human TSE
diseases, as PrPSc is detected in non-CNS tissues,
including lymph nodes, tonsils (18), and appendix
(19), from patients with vCJD but not from patients with
sporadic or even iatrogenic CJD, where infection is introduced via the
periphery. The risk of horizontal infection through transfusion and
transplantation of vCJD-contaminated tissue or use of contaminated
surgical instruments is a matter of urgent concern, particularly given
the fact that intraspecies transmissions usually increase the risk of infection.
Once TSEs spread to the CNS, the neurodegeneration they cause is most
likely irreversible. Treatments that interfere with the early stages of
infection in peripheral tissues can significantly decrease scrapie
susceptibility (8, 9). Therefore, the identification of FDCs
as critical cells in the peripheral pathogenesis of TSE diseases is
fundamental for determining the risk of iatrogenic spread and the
development of practical prophylactic and therapeutic strategies.
| |
ACKNOWLEDGMENTS |
We thank Jean Langhorne (Imperial College, London, United
Kingdom) for providing the IL-6/ mice, Marie
Kosco-Vilbois (Serono Pharmaceutical Research Institute, Geneva,
Switzerland) for helpful discussion and provision of FDC-M1 monoclonal
antiserum, and Louise Gibbard (Institute for Animal Health, Compton,
United Kingdom), Irene McConnell, Mary Brady, and Jenny Beaton
(Institute for Animal Health, Neuropathogenesis Unit, Edinburgh, United
Kingdom) for excellent technical support.
This work was supported by funding from the Medical Research Council
and the Biotechnology and Biological Sciences Research Council.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Institute for
Animal Health, Neuropathogenesis Unit, Ogston Building, West Mains Rd., Edinburgh EH9 3JF, Scotland, United Kingdom. Phone: 44 131 667 5204. Fax: 44 131 668 3872. E-mail:
neil.mabbott{at}bbsrc.ac.uk.
Present address: Department of Veterinary Pathology, Glasgow
University Veterinary School, Glasgow G61 1QH, Scotland, United Kingdom.
| |
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Top
Abstract
Introduction
