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Journal of Autoimmune Diseases
Open Access
Review
Virus-mediated autoimmunity in Multiple Sclerosis
Nikolaos Grigoriadis
1
and Georgios M Hadjigeorgiou*
2
Address:
1
B' Department of Neurology, Laboratory of Experimental Neurology and Neuroimmunology, AHEPA University Hospital, 1 Stilp
Kyriakidi Street, Aristotle University of Thessaloniki, Thessaloniki, 54636 Thessaloniki, Greece and
2
Department of Neurology, Neurogenetics
Unit, Medical School, University of Thessaly, 22 Papakyriazi Street, 41222 Larissa, Greece
Email: Nikolaos Grigoriadis - grigoria@med.auth.gr; Georgios M Hadjigeorgiou* - gmhadji@med.uth.gr
* Corresponding author
Abstract
Epidemiological data suggest the notion that in Multiple Sclerosis (MS) is an acquired autoimmune
disease and the cause may be an environmental factor(s), probably infectious, in genetically
susceptible individuals. Several cases of viral induced demyelinatimg encephalomyelitis in human
beings and in experimental models as well as the presence of IgG oligoclonal bands in the
cerebrospinal fluid indicate that the infectious factor may be viral. However, the absence of a
specific virus identification in MS central nervous system may hardly support this notion. On the
other hand, the partial response of patients with MS to immunosuppressive and
immunomodulatory therapy support the evidence of an autoimmune etiology for MS. However, the
autoimmune hypothesis shares the same criticism with the infectious one in that no autoantigen(s)
specific to and causative for MS has ever been identified. Nevertheless, the absence of identifiable
infectious agent, especially viral does not rule out its presence at a certain time – point and the
concomitant long term triggering of an autoimmune cascade of events thereafter. Several concepts
have emerged in an attempt to explain the autoimmune mechanisms and ongoing
neurodegeneration in MS on the basis of the infectious – viral hypothesis.
Background
Multiple sclerosis (MS) is widely believed to be an
autoimmune disorder characterized by multifocal lesions
of the CNS myelin and accumulating clinical signs due to
axonal damage [1]. The aetiology of MS has been debated
several times since the disease was first described. Myelin
is damaged due to an immune attack consisted of several
pathways and molecules, leading to impaired nerve func-
tion. Autoantibodies and autoreactive T cells activated
against myelin antigens such as myelin basic protein
(MBP), proteolipid protein (PLP), and myelin oli-
godendrocyte glycoprotein (MOG), have been detected in
MS patients [2]. The majority of researchers consider MS
as a CD4
+
T-helper 1 (Th1)-mediated inflammatory
demyelinating disease [3,4]. Several data indicate this
consideration, such as the cellular composition of brain
and cerebrospinal fluid (CSF)-infiltrating cells and data
from studies in a widely used animal model for MS, the
Experimental Alergic Encephalomyelitis (EAE) [5]. In the
EAE model, myelin components emulsified in complete
Freund's adjuvant (CFA) and injected in susceptible ani-
mals lead to a CD4
+
-mediated autoimmune disease that
shares clinical, immunological and pathological similari-
ties with MS. CFA creates an artificial inflammatory milieu
that does not reflect the natural environment in which self
or mimic peptides would be normally encountered. EAE
may also be induced passively by transferring anti-myelin
activated T-cells to naive animals (transfer EAE), a finding
Published: 19 February 2006
Journal of Autoimmune Diseases 2006, 3:1 doi:10.1186/1740-2557-3-1
Received: 31 October 2005
Accepted: 19 February 2006
This article is available from: http://www.jautoimdis.com/content/3/1/1
© 2006 Grigoriadis and Hadjgeorgiou; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0
),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Journal of Autoimmune Diseases 2006, 3:1 http://www.jautoimdis.com/content/3/1/1
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that clearly indicates the autoimmune component of the
disease.
Studies on EAE indicated that cytokines, chemokines and
adhesion molecules induce the recruitment of leukocytes
from periphery to CNS throughout a disrupted blood
brain barrier (BBB) and a cascade of inflammatory events
is established within the CNS. Eventually, axonal degener-
ation and loss is the hallmark in the disease process lead-
ing to a long-term disability [6]. Although EAE may not be
the ideal animal model for the disease, the model itself in
combination with several other experimental and clinical
data indicate that MS is an autoimmune disease [7]. How-
ever, the major criticism of the autoimmune hypothesis is
that autoantigen(s) specific to and causative for MS has
never been identified. In addition, although inflamma-
tion is considered to be a primary feature of demyelianat-
ing plaques thus favouring the autoimmune component
in this process, recent reports indicate that demyelination
may precede inflammation [8] On the other hand, there
are reports proposing that MS is not an autoimmune dis-
ease but a genetically determined disorder characterized
by metabolically dependent neurodegeneration [9]. The
latter may imply that immune reaction in MS may be a
secondary one to the ongoing degeneration of axons and
neurons. Nevertheless, while the autoimmune model may
not explain every aspect of MS, it is difficult to ignore the
considerable evidence that immunity plays a major role in
MS. Another intriguing idea regarding the aetiology of MS
may be that the immune response in MS could result from
a chronic viral infection rather than autoimmunity in the
usual sense [10-12].
The possible involvement of viruses in the aetiology of MS
is a rather controversial issue. Based on immigration data,
it has been suggested that environmental factor(s) may
trigger MS before the age of adolescence, while the disease
is clinically silent until years later. It is also apparent that
there is a genetic susceptibility related at least to the HLA
system [13-15] Among monozygotic twins there is a 70%
disconcordance of MS suggesting that an exogenous factor
causes the disease[14]. Evidently, these indications lead to
the hypothesis that MS is a disease triggered by an envi-
ronmental factor in genetically susceptible individuals
during childhood [12,16-20]. Moreover, it has been spec-
ulated that the environmental factor in MS could be a
virus [21-23] In addition, abnormal immune response to
a variety of viruses in MS patients as well as analogy with
animal models and other human diseases in which
viruses can cause diseases with long incubation periods,
relapse, and demyelination, further support the concept
that viruses may be implicated in the MS aetiology.
Although to date no virus has been recognized as a causa-
tive factor of MS, the possibility that both autoimmunity
and neurodegeneration in MS may coexist and commonly
be explained following a viral infection is reviewed here.
Experimental and clinical evidence for a virus-
related aetiology of MS
Animal models
Various viruses have been found to induce demyelination
in laboratory animals following various infection proto-
cols. The most studied experimental demyelination is
infection of mice with Theiler's murine encephalomyelitis
virus (TMEV) [24]. TMEV (a higly cytolytic picovarious)
infection in mice serves as a model to explain infectious
and parainfectious mechanisms underlying CNS demyeli-
nation. TMEV infection of oligodendrocytes is productive,
resulting in cell lysis and liberation of more virions. By
contrast, TMEV infection in macrophages is restricted, and
results in apoptosis of macrophages. TMEV antigen is
abundant in the cytoplasm of apoptotic macrophages.
Small amounts of TMEV are liberated from persistently
infected macrophages leading to infection of more macro-
phages as well as oligodendrocytes. A persistent CNS
infection is established as virus spreads from macrophage
to macrophage. Virus released from macrophages can
infect and damage more oligodendrocytes, thus adding to
immunopathological destruction of myelin [25].
Another animal model of virus-induced demyelination is
the one established in BALB/c mice following infection
with JHM virus (coronavirus). This strain infects predom-
inantly oligodendrocytes, and the induced demyelination
is not preceded by inflammation or any immune – related
mechanism [26,27]. The infected oligodendrocytes con-
tain intracisternal virions [28] and this model may be con-
sidered as a case of demyelination resulting simply from a
direct virus induced cytopathology of oligodendrocytes.
Autoimmune responses to myelin antigens are observed
following infection with TMEV. Despite the fact that this
autoimmunity to myelin components may not play a
major role in the initiation of demyelination, it may prob-
ably contribute to lesion progression in chronically dis-
eased animals [29].
CNS demyelination in host animals may also occur fol-
lowing infection of other viruses such as in mice with JHM
or MHV-4 (coronaviruses), dogs with canine distemper
virus, and sheep and goats with Visna virus and caprine
arthritis-encephalitis virus. Each of these viruses is capable
of establishing a persistent infection in their host, such
that there is continuous virus replication over a long
period without killing the host. Another virus-induced
demyelination animal model is Semliki Forest virus (SFV)
infection of mice [30,31]. The initial immune-mediated
demyelination may be due to targeting of SFV-infected
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oligodendrocytes by cytotoxic T-cells. SFV induces
repaired acute demyelination with no relapses.
Clinical studies supporting a role of virus in MS
pathogenesis
The application of modern sophisticated laboratory tech-
niques have led to a growing number of viruses associated
with MS albietno such a pathogen has been accepted as
the canditate causal agent in MS. In addition, interferon
beta, a currently applied treatment in MS patients [32],
was originally proposed as being capable of increasing the
resistance of host tissues against viral infections. However,
no scientific data to date support viral inhibition as one of
the underlying mechanisms of action interferon beta in
MS.
Several clinical studies have suggested that MS in general
as well as episodes of disease exacerbation are associated
with concomitant viral or microbial infections[12,33].
Upper respiratory tract infections can trigger acute
relapses of MS, resulting in an increase in the risk of clin-
ical exacerbations during the weeks that follow the onset
of virus infection[34] Most importantly, when recurrent,
these viral infections are associated with neurological pro-
gression [35,36].
Many of the studies related to the virus infection in MS are
serological and involve the demonstration of increased
antibody titers against a particular virus[12]. In addition,
in a number of studies, isolation of virus from MS mate-
rial has also been reported [37]. Antibody levels to various
viruses are elevated in MS patients, but it has not been
clarified whether this elevation is related to the aetiology
of MS or is a concomitant phenomenon. Many viruses
have been detected in CNS autopsy tissue from MS
patients [38,39]. Throughout the last decades (see table 1
for selected references), among the viral agents related to
demyelination were considered the measles virus [40],
parainfluenza virus [41], canine distemper [42], Epstein-
Barr virus [43], human herpes virus-6 (HHV-6) [44] and
retroviruses [45]. It is generally accepted that despite the
sensitive methods used, still there is no convincing evi-
dence that viruses are related to MS aetiology, mainly due
to controversies among the related studies. HHV-6 in par-
ticular, is a typical example of a virus recently tested in
details with various assays in order to investigate any rela-
tion to MS aetiology[46]. HHV-6 was subjected to detec-
tion both in MS patients and healthy controls or patients
suffering from other neurological disorders. Patients'
material examined was brain tissue [47-49], CSF [50-52],
serum/plasma [53-55], and peripheral blood mononu-
clear cells [53-57] using PCR [47,48,53-57], immunohis-
tochemistry [58-60], or in vitro virus culture assays [58].
Despite such a detailed investigation there is a lack of a
conclusive remark on whether HHV-6 is associated to
MS[46]. The controversy that is evident throughout the
various studies may be attributed either to differences in
the sensitivity of the applied methods or the patient selec-
tion, different methodology applied, etc. Hence, no mat-
ter whether there the viral aetiology of MS is not yet
Table 1: Selected studies exploring the relation of multiple sclerosis with human herpes virus-6
Material used Method followed Relation to MS Year of publication
Brain tissue Viral DNA-PCR, immunohistochemistry Positive 1995[44]
Viral DNA-PCR Negative 1996[49]
Viral DNA-PCR, immunohistochemistry Positive 1999[47]
Immunohistochemistry Positive 2000[58]
Viral DNA-PCR Positive 2000[59]
Viral DNA-PCR, immunohistochemistry Positive 2003[60]
Viral DNA-PCR Uncertain 2003[48]
CSF Viral DNA-PCR Negative 1999[50]
Viral DNA-PCR, antibodies titer Negative 2000[51]
Viral DNA-PCR, antibodies titer Positive 2002[52]
Serum Viral DNA-PCR Negative 1999[50]
Viral DNA-PCR, antibodies titer Positive 2000[52]
Viral DNA-PCR Positive 2000[53]
Viral DNA-PCR Positive 2001[54]
Viral DNA-PCR Negative 2002[55]
Viral DNA-PCR, antibodies titer Positive 2003[56]
Peripheral blood mononuclear cells Viral DNA-PCR Negative 2000[51]
Viral DNA-PCR Positive 2000[53]
Viral DNA-PCR Negative 2000[57]
Viral DNA-PCR Positive 2001[54]
Viral DNA-PCR Positive 2002[55]
Viral DNA-PCR Positive 2003[56]
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clarified, it should be emphasized that the absence of evi-
dence does not necessary imply the evidence of absence
[61].
Mechanisms of virus-induced CNS
autoimmunity
Following a virus infection, there may be two potential
options: the virus might reactivate after a long term
latency, up to years and lyse oligodendrocytes, or could
initiate a rather acute or subacute demyelinating immun-
opathology. Examples of the first option might be pro-
gressive multifocal leucoencephalopathy (PML) through
the infection of JC virus (a human papova virus) whereas
the later is the case of TMEV encephalomyelitis model, as
well as infections with corona viruses, and lenti viruses
[62].
Among the major indications for the association of demy-
elination with viral infection and a destructive host
immune response to autoantigens is the case of post-
infectious encephalomyelitis, a complication mainly
noticed following smallpox vaccination or measles virus
and to a lesser extend, varicella and rubella infection. The
underlying pathology share similarities with the one
induced in EAE [63]. Another example of virus-induced
demyelination with concomitant autoimmunity is the
one following infection with murine coronavirus in rats.
At the acute stage of this animal model demyelination is
restricted and related to the infection of glial cells from the
virus. However, at later stages, at a time when animals
recover from the viral infection, perivascular infiltrates
and extented demyelination are present. A transfer EAE
was performed by injecting in vitro activated anti-myelin
lymphocytes harvested from infected rats at a time that
the animals recovered from the initial infection to naive
recipients. The resulted EAE was mild with no evidence of
demyelination [64]. This finding may indicate that the
pre-exposure of the animal to virus may be necessary for
the induction of autoimmune demyelination. Similarly,
the canine distemper virus (paramyxovirus) – induced
demyelination has been reported to be associated with
perivascular infiltrations at the late phases following ini-
tial infection [65].
The example of TMEV – induced encephalomyelitis is
probably the best currently used model of virus-induced
immune-mediated demyelination in susceptible mice.
TMEV is divided into two subgroups: high-neurovirulent
strains, including GDVII and FA, which cause fatal
encephalitis, and low-neurovirulent strains, such as DA
and BeAn, which cause persistent infection and demyeli-
nation in mice [66,67]. The demyelinating phase is pre-
ceded by an inflammatory one consisted of macrophages
and MHC II – restricted T-cells. However, during the
demyelinating phase, cytotoxic and suppressor MHC I –
restricted T-cells gradually replace the initial inflamma-
tory subpopulation. In particular, the prevailing opinion
is that B- and T-lymphocytes play paradoxical functions in
the TMEV-induced CNS disease since they may participate
in the virus clearance in CNS cells during the acute phase
of the disease and aggravate the demyelinating process in
the chronic phase of the disease, thereafter. Therefore, in
this model, inflammatory cells are constant components
of the underlying demyelinating process [68]. The large
number of B- and T-lymphocytes in demyelinating areas
suggest that recruitment of these cells into the CNS is an
important step in the process of myelin destruction [69-
71]. In addition, the response to immunomodulatory or
immunosupressent agents [24,72,73] as well as the
expression of Ia antigens in glial cells [74], indicate the
immune-mediated mechanism of demyelination in this
animal model. It was hypothesized that the specificity of
primary white matter destruction in the TMEV model
depends on immune-sensitised cells, which interact with
viral antigen plus MHC antigens on the surfaces of oli-
godendrocytes or myelin sheaths[75]. The whole underly-
ing pathology shares similarities with the one in MS,
except that in the later no viruses are detected in oli-
godendrocytes as in TMEV encephalomyelitis [76].
It was suggested that virus infection may initiate or exac-
erbate organ-specific autoimmune diseases [77]. There is
growing evidence about possible mechanisms by which
virus infection can trigger autoimmunity. Among them
are: (a) molecular mimicry, (b) bystander activation, and
(c) epitope spreading (figure 1).
(a) Molecular mimicry involves the de novo activation of
autoreactive T cells due to the cross-reactivity between self
epitopes and viral epitopes during a virus infection [78].
Hence, an immune response of the host to a viral epitope
will recognize as nonself the crossreacting host epitope
even when the virus is no longer present. The concept of
molecular mimicry is among the most popular theories
about how virus may induce autoimmunity. Accordingly,
Proposed scheme for virus-mediated autoimmunity in multi-ple sclerosisFigure 1
Proposed scheme for virus-mediated autoimmunity in multi-
ple sclerosis.
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a molecular mimicry has been reported between anti-
TMEV antibody responses in TMEV-infected mice and the
myelin component galactocerebroside [67]. In TMEV-
induced demyelination, CD4+ T cell responses to myelin
epitopes arising via epitope spreading after initial CNS
damage approximately 45–60 days post-infection [29].
Interestingly, a molecular mimicry model for initiation of
autoimmune demyelination was developed following
virus infection with nonpathogenic TMEV which was con-
taining a self myelin epitope such as native or mimic
sequences of the immunodominant PLP139-151 epitope.
Infection of SJL mice infection with such a virus express-
ing a self epitope mimic, directly induced autoreactive T
cells with pathologic potential in the absence of CFA [79].
The later may be considered as a big advantage of this
molecular mimicry model since CFA is a chemical com-
pound imposing artificial inflammatory environment.
Alternatively, what is necessary i.e. the CFA, in EAE as a
model for autoimmunity in MS, is "provided" in the virus-
induced model by the virus per se. The antigen presenting
cells (macrophages, dendritic cells, microglia) as well as
the capability of the mimic peptide being processed from
the native pathogen protein, are two key factors that play
important role in the molecular mimicry mechanism dur-
ing the induction of autoimmunity. In addition, the
nature of the innate immune response to the pathogen
which determines the immunopathologic potential of the
induced cross-reactive T cells, the site(s) of the primary
infection in the host and the ability of the pathogen to
persist, and finally the potential requirement for multiple
infections with the same or different pathogens, are all
considered as contributing factors determining the mech-
anism of molecular mimicry [80].
MBP is among the most important targets in the immun-
opathogenesis of MS. In addition, the MBP(85–99) pep-
tide is a T-cell target for patients with the HLA-DR2
haplotype while the MBP(88–102) peptide may be a tar-
get for patients with other HLA-DR haplotypes. The HLA
antigen and the T-cell receptor (TCR) are key factors in the
constitution of the trimolecular complex (antigen pre-
senting cell – myelin antigen – T-cell) during lymphocyte
activation. Peptide-binding studies determined which
MBP peptide residues were important for binding to DR2
and which ones to TCR. These criteria have been applied
to generate a minimal molecular mimicry peptide by
searching a sequence database for viral and bacterial mim-
icry peptides of MBP(85–99). Finally, 8 yielded peptides
performed biological activity and stimulated MBP(85–
99)-specific T-cell clones. These peptides did not show
any significant linear homology to MBP(85–99), and they
were derived from human pathogens such as EBV, HSV,
CMV, influenza virus, and adenovirus [81].
(b) Bystander activation is the nonspecific activation of
autoreactive T cells resulting from the direct inflammatory
and/or necrotic effects of virus infection on tissue in the
target organ [82]. This mechanism requires destruction of
specific tissue such as CNS, release of sequestered antigen
such as those of myelin and increased local immune
inflammation. Lymphocytes would be recruited to the
injured CNS and those reactive to the released myelin
antigen would in turn be restimulated in the inflamma-
tory response. Consequently, autorreactive lymphocytes
would gain access to the target tissue without being
directly involved in the initial vira! insult or reactive to
viral antigens. Successive targeted viral infections over a
lifetime would fulfill the requirement for generation, acti-
vation and recruitment of autoimmune lymphocytes. The
role of virus in this mechanism is not only to select the tis-
sue, but also to induce a strong inflammatory response
[83].
(c) Epitope spreading is characterized by a widening of the
immune response from an initiating antigenic epitope to
different epitopes on the same molecule (intramolecular
spreading) or to a epitopes on a different antigenic mole-
cule (intermolecular spreading). The addition of func-
tional immunogenic myelin epitopes to the original viral
epitopes in TMEV infection, represents a classical example
of intermolecular epitope spreading [29,84]. In particular,
cells responding to the major PLP epitope139-152, iso-
lated from lymph nodes of TMEV infected mice, have the
ability to demyelinate organotypic cultures of spinal cord.
No similar results were obtained when the cells were stim-
ulated with MBP. These results suggest that in animals
infected with TMEV, the spreading of the immune
response from TMEV to PLP has functional significance,
and is specific[85] T cells specific for a secondary, non-
cross-reactive epitope, PLP178-191, have been reported to
mediate the primary clinical relapse [86]. This phenome-
non has been described in a number of autoimmune dis-
eases, TMEV included [87-90]. More importantly, naive T-
cells enter the inflammed CNS and are activated by local
antigen presenting cells to initiate epitope spreading [91].
Axonal degeneration in MS: is there any value
for viruses?
Injured axons are common in the lesions of multiple scle-
rosis, and axonal transection may be the pathologic corre-
late of the irreversible neurologic impairment in this
disease [92]. Axonal degeneration has been identified as
the major determinant of irreversible neurological disabil-
ity in patients with MS. Evidence for the axonal injury –
related hypothesis is provided by animal models with pri-
mary myelin or axonal pathology, and from pathological
or magnetic resonance studies on MS patients [93]. Dis-
ruption of axons is observed both in EAE and TMEV mod-
els [94].
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A correlation between inflammation and axonal loss with
neurological disability has been reported in chronic-
relapsing EAE. At the acute stage, CNS inflammation, but
not axon loss, correlated with the degree of neurological
disability. In contrast, fixed neurological impairment in
chronic EAE correlated with axon loss. As proposed for
MS, these observations imply a causal relationship
between inflammation, axon loss, and irreversible neuro-
logical disability [95,96]. It has also been demonstrated in
TMEV model that demyelination in the spinal cord is fol-
lowed by a loss of medium to large myelinated fibres. By
measuring spinal cord areas, motor-evoked potentials,
and motor coordination and balance, axonal loss follow-
ing demyelination was determined to be associated with
electrophysiological abnormalities and correlated
strongly with reduced motor coordination and spinal
cord atrophy. These findings demonstrate that axonal loss
can follow primary, immune-mediated demyelination in
the CNS and that the severity of axonal loss correlates
almost perfectly with the degree of spinal cord atrophy
and neurological deficits [97,98].
Axonal injury begins early at disease onset and correlates
with the degree of inflammation within lesions, indicat-
ing that inflammatory demyelination influences axon
pathology during relapsing-remitting MS (RR-MS) [93].
However, axonal injury exists even in the normal appear-
ing white matter [99] where inflammation may be mini-
mal or absent. In addition, the fact that currently applied
immunomodulators and immunosuppresants may
hardly reverse or even halt the long term disability and the
underlying neurodegeneration, may additionally indicate
that there is no absolute relation between the level of
inflammation and the extend of axonal degeneration and
loss. Moreover, evidence for widespread axonal damage at
the earliest clinical stage of MS lessens the validity of the
concept that the axonal pathology of MS is the end-stage
result of repeated inflammatory events [100].
Interesting information about a possible mechanism
under which axonal injury may exist without concomitant
demyelination, may emerge from TMEV animal model.
The extent and location of axonal injury following infec-
tions with both DA and GDVII, TMEV strains, was investi-
gated [101]. In DA virus infection, axonal injury was
detected as early as 1 week after infection. The number of
damaged axons increased throughout time. During the
subclinical phase, 2 and 3 weeks after infection, axonal
injury was associated with parenchymal infiltration of
microglia and T cells, and viral antigen and damaged
axons were present within intact myelin sheaths. How-
ever, vigorous inflammatory demyelinating lesions were
not seen until the chronic phase (4 weeks after infection).
In GDVII virus infection, extensive axonal injury was
noted 1 week after infection without association with
inflammation, virus, or demyelination. The distribution
of injured or damaged axons in both GDVII virus infec-
tion and the early phase of DA virus infection corre-
sponded to regions where subsequent demyelination
occurred during the chronic phase of DA virus infection.
These findings indicate that axonal injury may not follow
but rather herald demyelination in some virus models.
Somebody may therefore hypothesize that axonal injury
noticed during the earliest stages of MS or in the normal
appearing white matter, could be attributed to the activa-
tion of an as yet unidentified virus. The same or similar
virus may further contribute through induced autoimmu-
nity to axonal injury during later stages of the finally
established inflammatory demyelinating process.
There are two main animal models currently used in MS
research: EAE and TMEV. Both models contributed to a
greater understanding of MS and the development of clin-
ical therapies [6]. Although from a first point of view they
may represent fanatic supporters of either the autoim-
mune or the viral hypothesis on MS aetiology, it becomes
clear later on that the two models complement each other.
Both systems are powerful tools for an in-depth study of
the neuroinflammatory mechanisms potentially involved
in MS pathophysiology. Analysing therapeutic successes
and failures with both models may also help the develop-
ment of more directed, positive treatments for MS that
have fewer negative effects [102].
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