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Multiple Sclerosis (1998) 4, 93 ± 98
 1998 Stockton Press All rights reserved 1352 ± 4585/98 $12.00
http://www.stockton-press.co.uk/ms
Neuropathology in multiple sclerosis: new concepts
Hans Lassmann
Institute of Neurology, University of Vienna, Austria
Multiple sclerosis lesions are characterized by in¯ammation, demyelination and a variable degree of axonal loss. The patterns of in¯ammation in
MS lesions are compatible with a T-lymphocyte mediated immune reaction. The formation of demyelinated plaques, however, seem to require
additional immunological mechanisms. In this review evidence is discussed for a pathogenetic role of demyelinating antibodies, toxic macrophage
products, cytotoxic T-cells as well as metabolic disturbances of oligodendrocytes. It is suggested that the pathological heterogeneity regarding the
patterns and extent of demyelination, remyelination and axonal loss may be the outcome of variable dominant immunopathogenetic mechanisms
in different multiple sclerosis patients.
Keywords: Multiple sclerosis; pathology; demyelination; axon; oligodendrocyte
Introduction
Multiple sclerosis is a chronic in¯ammatory disease of
the central nervous system, which is associated with
selective destruction of myelin sheaths. This leads to
the formation of large demyelinated plaques, dispersed
throughout the entire brain and spinal cord. Axons in
the plaques are relatively spared, although emphasis
has to be laid on the term relative.1 In particular, in
cases with progressive disease course and severe
neurological de®cit axonal destruction and loss can
be profound, in some cases affecting more than 80% of
the axonal population in the plaques.2 Furthermore,
the degree of axonal loss and atrophy more closely
correlates with permanent clinical de®cit compared to
the total amount of lesions or the extent of demyelination.3 The demyelinating process is counteracted by
remyelination, at least in early stages of the disease.4,5
In such cases complete lesions may become remyelinated and may appear as so called `Markschattenherde'.4,6
The clinical spectrum of multiple sclerosis is broad,
including relapsing-remittent, primary and secondary
progressive and acute-subacute disease courses. Even
more pronounced is the pathologic heterogeneity of
the disease, in particular, when atypical disease
variants, such as acute MS, neuromyelitis optica,
concentric sclerosis and diffuse sclerosis are included
in the spectrum.7 ± 9 Even the classical variants of
chronic relapsing or progressive multiple sclerosis
are neuropathologically re¯ected in a broad spectrum
of different lesion subtypes.10 Recent studies suggest
that this heterogenous spectrum of multiple sclerosis
pathology may be due to a multitude of susceptibility
genes in affected patients and to a wide spectrum of
different immunological mechanisms, that may be
responsible for in¯ammation and demyelination of
the disease.11 ± 13
Correspondence: H Lassmann
T-cell mediated in¯ammation is a characteristic
feature of multiple sclerosis lesions, but alone is
unlikely to cause the disease
The in¯ammatory in®ltates in multiple sclerosis
lesions have been characterized during the last years
in detail. They are composed by T-lymphocytes, by
small numbers of B-lymphocytes and plasma cells
and ± in particular in actively demyelinating lesions ± by activated microglia or macrophages.14 ± 18
The latter cell population interacts with myelin
sheaths and apparently is actively engaged in the
demyelinating process. A variety of immune related
molecules, such as histocompatibility antigens, adhesion molecules and cytokines are locally produced or
expressed in the lesions.14,19 ± 22 These patterns suggest
that a T-cell mediated immune response is the basis of
brain in¯ammation in this disease. In experimental
models a pure encephalitogenic T-cell mediated
immune reaction in general leads to brain in¯ammation without demyelination.23,24 Similarly in humans,
the extensive T-cell mediated in¯ammation, that is the
hallmark of acute disseminated leucoencephalomyelitis, does not result in MS-like demyelinated plaques in
the nervous system. For these reasons it is likely that
additional, speci®c demyelinating ampli®cation factors
are required to induce the full blown multiple
sclerosis lesion.
Mechanisms of demyelination
Basic research in immunology and neurobiology
revealed that a selective destruction of myelin
sheaths can be induced by multiple different
mechanisms. They include speci®c cellular and
humoral immune mechanisms, the unspeci®c action
of certain macrophage toxins as well as causes that
reside in the metabolism of the myelin producing
cells, the oligodendrocytes. All these mechanisms are
potential candidates in the pathogenesis of multiple
sclerosis.
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Neuropathology in multiple sclerosis: new concepts
H Lassmann et al
94
In¯ammatory demyelination, induced by a synergy
of encephalitogenic T-cells and demyelinating
antibodies
It is well established now that this immunological
mechanism can induce an in¯ammatory demyelinating
disease in vivo, which closely resembles multiple
sclerosis. The basic principle of this immune reaction
has been documented in detail by transferring encephalitogenic T-lymphocytes and demyelinating antibodies
in experimental models in vivo.25,26 Intravenous injection of encephalitogenic T-cells alone induces an acute
in¯ammatory disease without demyelination. This
disease is ampli®ed, when demyelinating antibodies
are cotransferred, leading to widespread demyelination.
Repeated cotransfers of encephalitogenic T-cells and
demyelinating antibodies result in chronic relapsing
disease with plaques of demyelination and impaired
remyelination.27 Similar lesions can also be induced by
active sensitization with myelin oligodendrocyte glyco-
protein, which contains epitopes for both, encephalitogenic T-cells and demyelinating antibodies.28 ± 30
A variety of different observations suggests that ±
at least in some ± multiple sclerosis patients, demyelinating antibodies may be pathogenetically relevant.
Demyelinating activity of multiple sclerosis serum has
been found by Bornstein and Appel, which could in
part be related to the action of immunoglobulins.31,32
Immunoglobulin precipitation occurs at the active
edge of MS plaques, at sites where macrophages
interact with disintegrating myelin sheaths.33 In these
areas also complement components are present,34 even
in the form of the C9neo antigen, which appears,
when the lytic terminal complement complex is
activated.74 In exceptionally severe disease courses,
complement deposition in the lesions may be accompanied by granulocytes in the in¯ammatory in®ltrates
(Figure 1c). It is thus likely, that in this subgroup of
multiple sclerosis patients demyelinating antibodies
Figure 1 Immunopathology of Multiple Sclerosis. (a) actively demyelinating lesions. PLP mRNA in oligodendrocytes (black cells) is absent in the area of active myelin destruction, characterized by macrophages with myelin
degradation products (red granules); immunocytochemistry for PLP-protein (red) and in situ hybridization for PLP
mRNA (black).6400. (b) Oligodendrocytes (immunostained with a-MOG antibody; brown) undergoing DNAfragmentation visualized by in situ tailing (black nuclei). Some of the labeled nuclei show condensed chromatin,
similar to that found in apoptosis. 6900. (c) Exceptionally severe, destructive acute MS lesion with Complement
C9neo deposition (red) and in®ltration of the tissue with granulocytes. 6600
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Neuropathology in multiple sclerosis: new concepts
H Lassmann et al
are a pathogenetic ampli®cation factor, acting on the
background of a T-cell mediated in¯ammatory response.
The identi®cation of a combined T-cell and antibody mediated pathogenesis in some MS lesions has
profound therapeutic consequences. Immunomodulatory strategies, aimed to suppress a Th1 mediated
autoimmunity by stimulating the Th2 pathway may in
this particular situation be counterproductive by
increasing the pathogenic demyelinating antibody
response.35 As an example, oral tolerization with
myelin in primate chronic EAE may result in severe
relapses after cessation of therapy.36
T-cell mediated destruction of myelin and
oligodendrocytes
Several in vitro studies suggest that myelin and
oligodendrocytes can also be destroyed by T-cell
mediated immune mechanisms. Adding activated Tcells to myelinated tissue culture systems can result in
selective destruction of myelin and oligodendrocytes.37,38 This may be accomplished by T-cell
products, such as lymphotoxin or perforin.39,40 In
addition the activation of the Fas-signaling pathway
in oligodendrocytes by its speci®c ligand on T-cells
may destroy oligodendrocytes selectively.41 It is not
clear as yet whether speci®c antigen recognition on the
surface of oligodendrocytes ± in particular recognition
of stress proteins ± may contribute to demyelination
and destruction of myelin-forming cells.42,43
So far little evidence is available for a pathogenetic
role of T-cell mediated demyelinating mechanisms in
experimental models in vivo. In particular no model as
yet has demonstrated that demyelinated plaques can
be induced in vivo as a direct consequence of transfer
of any T-cell population. In contrast, in multiple
sclerosis lesions some indirect evidence accumulated,
which suggests that such immune reactions indeed
may be pathogenic. Fas receptor is expressed on a
variety of different glia cells in multiple sclerosis
lesions, in particular also on oligodendrocytes.41,44 The
respective Fas-ligand is found on activated T-cells, but
also on microglia cells.41 In addition, Fas-positive
oligodendrocytes have been found ingested in macrophages or microglia.44 Another indirect evidence for a
possible involvement of T-cell mediated immune
reactions in demyelination is the observed colocalization of stress protein reactive oligodendrocytes with Tlymphocytes carrying gamma/delta T-cell receptors.
From these data it was suggested that such T-cells may
lyse stressed ± possibly remyelinating ± oligodendrocytes in established lesions.42
Macrophage mediated demyelination
In vitro oligodendrocytes are particularly vulnerable to
the action of macrophage toxins. Thus they can be
selectively destroyed by complement components,
reactive oxygen intermediates or cytokines, such as
tumor necrosis factor alpha.45 ± 47 It was thus suggested
that demyelination in multiple sclerosis may be a
consequence of macrophage activation in the course of
T-cell mediated brain in¯ammation. However, it has to
be kept in mind that acute T-cell mediated in¯amma-
tory CNS diseases, such as acute disseminated
encephalomyelitis or acute virus induced encephalomyelitis, which in general are associated with
profound in®ltration of the tissue by activated macrophages, do not lead to the formation of con¯uent
demyelinated
plaques.
Therefore,
macrophage
mediated demyelination in multiple sclerosis is only
feasible, when there is a unique dysregulation of
macrophage toxicity or oligodendrocyte susceptibility.
Transgenic mice, which overexpress tumor necrosis
factor alpha in the central nervous system can ±
under some circumstances ± develop plaques of
in¯ammatory demyelination, which in many respects
re¯ect multiple sclerosis lesions.48 In these lesions an
early stage of vacuolar myelinopathy and oligodendroglia apoptosis is followed by widespread and
plaque like destruction of myelin sheaths.
Massive activation of macrophages is a cardinal
feature of the pathology of active multiple sclerosis.18
In addition, the local expression of toxic macrophage
products, such as tumor necrosis factor alpha has
convincingly been documented in MS plaques.49,50
Recently we found also that in some cases of multiple
sclerosis actively demyelinated lesions are not associated with deposition of immunoglobulin and complement, but are rather characterized by massive
macrophage and microglia activation together with
oligodendrocyte death by apoptosis (Figure 1b).
Demyelination by metabolic instability of
oligodendrocytes
Metabolic instability of oligodendrocytes may either be
induced by virus infection or by defects in the
regulation of myelin genes. There is ample evidence
that virus infection of oligodendrocytes directly may
lead to cell death.51 In addition however, acute virus
infection may disturb the expression of myelin gene
expression. As an example, infection of myelinforming cells with both Theiler's virus and corona
virus block the luxury function of these cells, the
production of myelin proteins, such as proteolipid
protein.52 ± 54
A different mechanism of metabolic instability of
oligodendrocytes is exempli®ed in transgenic animals,
which overexpress major myelin proteins, such as
proteolipid protein during myelin formation.55,56 In this
model, massive overexpression leads to oligodendrocyte death by apoptosis during the phase of myelination. However, a moderate overexpression can be
balanced, resulting in only slow degeneration of
oligodendrocytes, minor demyelination and repair of
myelin. As another example, de®ciency of myelin
associated glycoprotein does not prevent myelin
formation but ± with increasing age of the animals ± is associated with a peculiar type of distal
oligodendroglia damage, named `dying back' oligodendrogliopathy.57,58 It is possible, but so far not proven
that such metabolic disturbances may render oligodendrocytes more susceptible to immune mediated injury.
Evidence for an association between multiple
sclerosis susceptibility and myelin gene polymorphism
so far is controversial. Linkage of disease susceptibility
with myelin basic protein gene polymorphism has
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95
Neuropathology in multiple sclerosis: new concepts
H Lassmann et al
96
been disclosed, but did not become apparent in larger
genomic screens. It may thus be restricted to a special
cohort of multiple sclerosis patients. Similarly, virus
infection of oligodendrocytes has sometimes been
observed in multiple sclerosis lesions although no
particular MS-speci®c virus infection has been found
so far.59 Downregulation of the expression of myelin
protein mRNAs is frequent in active MS plaques
(Figure 1a) and on the protein basis in some cases a
pronounced loss of myelin associated glycoprotein can
be found.60 The alterations of `dying back' oligodendrogliopathy have been identi®ed in virus induced
experimental demyelinating diseases as well as in
some multiple sclerosis lesions.61 Finally, in some
patients with chronic progressive multiple sclerosis we
found a pattern of demyelination, suggesting a primary
oligodendrocyte destruction, followed by demyelination.62,70 All these data suggest that metabolic instability of oligodendroglia may occur in certain MS lesions,
its consequence for the pathogenesis of demyelination,
however, is as yet unde®ned.
Mechanisms of axonal damage
As mentioned above axons are destroyed to a variable
degree in multiple sclerosis plaques. This is a major
problem in MS pathogenesis, since axonal loss signi®cantly contributes to permanent functional de®cit.
In contrast to demyelination little attention in MS
research has been paid to the problem of axonal
pathology. From pathological studies it is evident, that
the extent and severity of the in¯ammatory reaction is
to some extent related to the amount of axonal
damage.63,64 As an example, the most extensive loss of
axons is found in plaques of Marburg's acute MS,
which are also characterized by a much more severe
nature of the in¯ammatory process, compared to
classical chronic MS. In experimental models axonal
damage can be induced by products of activated
macrophages. These cells are a major source of
endogenous excitotoxins, which may be responsible
for neuronal injury.65 Excitotoxins however exert their
damaging effect through glutamate receptors, which are
rather distributed on dendrites and neuronal pericarya
than on the axons themselves. Thus excitotoxicity
rather results in axon sparing neuronal damage than
to direct axonal pathology.66 Functional damage of
axons can also be induced by nitric oxide and this
effect is more pronounced in demyelinated compared
to intact nerve ®bers.67 It is, however, not clear so far
whether nitric oxide can also be responsible for
structural and permanent axonal destruction. In MS
pathology acute axonal damage in general takes place
during the period of lesional activity, although it seems
to follow the destruction of myelin sheaths. The reason
for the profound differences in the extent of axonal loss
between different multiple sclerosis patients, however,
remains to be elucidated.
Remyelination and lesional repairs
The occurrence of spontaneous remyelination in
multiple sclerosis lesions has been suggested already
in the earliest pathological descriptions. As an
example Marburg drew the attention to the occurrence
of very thin myelin sheaths in acute MS lesions, which
were only detectable after osmic acid impregnation of
the sections.1 Although at that time no experimental
evidence for remyelination in the central nervous
system was available, Marburg suggested a remyelinating process in analogy to the patterns of peripheral
nerve regeneration. It is now well established that
extensive remyelination may occur in multiple sclerosis spontaneously, forming the so called `shadow
plaques, which have primarily been de®ned by Schlesinger as incompletely demyelinated areas. Remyelination is a particular feature of early MS lesions, which
arise during the ®rst years after onset of the disease
and are abundantly found in biopsies taken at this
stage.4 ± 6,10,62,68 ± 70
The extent of remyelination in MS lesions apparently is determined by two factors: the availability of
oligodendrocytes or progenitor cells and the degree of
axonal damage in the lesions. Although oligodendrocytes may be preserved during the acute stage of
demyelination in MS lesions it is doubted that these
cells are responsible for remyelination.62,70 Recent
experimental studies rather suggest that the pool of
remyelinating cells is recruited from undifferentiated
glial progenitor cells.71 Lack of remyelination in
chronic MS plaques may thus be explained by
repeated de- and remyelination in the same lesion
and exhaustion of the progenitor cell fraction.72 Besides this, however, the plaque environment ± such as
the degree of astroglial scar formation or the lack of
proper trophic support ± may also impede remyelination. In line with this notion, chronic MS plaques not
infrequently contain signi®cant numbers of poorly
differentiated oligodendrocytes in the absence of
remyelination. Such cells potentially could be activated to start lesional repair by therapeutic intervention.73
Heterogeneity of multiple sclerosis pathology suggests
the involvement of different pathogenetic
mechanisms
As discussed above many different pathogenetic
mechanisms can be involved in demyelination, remyelination and axonal damage in multiple sclerosis
lesions. It is thus not surprising that active multiple
sclerosis lesions reveal a broad heterogeneity in their
neuropathological characteristics. With regard to structural aspects of demyelination, oligodendrocyte loss,
remyelination and axonal pathology we have recently
classi®ed multiple sclerosis lesions into at least ®ve
different subtypes: (a) demyelination with no or only
minor oligodendrocyte loss; (b) demyelination with
concomitant destruction and loss of oligodendrocytes;
(c) primary demyelination with a secondary gradient
loss of oligodendrocytes in inactive plaque areas; (d)
primary oligodendrocyte destruction in the periplaque
white matter and secondary demyelination and (e)
destructive lesions with profound additional loss of
axons and in part of astrocytes.10 Since all the lesions
were classi®ed with the same stringent criteria of
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Neuropathology in multiple sclerosis: new concepts
H Lassmann et al
lesional activity it is unlikely that these different
pathological patterns represent speci®c stages in the
evolution of the lesions. Similarly, the severity of the
immunological reaction was unlikely to be an explanation for this structural heterogeneity. Ongoing immunopathological
studies
rather
suggest
that
demyelination may be induced by different immunological mechanisms and that this will also result in
distinct patterns of structural pathology. Furthermore
the lesional pro®le was highly conserved in different
plaques of a single patient, while major differences were
present in the pathological patterns between different
patients. This indicates, that different multiple sclerosis
patients may preferentially use different immunopathogenetic pathways of demyelination in their lesions. It
will be a major task in future MS research to ®nd
clinical and paraclinical markers that allow to differentiate such pathogenetic subtypes of the disease and
design therapeutic strategies, which speci®cally target
the diverse mechanisms responsible for in¯ammation,
demyelination and axonal destruction.
Acknowledgements
This study was funded by a project of the Austrian
Science Foundation.
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