Inflammatory Demyelinating Diseases

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Handbook of Clinical Neurology, Vol. 145 (3rd series)
Neuropathology
G.G. Kovacs and I. Alafuzoff, Editors
http://dx.doi.org/10.1016/B978-0-12-802395-2.00019-5
Copyright © 2018 Elsevier B.V. All rights reserved
Chapter 19
Inflammatory demyelinating diseases of the central

nervous system
€
ROMANA HOFTBERGER 1
AND HANS LASSMANN2*
1
Institute of Neurology, Medical University of Vienna, Vienna, Austria
2
Center for Brain Research, Medical University of Vienna, Vienna, Austria
Abstract
Inflammatory demyelinating diseases are a heterogeneous group of disorders, which occur against the
background of an acute or chronic inflammatory process. The pathologic hallmark of multiple sclerosis
(MS) is the presence of focal demyelinated lesions with partial axonal preservation and reactive astroglio-
sis. Demyelinated plaques are present in the white as well as gray matter, such as the cerebral or cerebellar
cortex and brainstem nuclei. Activity of the disease process is reflected by the presence of lesions with
ongoing myelin destruction. Axonal and neuronal destruction in the lesions is a major substrate for per-
manent neurologic deficit in MS patients. The MS pathology is qualitatively similar in different disease
stages, such as relapsing remitting MS or secondary or primary progressive MS, but the prevalence of
different lesion types differs quantitatively. Acute MS and Balo’s type of concentric sclerosis appear to
be variants of classic MS. In contrast, neuromyelitis optica (NMO) and spectrum disorders (NMOSD)
are inflammatory diseases with primary injury of astrocytes, mediated by aquaporin-4 antibodies. Finally,
we discuss the histopathology of other inflammatory demyelinating diseases such as acute disseminated
encephalomyelitis and myelin oligodendrocyte glycoprotein antibody-associated demyelination. Knowl-
edge of the heterogenous immunopathology in demyelinating diseases is important, to understand the clin-
ical presentation and disease course and to find the optimal treatment for an individual patient.
associated with a specific spectrum of demyelinating dis-

INTRODUCTION
eases. Anti-aquaporin-4 antibodies (AQP4-abs) are asso-
Historically the first description of multiple sclerosis ciated with NMO and limited forms of the disease, such
(MS) as a neuropathologic entity dates from 1868 by as isolated optic neuritis or myelitis, which are now sub-
Charcot; subsequently, less prevalent disorders such as sumed under the term NMO spectrum disorders
neuromyelitis optica (NMO) (Devic, 1894), Marburg (NMOSD). Meanwhile, the use of AQP4-abs as bio-
type of MS (Marburg, 1906), or concentric sclerosis of marker for NMOSD is well established and has major
Balo (1928) were demonstrated and considered as sub- prognostic and therapeutic implications. Anti-myelin oli-
types of MS. With the availability of immunohistochem- godendrocyte glycoprotein (MOG) antibodies are found
ical markers it became apparent that there is a in patients with acute dissemimated encephalomyelitis
considerable pathologic distinction between these disor- (ADEM), NMOSD, and, rarely, MS-like clinical presen-
ders and the morphologic patterns were associated with tation (Lennon et al., 2004; Kim et al., 2015; Wingerchuk
different mechanisms of demyelination (Lucchinetti et al., 2015; Sepulveda et al., 2016), but they may define
et al., 2000, 2002). This observation was further sup- a unique and specific variant of inflammatory demyelin-
ported by the discovery of autoantibodies that are ating diseases. It is quite probable that, even within the
*Correspondence to: Hans Lassmann, MD, Center for Brain Research, Medical University of Vienna, Spitalgasse, 1090 Vienna,
Austria. E-mail: [email protected]
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R. HOFTBERGER AND H. LASSMANN
classic spectrum of MS, variabilities may represent dif- antibody natalizumab in relapsing remitting MS (Polman
ferent disease processes or perhaps different triggering et al., 2006).
factors and will classify future distinct entities. The high efficacy of natalizumab treatment is due to
its blockade of the migration of many different inflam-
MULTIPLE SCLEROSIS matory cell types. However, it has been suggested that
different inflammatory cell types use different entry path-
Clinical and diagnostic features ways, by using distinctly different adhesion molecule
The clinical diagnosis of MS is based on the demonstra- interactions or chemokines such as a4integrin, ICAM,
tion of demyelinating lesions disseminated in time and ALCAM, CCL5, CXCL10, and CCL2/CCR2 by Th1+,
space. In addition to the neurologic symptoms, the find- Th17+ and CD8+ T cells (Engelhardt and Ransohoff,
ing of magnetic resonance imaging (MRI) lesions consis- 2005; Cayrol et al., 2008; Ifergan et al., 2011) or
tent with MS (Barkhof et al., 1997; Tintore et al., 2000), CXCL12/CXCR4, CCR7/CCL19/TLR4 by monocytes
demonstration of oligoclonal bands in cerebrospinal (Man et al., 2012; Paradis et al., 2016). When these obser-
fluid (CSF) (Link and Tibbling, 1977), and/or detection vations are confirmed and validated in different human
of abnormal visual evoked potentials (delay with a well- diseases, including MS, more specific blockade of the
preserved wave form) are recommended to provide a cor- migration of those leukocytes, which are most relevant
rect diagnosis (McDonald et al., 2001). Patients with MS in driving disease and tissue damage, may lead to effec-
may present a monosymptomatic disease suggestive of tive therapies with fewer side-effects, compared to those
MS (clinically isolated syndrome), a classic relapsing currently available.
remitting course, or a primary or secondary progressive Morphologically, the disturbance of BBB permeabil-
disease. Disease progression is defined as continuous ity can be visualized with ultrastructural investigation
deterioration of neurologic symptoms despite only a and immunohistochemistry. By ultrastructure, endothe-
few new MRI lesions and a rare incidence of contrast- lial cells show an increase in pinocytic vesicles in active
enhancing lesions. The majority of patients with MS start MS lesions (Brown, 1978) and by immunohistochemis-
with a relapsing remitting MS, which later converts into a try, a perivascular leakage of serum proteins and, more
secondary progressive disease. In primary progressive specifically, an expression of molecular markers for
MS the disease starts with continuous progression from leaky endothelial cells is seen (Kirk et al., 2003;
its onset. The pathogenetic mechanism underlying pro- Hochmeister et al., 2006). In MRI studies, the BBB per-
gression is supposed to result at least in part from an meability is visualized with contrast enhancement. The
ongoing inflammatory reaction behind a closed blood– dynamic changes from nodular enhancement during
brain barrier (BBB). early lesion formation to a ring-enhancing lesion in a
later stage suggest that BBB leakage initally starts in
Pathologic features of classic MS the inflamed central vein and later mainly occurs at the
active margin (Gaitan et al., 2011). It is important to note
The histopathologic hallmark of MS is the formation of that contrast enhancement in MRI depicts BBB leakage,
inflammatory demyelinating lesions with variable axo- but is not a direct marker of inflammation. In particular,
nal damage and astrocytic gliosis. in patients with progressive MS, widespread and pro-
found inflammation is seen in the brain, which takes
INFLAMMATION place in part behind a closed or repaired BBB
(Hochmeister et al., 2006).
Blood–brain barrier
In the pathogenesis of MS plaques it is currently sup-
T lymphocytes
posed that autoreactive, myelin-specific lymphocytes
are activated outside the central nervous system Neuropathologic tissue examination recognizes peri-
(CNS), cross the BBB, and form new inflammatory vascular cell cuffs and meningeal inflammatory infil-
demyelinating lesions (Ciccarelli et al., 2014). The cross- trates composed of CD3 + and CD8 + T cells, while
ing of the BBB is dependent on the interaction of integ- CD4 + T cells, CD20-positive B cells, and plasma cells
rins on the surface of lymphocytes with cell adhesion are present in variable and lower numbers (Frischer
molecules on endothelial cells (Takeshita and et al., 2009). Lymphocytic inflammation is associated
Ransohoff, 2012). One of the most important interactions with profound macrophage infiltration and microglia
is the binding of the very late antigen-4 integrin on lym- activation, in particular in lesions with active demyelin-
phocytes to vascular cell adhesion molecule-1 on brain ation or tissue injury. Neutrophils and eosinophils are
vascular endothelium (Takeshita and Ransohoff, 2012), usually not observed but more characteristic for lesions
which can be therapeutically blocked by the monoclonal in NMO. In the parenchyma of MS plaques the
INFLAMMATORY DEMYELINATING DISEASES OF THE CENTRAL NERVOUS SYSTEM 265
inflammatory infiltrates are dominated by CD8 + T cells B lymphocytes
(Friese and Fugger, 2005) and show a clonal expansion
that persists over time (Babbe et al., 2000). In some cases B cells are sparse in the parenchyma of MS lesions in
large numbers of cytotoxic T cells were identified in comparison to T cells (Frischer et al., 2009). B cells
close contact with oligodendrocytes or axons and and plasma cells can mainly be found in the perivascular
showed a polarization of granzyme B towards the site and meningeal inflammatory infiltrates. In patients with
of contact (Neumann et al., 2002). For these reasons it pronounced inflammatory pathology, large B-cell aggre-
has been hypothesized that cytotoxic T cells may in part gates may occur and show features of tertiary lymphoid
selectively mediate the inflammatory demyelination in follicles with germinal center-like structural organization
MS and this view is supported by experimental models (Serafini et al., 2004; Aloisi and Pujol-Borrell, 2006;
of brain inflammation induced by oligodendrocyte- Magliozzi et al., 2007). It has been shown that meningeal
reactive CD8 + T cells, which unequivocally show pri- inflammation correlates with the extent of active demy-
mary demyelination (Saxena et al., 2008). However, it elination and neurodegeneration in the underlying cortex
turned out to be very difficult to induce demyelination (see later under demyelinating lesions in the gray matter)
by passive transfer of CD8 + T cells in animal models (Magliozzi et al., 2010; Howell et al., 2011; Fischer et al.,
(Huseby et al., 2001; Na et al., 2008; Saxena et al., 2013). B cells mature to plasma cells that produce immu-
2008). This was partly explained by an antigen-specific noglobulins that are mainly IgG1 and IgG3 isotypes and,
clonal deletion of cytotoxic T cells by oligodendrocytes less frequently, IgA and IgM isotypes. Lipid-specific
in the intact CNS (Na et al., 2012), and this effect IgM in the CSF has been documented in patients with
could be abolished with an immunologic priming of MS and may reflect a negative prognostic marker
the CNS by an infectious process (Na et al., 2012). (Thangarajh et al., 2008). Ig-producing B cells undergo
An alternative theory suggests that at least a subpopu- antigen-specific clonal expansion, which is supported by
lation of T cells may play a neuroprotective rather than a prominent somatic hypermutation of Ig chains within the
destructive role (Stadelmann et al., 2005). This is CSF and brain lesions of MS patients (Obermeier et al.,
supported also by the detection of HLA-E on endo- 2011; Beltran et al., 2014). Although the exact role of
thelial cells and astrocytes in active MS lesions that B lymphocytes in the formation of MS lesions is still
induce an immunoregulatory phenotype in CD8 + cells unclear, some patients show good response to therapies,
(Durrenberger et al., 2012). Interestingly, lower num- which target T- and B-cell infiltration into the CNS
bers of circulating regulatory T cells (FoxP3+, CD8+) (alemtuzumab) (Thompson et al., 2010) or which selec-
in the circulation of relapsing MS patients compared to tively eliminate circulating B cells (rituximab, ocrelizu-
those in remission were detected and held responsible mab) (Hauser et al., 2008, 2017; Montalban et al., 2017).
for the ongoing autoimmune attack in the MS lesion
(Boppana et al., 2011), but the numbers of FoxP3+
Microglia and macrophages
T cells within MS lesions is very low (Fritzsching
et al., 2011). The number of macrophages within MS lesions depends
The CD4 + T cells are present in variable amounts in on the stage of activity. Actively demyelinating plaques
perivascular and meningeal inflammatory infiltrates, contain high numbers of lipid-laden macrophages
but their number overall is small and clonal expansion throughout the lesion, chronically active plaques are
is rare in comparison to CD8 + cells (Babbe et al., 2000). delineated by a rim of macrophages and activated micro-
It is believed that helper T cells initiate the formation of glia, while the lesion center is devoid of macrophages,
MS lesions by recruitment of macrophages that subse- and chronically inactive plaques contain hardly any mac-
quently present antigens. The antigen that drives the rophages (Kuhlmann et al., 2017). The role of microglia
autoimmune process however is unknown and it is and macrophages in the pathogenesis of MS plaques has
supposed that the antigenic epitope repertoire may been extensively studied during the last decades. Origi-
increase and change over time (called epitope spread- nally they were mainly seen as proinflammatory cells
ing) (Davies et al., 2005). The theory that CD4 + helper exacerbating tissue damage by antigen presentation via
T cells are responsible for the formation of new demy- major histocompatibility complex (MHC) molecules,
elinating lesions is supported by animal models of production of oxygen and nitric oxide radicals, secretion
experimental autoimmune encephalomyelitis (EAE) of proinflammatory cytokines, and phagocytosis. Macro-
that are mainly induced by CD4 + T-cell-driven inflam- phages were used as parameters in the time staging of MS
mation (Billiau and Matthys, 2001). However, MS ther- lesions based on the presence of partly digested myelin
apies that selectively target CD4 + T-cell response were components within their cytoplasm (Bruck et al.,
shown to be ineffective (van Oosten et al., 1997; Segal 1995). In vitro MOG and myelin-associated glycoprotein
et al., 2008). (MAG) are degraded after 1 day (Fig. 19.1A), while the
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Fig. 19.1. Time course of myelin degradation in multiple sclerosis. Minor myelin proteins such as myelin oligodendrocyte gly-
coprotein (MOG) are degraded within 1–2 days of phagocytosis (A, arrows: MOG-positive myelin debris within macrophages),
while major myelin proteins such as myelin basic protein (MBP) may persist for up to 6 days (B, arrows: MBP-positive myelin
debris within macrophages). In later stages, macrophages contain periodic acid–Schiff (PAS)-positive residual glycoproteins
(C, arrows: PAS-positive macrophages) and lipids (D, arrows: foamy and vacuolated macrophages). 600.
degradation of proteolipid protein (PLP) and myelin neurofascin155/186 form glioaxonal junctions to keep
basic protein is much slower following myelin phagocy- sodium channels in the nodal region, which is critical
tosis (Fig. 19.1B) (van der Goes et al., 2005). for the efficient saltatory conduction of the action poten-
Immunohistochemical staining for these myelin pro- tial (Sherman et al., 2005).
teins can give an indication of the time interval between
actual myelin destruction and analysis of the tissue
(Bruck et al., 1995). In later stages, residual glycopro- Mechanisms of demyelination
teins in macrophage lysosomes can be stained with peri- Demyelination is the common final phase in the pathol-
odic acid–Schiff (Fig. 19.1 C and D). Later it became ogy of MS and comprises the stripping of myelin lamel-
clear that macrophages may also be involved in remye- lae and removal of myelin fragments by phagocytes.
lination and neuroprotection and their maturation into There is evidence that demyelination is driven by differ-
an anti-inflammatory M2 phenotype occurs after they ent mechanisms involving the adaptive and innate
have ingested myelin (Boven et al., 2006). So far, how- immune system (Lucchinetti et al., 2000). Diffusible
ever, a clear lesion stage-dependent macrophage polari- oxygen, nitric oxide, and nitrogen species, mainly pro-
zation has not become apparent; most macrophages and duced by macrophages and activated microglia, are the
microglia showed a phenotype, which is intermediate key mechanisms for myelin and oligodendrocyte damage
between M1 and M2 cells (Vogel et al., 2013). during early demyelination (Hill et al., 2004; Haider
et al., 2011). In a subgroup of patients (pattern 1) this rel-
DEMYELINATION atively indiscriminate damage is probably a major mech-
anism of injury. In about 50% of patients with short and
Myelin sheath
aggressive disease course an additional deposition of
Myelin sheaths are formed and maintained by oligoden- immunoglobulins and complement was shown within
drocytes (Dhaunchak and Nave, 2007). Myelin assembly the lesions, suggesting an antibody-mediated process
and long-term preservation require a number of proteins (pattern 2). First evidence for a direct antibody–antigen
that are either expressed in the myelin or at the axonal interaction was gained in EAE models that were induced
membrane. MOG is localized on the outermost surface by encephalitogenic T cells and modified by monoclonal
of the myelin sheath. The protein belongs to the immu- antibodies against MOG (Schluesener et al., 1987;
noglobulin superfamily and might serve as cell adhesion Linington et al., 1988). Later, autoantibodies to the astro-
molecule, a regulator of microtubule stability, and a cytic waterchannel AQP4 were discovered and are now
mediator of interactions between myelin and the immune sensitive and specific diagnostic markers for NMOSD.
system (Johns and Bernard, 1999). Structural myelin Indirect evidence for antibody-mediated damage
proteins such as proteolipid protein and myelin basic pro- was found in patients with IgM antibody deposition on
tein are necessary for exact membrane-to-membrane myelin and demyelinated axons that colocalized with
spacing, whereas 2’3’-cyclic nucleotide 3’phosphodies- complement C3b next to antibody–antigen immuncom-
terase (CNP) and MAG are expressed at the periphery of plexes in macrophages (Sadaba et al., 2012). In another
the oligodendrocytes and the latter plays a role in linking distinct group of patients, oxidative stress may cause an
the innermost periaxonal loop of oligodendrocytes oligodendrogliopathy that starts in the distal processes of
with the axon (Lappe-Siefke et al., 2003). At the node oligodendrocytes with preferential loss of MAG and later
of Ranvier axoglial proteins like contactin1 and results in apoptosis of the oligodendrocyte (pattern 3).
Since preferential MAG loss is a prominent feature of Finger-like protrusions may occur along inflamed veins
early white-matter stroke and some types of viral enceph- and are called Dawson fingers.
alitis, and HIF1alpha, a marker for hypoxia, is strongly
expressed in these lesions, it has been hypothesized that Classic active lesions. Actively demyelinating lesions
the “dying-back” oligodendrogliopathy may result from are mainly found in biopsy specimens or in autopsy tis-
a hypoxia-like tissue injury. This may be induced by dis- sue of patients who died early after disease onset
turbance of microcirculation or impairment of mitochon- (Fig. 19.4) (Frischer et al., 2015). Active lesions are char-
drial energy metabolism as a result of reactive oxygen acterized by numerous macrophages with early myelin
species produced by macrophages (Aboul-Enein et al., degradation products within their cytoplasm and expres-
2003; Mahad et al., 2008). Finally, very few cases have sion of the early macrophage marker MRP14 (Fig. 19.4
been identified with apoptotic oligodendrocytes in the A and B). Moreover a considerable number of T cells and
normal-appearing white matter (NAWM), which sug- a variable number of perivascular and meningeal B cells
gests a primary oligodendrogliopathy in these patients and plasma cells are visible (Fig. 19.4 C–F). Within the
(pattern 4). However, more cases are needed to elucidate lesions remaining oligodendrocytes show signs of acti-
the underlying pathogenetic mechanisms. vation with large, round nuclei and broadened cyto-
plasm, which may reflect early remyelination
(Goldschmidt et al., 2009; Hoftberger et al., 2010). When
Neuropathology of MS plaques the entire lesion is filled with myelin-containing macro-
phages, such a lesion is called acute plaque. Chronic
MS lesions can arise at any site in the CNS (Figs 19.2 and active lesions are present, when myelin-containing mac-
19.3); however, there is a predilection for areas with high rophages are densely packed at the edge of a lesion with
venous density, related to the fact that veins are the prime an inactive core. Acute axonal damage with amyloid pre-
sites for the egress of inflammatory cells through the cursor protein-positive spheroids is abundant within
blood to the brain (Waksman, 1960). In progressive active plaques (Kuhlmann et al., 2002). The astrocytes
MS, lesions in addition accumulate in watershed areas are strongly activated with enlarged cytoplasm and often
with low arterial blood supply, such as the periventricular bizarre or multiple nuclei (so-called Creutzfeldt cells)
white matter (Haider et al., 2016). This has been attrib- and form a protoplasmic gliosis. These astrocytic
uted to an amplification of oxidative injury and histo- changes are most likely nonspecific and seem to be the
toxic hypoxia in areas of reduced arterial perfusion and consequence of severe inflammation and microglia acti-
oxygen supply. The demyelinated lesions are typically vation (Sharma et al., 2010). However, activated astro-
well demarcated and centered by an inflamed vein. cytes can produce a large number of proinflammatory
Fig. 19.2. Macroscopic appearance of multiple sclerosis. Chronic multiple sclerosis in a 61-year-old female with a 33-year history;
section through the formalin-fixed brain (A) and the corresponding hemispheric section (B, luxol fast blue) shows multiple well-
demarcated demyelinated plaques in the periventricular white matter (arrows).
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Fig. 19.3. Macroscopic appearance of multiple sclerosis in the brainstem. Chronic multiple sclerosis lesions (arrows) in the pons
(A) and medulla oblongata (B) of a 47-year-old female with an 18-year history. Sections through the formalin-fixed brain (A, B)
and corresponding histologic sections (C, D, luxol fast blue) show multiple well-demarcated demyelinated plaques (arrows).
Fig. 19.4. Actively demyelinating lesion. Serial sections of the edge of an actively demyelinating multiple sclerosis plaque from a
white-matter biopsy of a 22-year-old female. Periplaque white matter is seen on the right side of (A) and (B) (arrows). The plaque
on the left side shows active demyelination with numerous macrophages containing myelin basic protein-positive myelin debris
within their cytoplasm (A, rectangle enlarged upper right). Numerous CD68-positive macrophages (B) are mixed with CD3 + (C),
CD4 + (D) and CD8 + parenchymal T cells (E) and perivenous CD79a + B cells/plasma cells (F, arrow). 200.
cytokines and chemokines and therefore these cells may hypothesized that a CNS-resident immune response
also be involved in the propagation of inflammation and might be involved (Metz et al., 2007).
tissue damage (Brosnan and Raine, 2013).
Chronic inactive lesions. In long-standing MS, the
most common lesion type is the chronic inactive demye-
Smoldering (slowly expanding) lesions. These
linated lesion. Such lesions are usually hypocellular in
lesions are mainly seen in patients with progressive
the center and may show thin myelin sheaths at the edge,
MS (Frischer et al., 2015) and show a rim of activated
representing remyelination (Fig. 19.5G). Only few mac-
microglia at the edge, while the lesion center is inactive
rophages and T cells are found, being present mainly in
(Fig. 19.5 A–D). They contain few macrophages at the
the perivascular space (Fig. 19.5 H and I). Although
edge that are digesting myelin components (Fig. 19.5B)
myelin is the primary target in MS, there is also pro-
and are accompanied by scattered T cells (Fig. 19.5
nounced axonal damage, which can lead to an average
E and F), suggesting an ongoing expansion into the sur-
axonal loss of 20–30% compared to control white matter
rounding NAWM. Slow expansion of such lesions
in newly formed lesions (van Waesberghe et al., 1999;
within a timeframe of 3 years was demonstrated in a
Kornek et al., 2000; Lovas et al., 2000) and of
recent prospective MRI study (Dal-Bianco et al.,
60–70% in chronic established lesions (Mews et al.,
2017). Acute axonal injury is prominent at the edge
1998; Bjartmar et al., 2000). The astrocytes form a dense
of these lesions. Moreover, accumulation of iron has
fibrillary gliosis.
been demonstrated in microglia at the lesion edge,
resulting in microglial dystrophy, while remyelination
Demyelinating lesions in the gray matter
is absent (Hametner et al., 2013). The driving force that
leads to a continuous expansion of the lesions is still In addition to predilection sites in the white matter, the
unclear. Since autologous stem cell transplantation cortex is especially vulnerable to demyelination. Cortical
failed to terminate the disease progression, it has been demyelination is more likely to be found in chronic
Fig. 19.5. Smoldering (slowly expanding) and inactive lesions. Serial sections of the edge of a smoldering demyelinating lesion
(A, rectangle enlarged in B; myelin basic protein (MBP)) shows a rim of activated microglia and macrophages at the edge (C,
rectangle enlarged in D; CD68). Few macrophages are digesting myelin components (B, arrow: macrophage with MPB-positive
degradation products) and are accompanied by scattered CD8 + T cells (E, rectangle enlarged in F), suggesting an ongoing expan-
sion into the surrounding normal-appearing white matter. In contrast, inactive lesions show thin myelin sheaths at the edge,
representing remyelination (G), and only contain few microglia/macrophages (H) and T cells (I) at the edge. A, C, F, G–I,
10; B, D, F, 400.
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Fig. 19.6. Cortical demyelination. Cortical demyelination located subpially (A, B), intracortically (C), and overlapping with the
white matter (so-called compound plaques) (D). A subpial lesion extends over several gyri and sulci and covers almost the entire
cortex (A, proteolipid protein, arrows; B, myelin basic protein (MBP), arrows). A small, demyelinated lesion is located intracor-
tically (C, MBP, arrows). A compound plaque is overlapping the cortex and the subcortical white matter (D, MBP, arrows).
B, 1.56; C, 40; D, 0.59.
disease stages (Kutzelnigg et al., 2005) and is associated distant lesions within the white or deep gray matter that
with cognitive deficites and, in some patients, with epi- are in topographic relation to the cortex (Kolasinski et al.,
lepsy. These lesions can be located subpially or intracor- 2012) may play a role in vulnerability.
tically, or overlap with the white matter (so-called
compound plaques) (Kidd et al., 1999), and subpial
Remyelination
lesions are disease-specific for MS (Moll et al., 2008;
Fischer et al., 2013). The subpial lesions often extend Remyelination of demyelinated lesions occurs spontane-
over several gyri and sulci and can cover up to 70% of ously but is often structurally and functionally incom-
the cortex in some patients (Fig. 19.6 A and B) plete. Remyelination is mediated by oligodendrocyte
(Kutzelnigg et al., 2005), while intracortical lesions are precursor cells (OPC) that are present in the normal white
mostly small and inconspicuous (Fig. 19.6C). The com- matter. During remyelination the OPCs are activated and
pound plaques affect the cortex and the underlying white subsequently migrate to the lesion and undergo differen-
matter and are mostly more inflammatory and have more tiation into myelin-generating cells. Remyelinated fibers
microglial and astroglial activation compared to other are characterized by thinner myelin sheaths and may be
cortical lesion types (Fig. 19.6D) (Peterson et al., only encountered at the border zone of a lesion or can
2001). Subpial cortical lesions are associated with also fully remyelinate a lesion, which is then called a
inflammatory infiltrates in the adjacent meninges and shadow plaque (Fig. 19.7 A–C). Some shadow plaques
are most pronounced in the invaginations of the brain may undergo new demyelination, either within or over-
surface, most likely due to the comparatively low CSF lapping the previously remyelinated areas (Prineas
flow in these areas (Haider et al., 2016). et al., 1993; Bramow et al., 2010). The extent of remye-
It has been hypothesized that soluble mediators are lination varies considerably between patients and seems
diffusing into the cortex and induce tissue damage either to be more prevalent in the early stage of the disease and
directly or indirectly through microglia activation and in lesions with inflammation and macrophage activity
oxidative stress (Howell et al., 2011; Fischer et al., (Foote and Blakemore, 2005). Repair capacity is also
2013). Not all patients with MS have cortical plaques; dependent on the lesion site, with periventricular lesions
however, accumulation of meningeal inflammation with showing less extensive remyelination (Patrikios et al.,
chronicity of the disease, aging of the patient with accu- 2006). The lack of remyelination in a considerable num-
mulation of iron in the brain (Lassmann, 2012), and ber of patients has been attributed to a failure of OPC
amyloid precursor protein that reflects disturbance of fast
axonal transport in dystrophic axons (Ferguson et al.,
1997; Trapp et al., 1998; Kuhlmann et al., 2002). The
loss of myelin contributes to axonal damgage because
of the loss of trophic factors. Moreover, oxidative injury
directly damages axons. In addition, antibodies have
been identified that target glioaxonal proteins in the jux-
taparanodal area, such as anti-neurofascin155 and anti-
contactin1 (Mathey et al., 2007), that later turned out
to play an important role in a proportion of patients with
chronic inflammatory demyelinating polyneuropathy
(Ng et al., 2012). In chronic MS lesions the axons are
markedly reduced, which is considered to contribute to
a failure of remyelination (Kornek et al., 2000).
Neuronal damage may be a consequence of retrograde
neurodegeneration when axons are transected and is
morphologically associated with chromatolysis in neuro-
nal cell bodies (Haider et al., 2016). In this case, the loss
of neurons is in topographic relation to the white-matter
lesions and the loss of neurons is most pronounced in the
deep layers of the cortex and deep gray-matter nuclei
(thalamus and globus pallidus). On the other hand, neu-
ronal damage may be directly mediated by oxidative
injury. These neurons are morphologically characterized
by dendritic beading and fragmentation and accumula-
tion of oxidized phospholipids in the cytoplasm. This
pattern of damage can mainly be found in demyelinating
cortical lesions (Haider et al., 2016).
Tumefactive MS
Tumefactive demyelination is a variant of MS that is
characterized by lesions with pseudotumoral appearance
Fig. 19.7. Remyelinating shadow plaque. Overlap of a sharply with a size often larger than 2 cm, cystic changes, or ring
demarcated chronic inactive plaque centered by a small vein, enhancement on MRI, and may have a mass effect
next to a remyelinated shadow plaque on the left, characterized (Enzinger et al., 2005). The lesions can be solitary or mul-
by thinly myelinated fibers, demonstraded in hematoxylin and
tiple and may occur at any site of the CNS, including the
eosin (A), luxol fast blue (B), and myelin basic protein (C).
spinal cord. Morphologically, they are typical active
demyelinating lesions with inflammation, numerous mac-
rophages, and bizarre reactive gliosis. It is important to
differentiation, which may be influenced by age and hor-
know this variant of MS because the lesions are often
mones (Chang et al., 2002; Chari et al., 2003; Kotter
biopsied or even resected and the differential diagnostic
et al., 2011), loss of axons in the lesions (Charles et al.,
workup may be challenging, especially in very small
2002), and the loss of macrophages in the chronic lesion.
biopsy specimens (Lucchinetti et al., 2008). For example,
the bizarre reactive gliosis in active MS lesions may
NEURODEGENERATION mimick a glioblastoma or inflammatory infiltrates may
raise the possibility of a vasculitis, infectious disease, or
During early and late stages of MS, axons, neurons, and
even lymphoproliferative disease (Kuhlmann et al., 2008).
synapses can be damaged, which is commonly termed
neurodegeneration (Peterson et al., 2001; Dutta and
Acute MS
Trapp, 2011). Axonal loss has been suggested to be a
substrate for permanent motor disability in MS Acute MS, also referred to as Marburg´s disease, is
(Tallantyre et al., 2010). Acute axonal damage is most an acute monophasic illness that usually follows a rap-
pronounced in the active demyelinating lesions and idly progressive or stepwise deterioriating process and
can be visualized with immunohistochemistry for leads to death within 1–6 months of clinical onset
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(Marburg, 1906). The demyelinating lesions show a the currently published diagnostic consensus criteria
similar distribution to that in chronic MS. The plaques for adult patients with NMO. These criteria are based on
appear relatively uniform within the lesion and from core clinical characteristics, AQP4 antibody status, and
one lesion to the other, which correlates with the mono- specific MRI requirements (Table 19.1) (Wingerchuk
phasic disease course. However, even within acute MS, et al., 2015) and allow the inclusion of spatially limited
there is often a dissemination in time, as shown by some forms (isolated optic neuritis, myelitis) or more extensive
variability in the lesion stages (Prineas et al., 1989). forms of the disease (with cerebral, diencephalic, or brain-
Acute MS is nowadays extremely rare due to the avail- stem lesions) into the spectrum of NMO (so-called
ability of effective anti-inflammatory treatments and NMOSD).
intensive care.
Pathologic features of NMOSD
Concentric sclerosis of Balo
In classic NMO the demyelinating lesions are usually
Concentric sclerosis of Balo is a variant of MS that is located in the optic nerve and myelon. In the myelon
characterized by concentric rings of demyelination that the lesions typically overlap with the gray matter and
alternate with rings of relatively preserved myelin. The extend over more than three vertebral segments
disease often shows an acute onset, progresses steadily, (Fig. 19.8 A–C). Moreover, lesions may affect the brain-
and may even lead to death, but can also show a benign stem and exceptionally can cause demyelinating lesions
course, with only mild residual deficits. It is supposed in the brain (Pittock et al., 2006; Wingerchuk et al.,
that the pathophysiologic mechanism responsible for 2015). Lesions in NMOSD can present with different
the formation of concentric lesions is an extensive morphologic features (Misu et al., 2013).
production of oxidative radicals leading to hypoxia-like The classic pattern is characterized by demyelination
tissue injury and dying-back oligodendrogliopathy and necrosis with loss of axons and astrocytes, leading to
(Lucchinetti et al., 2000). The zone of periplaque white cystic cavitation and loss of AQP4, AQP1, and glial
matter next to the actively demyelinating plaque reacts fibrillary acidic protein immunoreactivity. In the active
with the expression of hypoxic preconditioning mole- stage, inflammatory infiltrates often contain eosinophilic
cules, such as HIF1alpha and Hsp-70. These molecules granulocytes (Fig. 19.9A) next to macrophages and lym-
have a protective effect and help to preserve a small ring phocytes and deposition of IgG (Fig. 19.9B) and IgM as
of myelin. In case of aggressive lesion progression, well as activated complement (Fig. 19.9C) (Lucchinetti
however, the oxidative tissue injury extends beyond et al., 2002). In other lesions myelin is only mildly
the protected tissue ring and leads to a new ring of affected and the pathology mainly concentrates on the
demyelination (Stadelmann et al., 2005). This may astrocytes with selective loss of AQP4 (Fig. 19.9 D
finally end up in the pattern of concentric demyelination and E) and/or deposition of complement, loss of perivas-
and preserved myelin. cular astrocyte processes, and accumulation of bizarre
astrocytes with beading and clumping of cell processes
NEUROMYELITIS OPTICA (so-called clasmatodendrosis) (Fig. 19.9 F). Some
lesions with preserved myelin and loss of AQP4 may
Clinical and diagnostic features
show apoptotic oligodendroycytes and expansion of
NMO is a disease entity distinct from MS, which is char- the extracellular space or vacuolation consistent with
acterized by inflammatory demyelination that primarily intramyelinic edema (Fig. 19.10 A–H).
affects the spinal cord and the optic nerves. The disorder Lesions at the floor of the fourth ventricle often show
is also termed Devic disease, according to one of the first intense inflammation and AQP4 loss, with reactive glial
descriptions that date from 1894. NMO was long con- fibrillary acidic protein-positive astrocytes and preserved
sidered as a topographically restricted form of MS, myelin. Whether these different morphologic patterns
although it soon became clear that NMO patients were represent a different lesion age or reflect variable patho-
different from classic MS in terms of disease course, genetic processes is presently unclear. The loss of AQP4
treatment requirements, and lesion morphology, in in active NMO lesions is in contrast to active lesions in
particular reflected by very prominent perivascular MS that are charaterized by upregulation of AQP4 on
immunoglobulin deposition and complement activation reactive astrocytes. However, in chronic inactive demye-
(Lucchinetti et al., 2002). The discovery of autoanti- linated MS plaques, AQP4 may sometimes be absent
bodies to the astrocytic waterchannel AQP4 in a major- (Roemer et al., 2007), which may give rise to an errone-
ity of NMO patients (Lennon et al., 2004) was an ous NMO diagnosis.
important step towards the classification of NMO as a The deposition of complement and immunoglobulin
distinct entity and this feature is now incorporated into on perivascular astrocytic processes that show the
Table 19.1
Diagnostic criteria of neuromyelitis optica and spectrum disorders (NMOSD) for adult patients (Wingerchuk et al., 2015)
AQP4 antibody-positive
All of the following requirements:
1. At least one core clinical featurea
2. Positive AQP4 antibodies
3. Reasonable exclusion of alternative causes
AQP4 antibody-negative or unknown
All of the following requirements:
1. At least two core clinical features; one of them has to be optic neuritis, acute myelitis with LETM, or area postrema syndromea
2. Dissemination in space
3. Fulfillment of additional MRI requirementsb
4. Negative test for AQP4 antibodies (using the best available detection method) or testing unavailable
5. Reasonable exclusion of alternative causes
a
Core clinical features: (1) optic neuritis; (2) acute myelitis; (3) area postrema syndrome (hiccups, nausea, and/or vomiting); (4) acute brainstem
syndrome; (5) narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical diencephalic MRI lesions; (6) symptomatic cerebral
syndrome with NMOSD-typical brain lesions.
b
Additional magnetic resonance imaging (MRI) requirements for AQP4 antibody-negative NMOSD: (1) optic neuritis with either normal/nonspecific
MRI or T2-hyperintense or T1-weighted gadolinium enhancing lesions extending over >1/2 optic nerve length or involving optic chiasm; (2) acute
myelitis with intramedullary MRI lesion extending over three or more vertebral segments (longitudinal extensive transverse myelitis: LETM); (3) area
postrema syndrome: dorsal medulla/area postrema lesions in MRI; (4) acute brainstem syndrome: periependymal brainstem lesions in MRI.
AQP-4, aquaporin-4.
Fig. 19.8. Spinal cord lesion in neuromyelitis optica. Destructive demyelinating lesion in the spinal cord (A, myelin basic protein)
shows loss of astrocytes (B, aquaporin-4; C, aquaporin-1) and overlaps with the gray matter. 1.1.
hightest concentration of AQP4 is consistent with the an infectious disease or, less frequently, by vaccination
current concept that humoral autoimmunity to AQP4 (Wingerchuk, 2003; Karussis and Petrou, 2014), and sea-
mediates the disease and distinguishes it from MS. How- sonal accumulation of the disease in winter and spring
ever, it is still unclear why NMO lesions have a particular months has been reported (Dale et al., 2000; Leake
predilection for the optic nerves and the myelon. et al., 2004). Clinical diagnostic criteria are currently
only available for the pediatric age group and include
ACUTE DISSEMINATED neurologic symptoms and specific MRI features and
ENCEPHALOMYELITIS AND RELATED are summarized in Table 19.2 (Krupp et al., 2013).
DISORDERS A subgroup of patients with ADEM has antibodies to a
conformational epitope of MOG in serum. These anti-
bodies are particularly prevalent in children and can be
ADEM is an acute monophasic inflammatory demyelin- used as biomarkers. Relapsing variants of ADEM are
ating disease of the CNS. Although it can occur at any multiphasic disseminated encephalomyelitis (MDEM)
age, it mainly affects children and young adults and ADEM followed by episodes of optic neuritis
(Wingerchuk, 2006). The disease may be preceded by (ADEMON). Recurrences in MDEM can either affect
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Fig. 19.9. Active stage of neuromyelitis optica (NMO) lesion. An active NMO lesion shows inflammatory infiltrates with eosin-
ophils (A, hematoxylin and eosin) next to macrophages and lymphocytes, deposition of immunoglobulin G (B, IgG), and C9 neoan-
tigen (C, arrows). Some lesions show selective loss of aquaporin-4 (D, asterisk marks lesion) while aquaporin-1 is well preserved
(E) and there is accumulation of bizarre astrocytes with beading and clumping of cell processes (clasmatodendrosis) (F, glial fibril-
lary acidic protein). A, B, F, 600; C, 200; D, E, 100.
Fig. 19.10. Vacuolated lesions in neuromyelitis optica (NMO). A vacuolated lesion in NMO is characterized by expansion of the
extracellular space and shows some apoptotic nuclei (A, B, hematoxylin and eosin, arrow: apoptotic cell). The myelin is relatively
well preserved with only few demyelinating macrophages (C, D, luxol fast blue (LFB); arrow: macrophage with LFB-positive
degradation products; E, F, myelin basic protein; arrowhead: apoptotic cell), in contrast, astrocytes are lost (G, H, glial fibrillary
acid protein). B, D, F, H: 250.
Table 19.2 different brain loci or occur at the same site in each
Diagnostic criteria of acute dissemimated relapse (Cohen et al., 2001) and may reflect either a spe-
encephalomyelitis (Krupp et al., 2013) cific susceptibility or an antigenic modification in the
affected brain areas after a local infection. The rate of
All of the following requirements: recurrent variants of ADEM has been reported in up to
1. A first multifocal, clinical central nervous system event of one-third of patients (Anlar et al., 2003) and the clinical
presumed inflammatory demyelinating cause
differentiation to MS in these patients is particularly
2. Encephalopathy that cannot be explained by fever
challenging.
3. Abnormal brain magnetic resonance imaging (MRI):
a. Diffuse, poorly limited, large (>1–2 cm) lesions that
predominantly involve the cerebral white matter Pathologic features of ADEM
b. T1 hypointense lesions in the white matter are rare
The characteristic lesions of ADEM consist of small
c. Deep gray-matter lesions (e.g., thalamus or basal ganglia)
veins that are surrounded by foamy macrophages with
can be present
4. No new clinical and MRI findings after 3 months of or without T-cell-dominated inflammatory infiltrates
symptom onset (Fig. 19.11A). The adjacent parenchyma shows active
demyelination with macrophages that contain luxol fast
Fig. 19.11. Acute disseminated encephalomyelitis (ADEM). Lesions in ADEM are characterized by small perivenous demyelin-
ating areas (A, luxol fast blue (LFB)), with numerous macrophages containing LFB-positive degradation products (B, LFB; C,
CD68). A, C, 100; B, 600.
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blue-positive myelin components and neutral lipids serum of patients with inflammatory demyelination,
(Fig. 19.11 B and C). The demyelination is restricted including a subgroup of patients with ADEM, ADEMON,
to the perivascular region and axons are relatively pre- seronegative (AQP4-negative) NMOSD, monophasic, or
served but also show features of acute injury (Young recurrent isolated optic neuritis and transverse myelitis,
et al., 2010). The vessel walls may sometimes show fibri- MDEM, N-methyl-D-aspartate receptor encephalitis over-
nous exudates and the adjacent parenchyma may lapping with demyelinating syndromes, and, rarely, MS
undergo necrosis, indicating an overlap of ADEM and (Di Pauli et al., 2011; Mader et al., 2011; Probstel et al.,
acute hemorrhagic leukoencephalitis. In typical ADEM 2011; Kitley et al., 2012, 2014; Rostasy et al., 2012,
the demyelinating perivenous lesions appear to be of 2013; Huppke et al., 2013; Sato et al., 2014; Titulaer
the same histologic age. et al., 2014; Hoftberger et al., 2015b; Baumann et al.,
The lesions can be located throughout the CNS or lim- 2016; Jarius et al., 2016b).
ited to a single region. Although they are most numerous The detection of MOG antibodies in serum and CSF
in white matter, the lesions can also involve the cortex, of patients depends on the use of appropriate test
thalamus, and basal ganglia (Tenembaum et al., 2002). methods that conserve the conformation of the protein,
Involvment of spinal cord, brainstem, and cerebellum such as in live cell-based assays transfected with the
is also common. Although the occurrence of nonconflu- full-length human MOG (Mader et al., 2011). MOG
ent perivenous lesions is characteristic of ADEM and dis- antibodies that are tested with these methods serve
tinguishes them from the large confluent perivenous as sensitive and specific diagnostic markers. MOG
lesions of MS (Young et al., 2010), there are occasional antibodies are particularly prevalent among pediatric
patients in whom the clincal history is suggestive of ADEM patients, where they occur in up to 50%.
ADEM but pathology overlaps with MS. Whether this Children with MOG antibody-positive ADEM show a
represents a different pathogenic process (e.g., anti- characteristic MRI pattern with large, hazy, bilateral
MOG antibody-associated ADEM) or patients who have lesions and wide anatomic involvement, including the
a higher likelihood to convert to MS remains to be myelon with longitudinal extensive transverse myelitis
clarified. (Baumann et al., 2015). While MOG antibodies are usu-
ally transient in patients with ADEM and associated
Immunopathogenesis with a monophasic disease course (Probstel et al.,
2011), they often persist in patients with optic neuritis
ADEM is usually preceded by infectious diseseases or, and myelitis and may be associated with a relapsing
less frequently, by vaccination. It has been shown that course and severe disability in a substantial number of
some myelin peptides resemble antigens of viruses such patients (Jarius et al., 2016b). Demyelinating diseases
as influenza virus, Epstein–Barr virus, human associated with MOG antibodies are often difficult to
herpesvirus-6, or coronavirus (Giovannoni et al., categorize and some patients meet the diagnostic criteria
2006). Thus it has been postulated that the infectious of AQP4 antibody-positive NMOSD, while others can
agents may stimulate T cells that subsequently attack be classified as MS. Since it is assumed that all MOG
similar or even identical CNS epitopes. Alternatively, a antibody-positive patients have the same underlying
direct infection of the brain parenchyma exposes CNS immunopathogenesis that requires the same therapy, it
antigens to the immune system, affects the BBB, and has been suggested that it may be useful to subsume
triggers the autoimmune disease (Steiner and Kennedy, them as a distinct disease entity. It is important to note
2015). Finally it has been shown that certain MHC class that the therapeutic response in MOG antibody-positive
II alleles are associated with the condition (Woody patients is similar to that in NMO, but different from that
et al., 1989). in MS patients (Jarius et al., 2016b).
MOG ANTIBODY-ASSOCIATED
Pathologic features of MOG antibody-
DEMYELINATING
associated demyelinating encephalomyelitis
ENCEPHALOMYELITIS
Neuropathology of MOG-antibody associated demye-
lination has been described in a few patients with relaps-
MOG is a minor myelin protein and expressed on the sur- ing remitting MS, atypical demyelination, clinically
face of CNS myelin sheaths (Delarasse et al., 2006). isolated syndrome, ADEM, and NMOSD (Table 19.3)
MOG belongs to the immunoglobulin superfamily and (Konig et al., 2008; Di Pauli et al., 2015; Spadaro
is believed to play a role as surface receptor or cell adhe- et al., 2015; Jarius et al., 2016a; Wang et al., 2016). Irre-
sion molecule (Martini and Schachner, 1986). Antibodies spective of the clinical nosology, all cases showed demy-
of the IgG1 subclass against MOG have been found in elinating features of MS pattern 2, with well-demarcated
Table 19.3
Neuropathological reports of myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination
Sex,
age
Demyelinating disease (years) n Reference Neuropathology
Relapsing remitting MS F, 49 1 Konig et al., MS pattern II; oligodendrocytes preserved (CNPase +;

2008 MOG n.d.)
Recurrent myelitis with F, 66 1 Spadaro et al., MS pattern II; oligodendrocytes preserved (CNPase +;
brainstem involvement 2015 MOG–)
ADEM/acute MS; seropositive M, 71 1 Di Pauli et al., MS-pattern II; oligodendrocytes preserved (CNPase+,
for MOG and AQP4 2011 MOG–)
Clinically isolated syndrome F, 63 1 Jarius et al., MS pattern II; oligodendrocytes preserved (CNPase+,
2016a MOG +)
NMOSD F, 67 1 Wang et al., Pattern classification not done; well-demarcated
2016 demyelinating lesion with preserved astrocytes and
axons
ADEM M, 49 2 K€ortvelyessy Case 1: overlapping features of MS pattern II and III
intrathecal MOG-antibody M, 34 et al., 2017 (early MAG loss, apoptotic oligodendrocytes in
synthesis addition to complement deposition)
Case 2: MS pattern III; oligodendrocytes preserved
(CNPase+, MOG +)
ADEM, acute dissemimated encephalomyelitis; AQP4, aquaporin-4; MAG, myelin-associated glycoprotein; MS, multiple sclerosis; NMOSD,
neuromyelitis optica and spectrum disorders.
Fig. 19.12. Myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelinating encephalomyelitis. A demyelinating
lesion associated with MOG antibodies is well demarcated (A, luxol fast blue) and shows relatively well-preserved (B, CNPase;
C, MOG) oligodendrocytes and deposition of C9 neoantigen (D, arrows). 200.
confluent plaques with loss of myelin (Fig. 19.12A), rel- parenchymal T cells and some perivascular B cells.
ative preservation of axons, numerous macrophages, and Lesions were characterized by relatively well-preserved,
well-preserved astrocytes. The inflammaotry infiltrates partly MOG-negative oligodendrocytes, most likely com-
were predominantely composed of perivascular and patible with preoligodendrocytes (Fig. 19.12 B and C)
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and deposition of terminal complement complex C9neo, Babbe H, Roers A, Waisman A et al. (2000). Clonal expan-
indicating a complement-mediated demyelination sions of CD8(+) T cells dominate the T cell infiltrate in
(Fig. 19.12D). Whether MOG antibodies have a patho- active multiple sclerosis lesions as shown by micromanip-
genetic role in disease formation is unclear. Different ulation and single cell polymerase chain reaction. J Exp
Med 192: 393–404.
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