cells

Review
Macrophages and Autoantibodies in Demyelinating Diseases
Haruki Koike * and Masahisa Katsuno

Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan;
ka2no@med.nagoya-u.ac.jp
* Correspondence: koike-haruki@med.nagoya-u.ac.jp; Tel.: +81-52-744-2391

Abstract: Myelin phagocytosis by macrophages has been an essential feature of demyelinating

diseases in the central and peripheral nervous systems, including Guillain–Barré syndrome (GBS),
chronic inflammatory demyelinating polyneuropathy (CIDP), and multiple sclerosis (MS). The dis-
covery of autoantibodies, including anti-ganglioside GM1 antibodies in the axonal form of GBS,
anti-neurofascin 155 and anti-contactin 1 antibodies in typical and distal forms of CIDP, and anti-
aquaporin 4 antibodies in neuromyelitis optica, contributed to the understanding of the disease pro-
cess in a subpopulation of patients conventionally diagnosed with demyelinating diseases. However,
patients with these antibodies are now considered to have independent disease entities, including
acute motor axonal neuropathy, nodopathy or paranodopathy, and neuromyelitis optica spectrum
disorder, because primary lesions in these diseases are distinct from those in conventional demyelinat-
ing diseases. Therefore, the mechanisms underlying demyelination caused by macrophages remain
unclear. Electron microscopy studies revealed that macrophages destroy myelin as if they are the
principal players in the demyelination process. Recent studies suggest that macrophages seem to
select specific sites of myelinated fibers, including the nodes of Ranvier, paranodes, and internodes,
for the initiation of demyelination in individual cases, indicating that specific components localized



to these sites play an important role in the behavior of macrophages that initiate myelin phagocytosis.


Along with the search for autoantibodies, the ultrastructural characterization of myelin phagocytosis
Citation: Koike, H.; Katsuno, M. by macrophages is a crucial step in understanding the pathophysiology of demyelinating diseases
Macrophages and Autoantibodies in and for the future development of targeted therapies.
Demyelinating Diseases. Cells 2021,
10, 844. https://doi.org/10.3390/ Keywords: demyelination; electron microscopy; macrophage; paranode; pathogenesis; pathology;
cells10040844 Schwann cell; the node of Ranvier; treatment

Academic Editor: Toshiyuki Araki

Received: 9 March 2021

1. Introduction
Accepted: 5 April 2021
Published: 8 April 2021
Macrophages play an important role, not only in normal immune system mainte-
nance, but also in pathological conditions. Myelin phagocytosis by macrophages has
Publisher’s Note: MDPI stays neutral
been an essential feature of demyelinating diseases in the central and peripheral nervous
with regard to jurisdictional claims in
systems, including Guillain–Barré syndrome (GBS), chronic inflammatory demyelinating
published maps and institutional affil- polyneuropathy (CIDP), and multiple sclerosis (MS) [1–5]. Particularly, early ultrastructural
iations. studies, using biopsy specimens from patients with GBS and CIDP, have demonstrated
the stripping of morphologically normal myelin lamellae by cytoplasmic processes of
macrophages [1,6]. These macrophages caused researchers to assume that they are active
players in the disease process, rather than mere scavengers of unnecessary materials. The
Copyright: © 2021 by the authors.
discovery of autoantibodies directed against the constituents of the nervous system, by later
Licensee MDPI, Basel, Switzerland.
researchers, contributed to the understanding of the disease process in a subpopulation of
This article is an open access article
patients diagnosed with these diseases. For example, a concept that molecular mimicry
distributed under the terms and between gangliosides located at the axolemma and the surface epitopes of exogenous
conditions of the Creative Commons pathogens induces the production of anti-ganglioside antibodies has been established
Attribution (CC BY) license (https:// in the axonal form of GBS [7]. Recent studies revealed that IgG4 autoantibodies against
creativecommons.org/licenses/by/ paranodal junction proteins found in a subpopulation of patients diagnosed with CIDP
4.0/). cause aberrant nerve conduction owing to paranodal dissection [8,9]. Regarding diseases

Cells 2021, 10, 844. https://doi.org/10.3390/cells10040844 https://www.mdpi.com/journal/cells

Cells 2021, 10, 844 2 of 14

of the central nervous system, anti-aquaporin 4 (AQP4) antibodies were found to be pos-
itive in patients with neuromyelitic optica [10]. However, lesions in the nervous system
caused by these antibodies are distinct from those of conventional demyelination caused
by macrophages [8,11,12]. Hence, the mechanisms underlying demyelination owing to
myelin phagocytosis by macrophages remain unclear.
In this article, the mechanisms of demyelinating diseases are described by focusing on
the role of macrophages and autoantibodies.

2. Role of Macrophages and Autoantibodies in Demyelinating Diseases

2.1. GBS
GBS is an acute polyneuropathy, which typically occurs following infection [13]. This
disease was initially considered to be a demyelinating neuropathy, called acute inflam-
matory demyelinating polyneuropathy (AIDP), because a previous report demonstrated
demyelinating lesions owing to myelin phagocytosis by macrophages [1]. Later studies
revealed the presence of an axonal counterpart without the macrophage-associated de-
myelination as another form of GBS [11,14,15]. This axonal form of GBS is called acute
motor axonal neuropathy (AMAN) or acute motor sensory axonal neuropathy depending
on the absence or presence of sensory involvement [11]. The concept of molecular mimicry
was established through studies on AMAN with anti-ganglioside GM1 antibodies that
occurred after a Campylobacter jejuni infection [13]. The widely accepted theories are that
the attachment of IgG autoantibodies to GM1, which is localized to the axolemma of motor
fibers, and subsequent activation of complement cascades result in motor dysfunction in
patients with AMAN [13,16,17]. Although the autopsy specimens revealed the presence of
macrophages in the periaxonal space, macrophage-associated demyelinating lesions were
not found in patients with AMAN [11].
Conversely, an association between specific autoantibodies with the occurrence of
macrophage-associated demyelination in AIDP has not been clearly demonstrated. How-
ever, the presence of antecedent infections in patients with AIDP is similar to that in
patients with AMAN, which indicates similar immunological processes [18]. An associa-
tion between antibodies against moesin, which is expressed in the microvilli of Schwann
cells at the nodes of Ranvier, and AIDP has been suggested after cytomegalovirus infec-
tion [19]. An increased occurrence of AIDP after the Zika virus infection has also been
demonstrated [20]. Although an association between a specific anti-ganglioside antibody
and Zika virus-related GBS has not been demonstrated [21], peptide sharing was suggested
among proteins of the Zika virus, cytomegalovirus, and the human peripheral nervous
system [22,23]. Recently, a conflicting discussion on the association between SARS-CoV2
infection (i.e., COVID-19) and AIDP has become a topic of research [24–26].

2.2. CIDP
CIDP has been a chronic counterpart of AIDP because similar macrophage-associated
demyelination was reported as a pathological hallmark [2,4]. In contrast to AIDP, this
disease is rarely accompanied by antecedent infections. CIDP was initially defined as
neuropathy with a diffuse weakness of the limbs [2,27]. This classic form of CIDP was
designated as “typical CIDP” in the criteria proposed by the European Federation of
Neurological Societies and Peripheral Nerve Society (EFNS/PNS) and it is now frequently
used in daily practice [28]. In addition to the typical CIDP, the EFNS/PNS criteria define
five forms of “atypical CIDP”, which comprised multifocal acquired demyelinating sensory
and motor (MADSAM), distal acquired demyelinating symmetric (DADS), pure sensory,
pure motor, and focal subtypes [28]. Macrophage-associated demyelination was found
not only in a typical CIDP but also in major atypical CIDP subtypes, including MADSAM,
DADS, and pure sensory subtypes—although it is not found in all patients [29].
Recent studies demonstrated the presence of autoantibodies against paranodal junc-
tion components, including neurofascin 155 and contactin 1, in some patients diagnosed
with typical CIDP and DADS [8,30–34]. In patients with these antibodies, aberrant
Cells 2021, 10, 844 3 of 14

nerve conduction is caused by the detachment of paranodal myelin terminal loops from
the axolemma resulting from the deposition of autoantibodies to the paranodal junc-
tions [4,8,35,36]. Unlike AMAN, the deposition of complements is not found at the paran-
odes because the immunoglobulin subclass of these antibodies is IgG4 [8]. Because classical
demyelinating lesions associated with macrophages are not observed in patients with these
antibodies, the concept of nodopathy or paranodopathy has recently been proposed for
these patients [9,34]. However, patients with these antibodies constitute a minority in
the total CIDP population [8,32,33]. The mechanisms underlying macrophage-associated
demyelination remain to be elucidated.

2.3. MS and Related Diseases

MS is an inflammatory demyelinating disease of the central nervous system [3,37].
Based on the mode of progression, this disease is classified into four types: clinically
isolated syndrome, relapsing remitting MS, primary progressive MS, and secondary pro-
gressive MS [38]. Although MS has traditionally been considered a disease mediated by
T cells, particularly CD4-positive T cells reactive to myelin antigens [39], a recent study
regarding the efficacy of rituximab, a chimeric monoclonal antibody to CD20, in patients
with relapsing remitting MS suggested that B cells also play an important role in the
pathogenesis of this disease [40]. In actual fact, the presence of oligoclonal IgG bands in
the cerebrospinal fluid and deposition of IgG in active lesions have long been known as
hallmarks of this disease [3]. Additionally, increasing evidence suggests that macrophages
derived from circulating monocytes and resident macroglia play a pivotal role in the patho-
genesis of MS [41,42]. Autopsy specimens from patients with MS revealed macrophages
containing myelin debris in active lesions [43].
Whether neuromyelitis optica (also known as Devic’s disease), that preferentially
affects the optic nerve and spinal cord, is a subtype of MS or an independent disease
entity has been a controversy for a long time [44]. The discovery of disease-specific
antibodies against AQP4 in the sera from patients with neuromyelitis optica resulted in
significant progress regarding this concern [10]. Because AQP4 is expressed in astrocyte foot
processes at the blood–brain barrier [45], pathological findings of AQP4 are characterized
by perivascular lesions accompanied by deposition of IgG and complement [12]. Compared
with demyelinating lesions found in conventional MS, the myelinated fibers are relatively
preserved in these lesions [12]. Based on these findings, neuromyelitis optica is now
regarded as a primary astrocytopathy and is distinct from MS. As anti-AQP4 antibodies
are found to be associated with not only lesions in the optic nerves and spinal cord, but
also those in other sites of the central nervous system, the concept of neuromyelitis optica
spectrum disorder (NMOSD) has been proposed [46].

3. Morphology of Macrophages in Demyelination

Ultrastructural studies using nerve biopsy specimens obtained from patients with the
demyelinating form of GBS (i.e., AIDP) and those with CIDP have demonstrated putative
chronological sequence in the progression of demyelination resulting from myelin phago-
cytosis by macrophages [4,5]. Generally, the morphology and behavior of macrophages
participating in the demyelination process seem to be similar between AIDP and CIDP [4,5].
Various stages of demyelination may be seen in a single specimen (Figure 1), particularly
in specimens from patients with CIDP [4].
Although resident macrophages are present in the peripheral nervous system, blood-
derived macrophages that enter the endoneurium under the guidance of adhesion molecules,
such as ICAM-1, VCAM-1, and ELAM-1, can also participate in the demyelination pro-
cess [47–50]. Morphological distinction between these macrophages has not been clearly
established despite their functional differences [51]. Macrophages approach the myelinated
fibers and extend their cytoplasmic processes to enter the basement membrane tube sur-
rounding the myelinated fibers (Figure 2) [4]. A recent review by Park et al. suggested that
the entry sites of macrophages are limited to where myelin lamellae are partially degener-
Cells 2021, 10, 844 4 of 14

ated or separated from Schwann cell cytoplasm [52]. Along with invading the basement
membrane tube, the cytoplasm of macrophages apposed to myelin initiates degradation of
the myelin lamellae. Macrophages seem to peel off layers of myelin using their cytoplasmic
Cells 2021, 10, x FOR PEER REVIEW processes (Figure 3) [4,5]. Unraveling and disruption of the myelin lamellae apposed to the
4 of 15
cytoplasm of macrophages are also frequently observed [4,5,53].

Figure 1. Representative electron microscopy photograph of demyelination caused by myelin phagocytosis by macro-
phages.1.ARepresentative
Figure electron
cross section of microscopy
a sural photograph
nerve biopsy specimen ofobtained
demyelination
from acaused bywith
patient myelin phagocytosis
AIDP. by macrophages.
Various stages of demye-
A cross section of a sural nerve biopsy specimen obtained from a patient with AIDP. Various
lination are observed. The arrow indicates a myelinated fiber surrounded by the cytoplasm of macrophagestages of demyelination
containing
are observed.
myelin debris.The
Boldarrow
blackindicates a myelinated
circles indicated fiberasterisks
by white surrounded by the cytoplasm
are myelin. of macrophage
The arrowhead indicates acontaining
macrophage myelin
that
debris. Bold black circles indicated by white asterisks are myelin. The arrowhead indicates a macrophage that
completed demyelination. Demyelinated axons are indicated by black asterisks. Uranyl acetate and lead citrate staining.completed
Scale bar = 2 m.Demyelinated axons are indicated by black asterisks. Uranyl acetate and lead citrate staining. Scale
demyelination.
bar = 2 µm.
Although resident macrophages are present in the peripheral nervous system,
blood-derived macrophages that enter the endoneurium under the guidance of adhesion
molecules, such as ICAM-1, VCAM-1, and ELAM-1, can also participate in the demye-
lination process [47–50]. Morphological distinction between these macrophages has not
been clearly established despite their functional differences [51]. Macrophages approach
the myelinated fibers and extend their cytoplasmic processes to enter the basement
membrane tube surrounding the myelinated fibers (Figure 2) [4]. A recent review by Park
et al. suggested that the entry sites of macrophages are limited to where myelin lamellae
Cells 2021, 10, 844 5 of 14
Cells 2021, 10, x FOR PEER REVIEW 6 of 15

Figure 2. A macrophage invading the basement membrane tube surrounding the myelinated fiber. A cross section of a
A macrophage
Figure 2.sural nerve biopsy invading the basement
specimen obtained from amembrane
patient withtube surrounding
AIDP. the whose
A macrophage myelinated
nucleusfiber. A crossby
is indicated section of a sural
a black
nerve biopsy specimen
asterisk obtained
is invading from amembrane
the basement patient with
tube AIDP. A macrophage
that normally surroundswhose nucleus
myelinated is indicated
fibers. Along withbythea black asterisk is
invasion
invading the basement membrane tube that normally surrounds myelinated fibers. Along with the invasion into the basement
membrane tube, the cytoplasm of macrophages apposed to myelin initiates degradation of myelin (white asterisks). Note
that the cytoplasm of this macrophage located outside the basement membrane tube does not contain myelin debris. A
high-powered view of the region in the box in (A) is shown in (B). Basement membranes surrounding myelinated fibers are
indicated by arrowheads. Uranyl acetate and lead citrate staining. Scale bars = 2 µm (A) and 0.5 µm (B).
Cells 2021, 10, x FOR PEER REVIEW 7 of 15

into the basement membrane tube, the cytoplasm of macrophages apposed to myelin initiates degradation of myelin
(white
Cells 2021, asterisks). Note that the cytoplasm of this macrophage located outside the basement membrane tube does not6 of 14
10, 844
contain myelin debris. A high-powered view of the region in the box in (A) is shown in (B). Basement membranes sur-
rounding myelinated fibers are indicated by arrowheads. Uranyl acetate and lead citrate staining. Scale bars = 2 m (A)
and 0.5 m (B).

Figure 3. Stripping of the myelin lamellae by a cytoplasmic process of the macrophage. A cross section of a sural nerve
Figure
biopsy 3. Stripping
specimen of the myelin
obtained lamellaewith
from a patient by aAIDP.
cytoplasmic process
Cytoplasmic of the macrophage.
processes A crossindicated
of the macrophage section ofbya arrows
sural nerve
peel
biopsy specimen obtained from a patient with AIDP. Cytoplasmic processes of the macrophage indicated by
off the myelin layers. A basement membrane surrounding the myelinated fibers is indicated by arrowheads. Uranyl arrows peel ac-
off
the myelin layers. A basement membrane surrounding
etate and lead citrate staining. Scale bar = 0.5 m. the myelinated fibers is indicated by arrowheads. Uranyl acetate
and lead citrate staining. Scale bar = 0.5 µm.
Vesicular dissolution of the myelin has been reported as another important lesion
Vesicular
associated withdissolution of thediseases,
demyelinating myelin has been reported
including as another
AIDP and important
MS (Figure lesion
4) [1,54–58].
associated with demyelinating diseases, including AIDP and MS (Figure 4) [1,54–58].
Most studies describing this finding used autopsy specimens [54–58]. One of these stud- Most
studies describing this finding used autopsy specimens [54–58]. One of these
ies used specimens from patients with AIDP, which demonstrated that the vesicular studies used
specimens from
dissolution patients
occurred wherewith AIDP, which
complements demonstrated
were thatmacrophages
deposited but the vesicularwere
dissolution
absent
[56]. Therefore, this finding might be an early morphological change occurringTherefore,
occurred where complements were deposited but macrophages were absent [56]. before a
this finding might be an early morphological change occurring before a macrophage
macrophage invasion into the basement membrane tube of the myelinated fibers. How-
invasion into the basement membrane tube of the myelinated fibers. However, similar
ever, similar findings also seem to be closely associated with macrophages invading the
findings also seem to be closely associated with macrophages invading the basement
basement membrane tube (Figure 5) [5,59]. Therefore, hydrolases released from macro-
membrane tube (Figure 5) [5,59]. Therefore, hydrolases released from macrophages may be
phages may be involved in myelin lesions, including unraveling, disruption, and vesic-
involved in myelin lesions, including unraveling, disruption, and vesicular dissolution.
ular dissolution.
Cells 2021, 10, 844 7 of 14
Cells 2021, 10, x FOR PEER REVIEW 8 of 15

Figure4.4.Vesicular
Figure Vesiculardissolution
dissolutionofofmyelin.
myelin.A Across
cross section
section of
of aa sural
sural nerve
nerve biopsy
biopsy specimen
specimen obtained
obtainedfrom
fromaapatient
patientwith
with
AIDP. Vesicular dissolution of the myelin is seen in a space between the myelin lamellae indicated by asterisks. Vesicles
AIDP. Vesicular dissolution of the myelin is seen in a space between the myelin lamellae indicated by asterisks. Vesicles
seem to be formed by the separation of the major dense lines (arrowheads). A process of macrophage indicated by an
seem
arrowtoseems
be formed
to be by the separation
invading of thebymajor
a gap created dense lines
the dissolution of(arrowheads). A Uranyl
myelin lamellae. processacetate
of macrophage indicated
and lead citrate by an
staining.
arrow seems to be
Scale bar = 0.2 m. invading a gap created by the dissolution of myelin lamellae. Uranyl acetate and lead citrate staining.
Scale bar = 0.2 µm.

Despite these findings resulting in the breakdown of compacted myelin lamellae,

the uncompacted Schwann cell cytoplasm located outside the myelin lamellae remains
intact [4]. Once the myelin breakdown is completed, macrophages containing myelin
debris penetrate the basement membrane again to escape to the outer space (Figure 6) [4,5].
A similar demyelination process has also been reported in studies of experimental
allergic neuritis, which is an experimental model of GBS or CIDP [60,61], and experimental
allergic encephalomyelitis: a model of MS [62–64].
Cells 2021, 10, 844 8 of 14
Cells 2021, 10, x FOR PEER REVIEW 9 of 15

Figure 5. A demyelinated axon. A cross section of a sural nerve biopsy specimen obtained from a patient with AIDP. A
Figure 5. A demyelinated axon. A cross section of a sural nerve biopsy specimen obtained from a patient with AIDP. A
demyelinated axon indicated by an asterisk is surrounded by a space filled with vesicular dissolution of the myelin. The
demyelinated
cytoplasm of aaxon indicatedindicated
macrophage by an asterisk
by an is surrounded
arrow by a space
is also within filled withmembrane
the basement vesicular dissolution
tube. Uranylofacetate
the myelin. The
and lead
cytoplasm
citrate of a macrophage
staining. Scale bar = 1 indicated
m. by an arrow is also within the basement membrane tube. Uranyl acetate and lead
citrate staining. Scale bar = 1 µm.
Despite these findings resulting in the breakdown of compacted myelin lamellae,
the uncompacted Schwann cell cytoplasm located outside the myelin lamellae remains
intact [4]. Once the myelin breakdown is completed, macrophages containing myelin
debris penetrate the basement membrane again to escape to the outer space (Figure 6)
[4,5].
Cells 2021, 10, 844 9 of 14
Cells 2021, 10, x FOR PEER REVIEW 10 of 15

Figure 6. A macrophage escaping from the basement membrane tube surrounding the myelinated fiber. A cross section of
Figure 6. A macrophage escaping from the basement membrane tube surrounding the myelinated fiber. A cross section of a
a sural nerve biopsy specimen obtained from a patient with AIDP. The sites at which the basement membrane was dis-
sural nerve
rupted are biopsy specimen
indicated obtained The
by arrowheads. fromnucleus
a patient
of with AIDP. The sites
this macrophage at which
is located the basement
outside membrane
of the basement was disrupted
membrane tube.
are indicated
Note that anby arrowheads.
axon The nucleus
located within of thismembrane
the basement macrophage is located
tube outsidedemyelinated.
is completely of the basement membrane tube.
A demyelinated Note
axon andthat
a
macrophage
an axon locatednucleus
withinaretheindicated
basementby a black asterisk
membrane and a whitedemyelinated.
tube is completely asterisk, respectively. Uranyl acetate
A demyelinated anda lead
axon and citrate
macrophage
staining.
nucleus Scale
are bar = 2by
indicated m.
a black asterisk and a white asterisk, respectively. Uranyl acetate and lead citrate staining. Scale
bar = 2 µm.
A similar demyelination process has also been reported in studies of experimental
allergic
4. neuritis, Macrophages
What Attracts which is an experimental
to Myelin? model of GBS or CIDP [60,61], and experi-
mental allergic encephalomyelitis:
Unlike that on anti-ganglioside a model of MS [62–64].
GM1 antibodies in AMAN, anti-neurofascin 155 an-
tibodies in nodopathy or paranodopathy, and anti-AQP4 antibodies in NMOSD, knowl-
4. What Attracts Macrophages to Myelin?
edge of the relationship between specific autoantibodies and demyelination caused by
Unlike that
macrophages on anti-ganglioside
is still GM1 antibodies
limited. An association between in AMAN, anti-neurofascin
antibodies 155 an-is
against moesin, which
tibodies in
expressed nodopathy
at the microvillior paranodopathy,
of the Schwann cells at and
theanti-AQP4 antibodies
nodes of Ranvier, in NMOSD,
and AIDP following
knowledge of the
cytomegalovirus relationship
infection has beenbetween specific
suggested [19]. autoantibodies and demyelination
Gliomedin, galactocerebroside, and
ganglioside LM1 have also been suggested as target antigens in AIDPantibodies
caused by macrophages is still limited. An association between against
[65–68]. Although
moesin,
recent which is infectious
emerging expressed at the microvilli
diseases, of the
including Schwann
Zika cells at theand
virus infection nodes of Ranvier,
COVID-19, are
and AIDP
reported to following
be associated cytomegalovirus
with AIDP rather infection has been[20,26],
than AMAN suggested [19]. autoantibod-
causative Gliomedin,
galactocerebroside,
ies associated with theseand ganglioside
viruses have LM1nothave
beenalso been suggested
detected as target antigens
to date. Regarding in
CIDP, sural
Cells 2021, 10, 844 10 of 14

nerve biopsy specimens from a patient with antibodies to LM1 ganglioside, which is
abundant in myelin, revealed complement deposition on myelin and demyelination by
macrophages [69]. However, patients with anti-LM1 antibodies constitute only a minority
of the total CIDP population [70]. Recent studies revealed that antibodies to myelin oligo-
dendrocyte glycoprotein (MOG), expressed in the outermost layer of the myelin sheath,
were found in some of the patients with NMOSD negative for anti-AQP4 antibodies [71].
The location of the target antigen suggests myelin damage, which is distinct from astro-
cyte damage in NMOSD positive for anti-AQP4 antibodies [12]. However, patients with
conventional MS are typically negative for anti-MOG antibodies [72].
Based on the abovementioned results, the mechanism underlying demyelination, re-
sulting from myelin phagocytosis by macrophages, remains an enigma from the viewpoint
of autoantibodies. A recent electron microscopy study using longitudinal sections of biopsy
specimens from patients with AIDP suggested that macrophages seemed to select specific
sites of myelinated fibers, including the nodes of Ranvier, paranodes, and internodes, for
the initiation of demyelination in individual cases [5]. The sites of complement deposition
corresponded to the distribution of macrophages in that study, suggesting the presence
of undiscovered autoantibodies directed against the components of myelinated fibers in
AIDP [5]. The efficacy of eculizumab, a humanized monoclonal antibody to complement
component 5, for not only AMAN, but also AIDP, supports this view [73]. Similar selec-
tivity of the sites at which macrophages initiate myelin phagocytosis was also reported
in CIDP [4]. However, the pathogenesis of CIDP might be more complex than that of
AIDP, considering the heterogeneity of its clinical features and its response to immunother-
apies [9]. The mechanisms of demyelination in MS are also considered complex, involving
both innate and adoptive (i.e., humoral and cellular) immunities [37,41]. Additionally,
it has been gradually established that macrophages not only contribute to the initiation
and development of demyelination by boosting inflammatory events, but they also play a
protective role by suppressing inflammation, eliminating debris, and promoting repair [74].
Particularly, immunoregulatory M2 macrophages are considered to be predominant during
the recovery and repair process [75]. Further studies focusing on the mechanisms leading
to myelin phagocytosis by macrophages are required to elucidate the pathogenesis of
demyelinating diseases.

5. Summary and Conclusions

Myelin phagocytosis by macrophages has traditionally been considered an essential
feature of demyelinating diseases of the central and peripheral nervous systems, including
GBS, CIDP, and MS [1–5]. The discovery of autoantibodies directed against the constituents
of the nervous system contributed to the understanding of the disease process in a subpop-
ulation of patients conventionally diagnosed with these diseases. For example, a concept
that molecular mimicry between gangliosides located at the axolemma and the surface
epitopes of exogenous pathogens induces the production of anti-ganglioside antibodies has
been established in the axonal form of GBS, called AMAN [7,13]. In patients with AMAN,
the attachment of autoantibodies to ganglioside GM1 localized to the axolemma of motor
fibers and subsequent activation of complement cascades result in the conduction failure of
the motor nerve fibers [13,16,17]. In a subpopulation of patients with CIDP, autoantibodies
against paranodal junction components, including neurofascin 155 and contactin 1, cause
aberrant nerve conduction, owing to the detachment of paranodal myelin terminal loops
from the axolemma [8]. As demyelinating lesions associated with macrophages are not
found in patients with these antibodies, the concept of nodopathy or paranodopathy has
recently been proposed [9,34]. Moreover, NMOSD associated with anti-AQP4 antibod-
ies is now considered a disease entity distinct from MS because astrocytes, rather than
oligodendrocytes, are primarily affected [12].
Despite the discovery of these antibodies, the mechanisms underlying demyelination
owing to myelin phagocytosis by macrophages remain unclear. Ultrastructural studies
revealed that macrophages strip morphologically intact myelin lamellae by their cyto-
Cells 2021, 10, 844 11 of 14

plasmic processes as if they are principal players in the demyelination process [4,5]. Un-
raveling, disruption, and vesicular dissolution of the myelin lamellae are also frequently
observed where the cytoplasm of macrophages is present [5], as if hydrolases released from
macrophages may also be involved. Recent electron microscopy studies using longitudinal
sections of biopsy specimens from patients with AIDP and those with CIDP suggested
that macrophages seemed to select specific sites of myelinated fibers, including the nodes
of Ranvier, paranodes, and internodes, for the initiation of demyelination in individual
cases [4,5]. Hence, specific components localized to these sites may play an important
role in the behavior of macrophages that initiate myelin phagocytosis. Along with the
search for autoantibodies, the ultrastructural characterization of myelin phagocytosis by
macrophages is a crucial step in understanding the pathophysiology of demyelinating
diseases and for the future development of targeted therapies.

Author Contributions: H.K. conceived and wrote the first draft and M.K. revised it for intellectual
content. All authors have read and agreed to the published version of the manuscript.
Funding: This work was supported in part by the Health and Labour Sciences Research Grant
on Intractable Diseases (Neuroimmunological Diseases) from the Ministry of Health, Labour and
Welfare of Japan (20FC1030).
Conflicts of Interest: The authors declare no conflict of interest.

References
1. Prineas, J.W. Acute idiopathic polyneuritis. An electron microscope study. Lab. Investig. 1972, 26, 133–147. [PubMed]
2. Dyck, P.J.; Lais, A.C.; Ohta, M.; Bastron, J.A.; Okazaki, H.; Groover, R.V. Chronic inflammatory polyradiculoneuropathy. Mayo
Clin Proc. 1975, 50, 621–637. [PubMed]
3. Frohman, E.M.; Racke, M.K.; Raine, C.S. Multiple sclerosis—The plaque and its pathogenesis. N. Engl. J. Med. 2006, 354, 42–55.
[CrossRef] [PubMed]
4. Koike, H.; Nishi, R.; Ikeda, S.; Kawagashira, Y.; Iijima, M.; Katsuno, M.; Sobue, G. Ultrastructural mechanisms of macrophage-
induced demyelination in CIDP. Neurology 2018, 91, 1051–1060. [CrossRef]
5. Koike, H.; Fukami, Y.; Nishi, R.; Kawagashira, Y.; Iijima, M.; Katsuno, M.; Sobue, G. Ultrastructural mechanisms of macrophage-
induced demyelination in Guillain-Barré syndrome. J. Neurol. Neurosurg. Psychiatry 2020, 91, 650–659. [CrossRef]
6. Prineas, J.; McLeod, J. Chronic relapsing polyneuritis. J. Neurol. Sci. 1976, 27, 427–458. [CrossRef]
7. Kuwabara, S.; Yuki, N. Axonal Guillain-Barré syndrome: Concepts and controversies. Lancet Neurol. 2013, 12, 1180–1188.
[CrossRef]
8. Koike, H.; Kadoya, M.; Kaida, K.-I.; Ikeda, S.; Kawagashira, Y.; Iijima, M.; Kato, D.; Ogata, H.; Yamasaki, R.; Matsukawa, N.; et al.
Paranodal dissection in chronic inflammatory demyelinating polyneuropathy with anti-neurofascin-155 and anti-contactin-1
antibodies. J. Neurol. Neurosurg. Psychiatry 2017, 88, 465–473. [CrossRef]
9. Koike, H.; Katsuno, M. Pathophysiology of Chronic Inflammatory Demyelinating Polyneuropathy: Insights into Classification
and Therapeutic Strategy. Neurol. Ther. 2020, 9, 213–227. [CrossRef]
10. Lennon, V.A.; Kryzer, T.J.; Pittock, S.J.; Verkman, A.S.; Hinson, S.R. IgG marker of optic-spinal multiple sclerosis binds to the
aquaporin-4 water channel. J. Exp. Med. 2005, 202, 473–477. [CrossRef]
11. Griffin, J.W.; Li, C.Y.; Ho, T.W.; Xue, P.; Macko, C.; Gao, C.Y.; Yang, C.; Tian, M.; Mishu, B.; Cornblath, D.R.; et al. Guillain-Barré
syndrome in northern China: The spectrum of neuropathological changes in clinically defined cases. Brain 1995, 118, 577–595.
[CrossRef]
12. Misu, T.; Fujihara, K.; Kakita, A.; Konno, H.; Nakamura, M.; Watanabe, S.; Takahashi, T.; Nakashima, I.; Itoyama, Y. Loss of
aquaporin 4 in lesions of Neuromyelitis optica: Distinction from multiple sclerosis. Brain 2007, 130, 1224–1234. [CrossRef]
13. Yuki, N.; Hartung, H.P. Guillain-Barré syndrome. N. Engl. J. Med. 2012, 366, 2294–2304. [CrossRef] [PubMed]
14. Feasby, T.E.; Gilbert, J.J.; Brown, W.F.; Bolton, C.F.; Hahn, A.F.; Koopman, W.F.; Zochodne, D.W. An acute axonal form of
Guillain-Barré polyneuropathy. Brain 1986, 109, 1115–1126. [CrossRef] [PubMed]
15. Sobue, G.; Li, M.; Terao, S.; Aoki, S.; Ichimura, M.; Ieda, T.; Doyu, M.; Yasuda, T.; Hashizume, Y.; Mitsuma, T. Axonal pathology in
Japanese Guillain-Barré syndrome: A study of 15 autopsied cases. Neurology 1997, 48, 1694–1700. [CrossRef]
16. Hafer-Macko, C.; Hsieh, S.T.; Li, C.Y.; Ho, T.W.; Sheikh, K.; Cornblath, D.R.; McKhann, G.M.; Asbury, A.K.; Griffin, J.W. Acute
motor axonal neuropathy: An antibody-mediated attack on axolemma. Ann. Neurol. 1996, 40, 635–644. [CrossRef]
17. Susuki, K.; Rasband, M.N.; Tohyama, K.; Koibuchi, K.; Okamoto, S.; Funakoshi, K.; Hirata, K.; Baba, H.; Yuki, N. Anti-GM1
Antibodies Cause Complement-Mediated Disruption of Sodium Channel Clusters in Peripheral Motor Nerve Fibers. J. Neurosci.
2007, 27, 3956–3967. [CrossRef] [PubMed]
Cells 2021, 10, 844 12 of 14

18. Matsui, N.; Nodera, H.; Kuzume, D.; Iwasa, N.; Unai, Y.; Sakai, W.; Miyazaki, Y.; Yamazaki, H.; Osaki, Y.; Mori, A.; et al.
Guillain-Barré syndrome in a local area in Japan, 2006–2015: An epidemiological and clinical study of 108 patients. Eur. J. Neurol.
2018, 25, 718–724. [CrossRef]
19. Sawai, S.; Satoh, M.; Mori, M.; Misawa, S.; Sogawa, K.; Kazami, T.; Ishibashi, M.; Beppu, M.; Shibuya, K.; Ishige, T.; et al. Moesin
is a possible target molecule for cytomegalovirus-related Guillain-Barre syndrome. Neurology 2014, 83, 113–117. [CrossRef]
20. Uncini, A.; Shahrizaila, N.; Kuwabara, S. Zika virus infection and Guillain-Barré syndrome: A review focused on clinical and
electrophysiological subtypes. J. Neurol. Neurosurg. Psychiatry 2017, 88, 266–271. [CrossRef]
21. Leonhard, S.E.; Halstead, S.; Lant, S.B.; Albuquerque, M.D.F.P.M.D.; De Brito, C.A.A.; De Albuquerque, L.B.B.; Ellul, M.A.; França,
R.F.D.O.; Gourlay, D.; Griffiths, M.J.; et al. Guillain-Barré syndrome during the Zika virus outbreak in Northeast Brazil: An
observational cohort study. J. Neurol. Sci. 2021, 420, 117272. [CrossRef]
22. Lucchese, G.; Kanduc, D. Zika virus and autoimmunity: From microcephaly to Guillain-Barré syndrome, and beyond. Autoimmun.
Rev. 2016, 15, 801–808. [CrossRef]
23. Lucchese, G.; Kanduc, D. Minimal immune determinants connect Zika virus, human Cytomegalovirus, and Toxoplasma gondiito
microcephaly-related human proteins. Am. J. Reprod. Immunol. 2017, 77, e12608. [CrossRef]
24. Fragiel, M.; Miró, Ò.; Llorens, P.; Jiménez, S.; Piñera, P.; Burillo, G.; Martín, A.; Martín-Sánchez, F.J.; García-Lamberechts, E.J.;
Jacob, J.; et al. SIESTA (Spanish Investigators in Emergency Situations Team) network. Incidence, clinical, risk factors and
outcomes of Guillain-Barré in Covid-19. Ann. Neurol. 2021, 89, 598–603. [CrossRef] [PubMed]
25. Keddie, S.; Pakpoor, J.; Mousele, C.; Pipis, M.; Machado, P.M.; Foster, M.; Record, C.J.; Keh, R.Y.S.; Fehmi, J.; Paterson, R.W.; et al.
Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barré syndrome. Brain 2021, 144, 682–693.
(in press). [CrossRef]
26. Sriwastava, S.; Kataria, S.; Tandon, M.; Patel, J.; Patel, R.; Jowkar, A.; Daimee, M.; Bernitsas, E.; Jaiswal, P.; Lisak, R.P. Guillain
Barré Syndrome and its variants as a manifestation of COVID-19: A systematic review of case reports and case series. J. Neurol.
Sci. 2021, 420, 117263. [CrossRef] [PubMed]
27. Cornblath, D.R.; Asbury, A.K.; Albers, J.W.; Feasby, T.E. Research criteria for diagnosis of chronic inflammatory demyelinating
polyneuropathy (CIDP). Neurology 1991, 41, 617–618. [CrossRef]
28. Van den Bergh, P.Y.; Hadden, R.D.; Bouche, P.; Cornblath, D.R.; Hahn, A.; Illa, I.; Koski, C.L.; Léger, J.M.; Nobile-Orazio, E.;
Pollard, J.; et al. European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic
inflammatory demyelinating polyradiculoneuropathy: Report of a joint task force of the European Federation of Neurological
Societies and the Peripheral Nerve Society—First revision. Eur. J. Neurol. 2010, 17, 356–363. [PubMed]
29. Ikeda, S.; Koike, H.; Nishi, R.; Kawagashira, Y.; Iijima, M.; Katsuno, M.; Sobue, G. Clinicopathological characteristics of subtypes
of chronic inflammatory demyelinating polyradiculoneuropathy. J. Neurol. Neurosurg. Psychiatry 2019, 90, 988–996. [CrossRef]
[PubMed]
30. Querol, L.; Nogales-Gadea, G.; Rojas-Garcia, R.; Martinez-Hernandez, E.; Diaz-Manera, J.; Suárez-Calvet, X.; Navas, M.; Araque,
J.; Gallardo, E.; Illa, I. Antibodies to contactin-1 in chronic inflammatory demyelinating polyneuropathy. Ann. Neurol. 2013, 73,
370–380. [CrossRef]
31. Doppler, K.; Appeltshauser, L.; Wilhelmi, K.; Villmann, C.; Dib-Hajj, S.D.; Waxman, S.G.; Mäurer, M.; Weishaupt, A.; Sommer, C.
Destruction of paranodal architecture in inflammatory neuropathy with anti-contactin-1 autoantibodies. J. Neurol. Neurosurg.
Psychiatry 2015, 86, 720–728. [CrossRef]
32. Ogata, H.; Yamasaki, R.; Hiwatashi, A.; Oka, N.; Kawamura, N.; Matsuse, D.; Kuwahara, M.; Suzuki, H.; Kusunoki, S.; Fujimoto,
Y.; et al. Characterization of IgG4 anti-neurofascin 155 antibody-positive polyneuropathy. Ann. Clin. Transl. Neurol. 2015, 2,
960–971. [CrossRef]
33. Kadoya, M.; Kaida, K.; Koike, H.; Takazaki, H.; Ogata, H.; Moriguchi, K.; Shimizu, J.; Nagata, E.; Takizawa, S.; Chiba, A.; et al.
IgG4 anti-neurofascin155 antibodies in chronic inflammatory demyelinating polyradiculoneuropathy: Clinical significance and
diagnostic utility of a conventional assay. J. Neuroimmunol. 2016, 301, 16–22. [CrossRef]
34. Vallat, J.M.; Magy, L.; Corcia, P.; Boulesteix, J.M.; Uncini, A.; Mathis, S. Ultrastructural lesions of nodo-paranodopathies in
peripheral neuropathies. J. Neuropathol. Exp. Neurol. 2020, 79, 247–255. [CrossRef]
35. Vallat, J.-M.; Yuki, N.; Sekiguchi, K.; Kokubun, N.; Oka, N.; Mathis, S.; Magy, L.; Sherman, D.L.; Brophy, P.J.; Devaux, J.J. Paranodal
lesions in chronic inflammatory demyelinating polyneuropathy associated with anti-Neurofascin 155 antibodies. Neuromuscul.
Disord. 2017, 27, 290–293. [CrossRef] [PubMed]
36. Koike, H.; Nishi, R.; Ikeda, S.; Kawagashira, Y.; Iijima, M.; Atsuta, N.; Nakamura, T.; Hirayama, M.; Ogata, H.; Yamasaki, R.; et al.
Restoration of a conduction block after the long-term treatment of CIDP with anti-neurofascin 155 antibodies: Follow-up of a case
over 23 years. Intern. Med. 2018, 57, 2061–2066. [CrossRef] [PubMed]
37. Reich, D.S.; Lucchinetti, C.F.; Calabresi, P.A. Multiple Sclerosis. N. Engl. J. Med. 2018, 378, 169–180. [CrossRef] [PubMed]
38. Lublin, F.D.; Reingold, S.C.; Cohen, J.A.; Cutter, G.R.; Sørensen, P.S.; Thompson, A.J.; Wolinsky, J.S.; Balcer, L.J.; Banwell, B.;
Barkhof, F.; et al. Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology 2014, 83, 278–286. [CrossRef]
[PubMed]
39. Sospedra, M.; Martin, R. Immunology of multiple sclerosis. Ann. Rev. Immunol. 2005, 23, 683–747. [CrossRef]
Cells 2021, 10, 844 13 of 14

40. Hauser, S.L.; Waubant, E.; Arnold, D.L.; Vollmer, T.; Antel, J.; Fox, R.J.; Bar-Or, A.; Panzara, M.; Sarkar, N.; Agarwal, S.; et al.
B-Cell Depletion with Rituximab in Relapsing–Remitting Multiple Sclerosis. N. Engl. J. Med. 2008, 358, 676–688. [CrossRef]
[PubMed]
41. Mishra, M.K.; Yong, V.W. Myeloid cells—Targets of medication in multiple sclerosis. Nat. Rev. Neurol. 2016, 12, 539–551.
[CrossRef]
42. Grajchen, E.; Hendriks, J.J.A.; Bogie, J.F.J. The physiology of foamy phagocytes in multiple sclerosis. Acta Neuropathol. Commun.
2018, 6, 124. [CrossRef] [PubMed]
43. Prineas, J.W.; Graham, J.S. Multiple sclerosis: Capping of surface immunoglobulin G on macrophages engaged in myelin
breakdown. Ann. Neurol. 1981, 10, 149–158. [CrossRef]
44. Kira, J. Multiple sclerosis in the Japanese population. Lancet Neurol. 2003, 2, 117–127. [CrossRef]
45. Jung, J.S.; Bhat, R.V.; Preston, G.M.; Guggino, W.B.; Baraban, J.M.; Agre, P. Molecular characterization of an aquaporin cDNA
from brain: Candidate osmoreceptor and regulator of water balance. Proc. Natl. Acad. Sci. USA 1994, 91, 13052–13056. [CrossRef]
[PubMed]
46. Wingerchuk, D.M.; Banwell, B.; Bennett, J.L.; Cabre, P.; Carroll, W.; Chitnis, T.; De Seze, J.; Fujihara, K.; Greenberg, B.M.; Jacob,
A.; et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 2015, 85, 177–189.
[CrossRef] [PubMed]
47. Griffin, J.W.; Stoll, G.; Li, C.Y.; Tyor, W.; Cornblath, D.R. Macrophage responses in inflammatory demyelinating neuropathies.
Ann. Neurol. 1990, 27, S64–S68. [CrossRef]
48. Hartung, H.-P.; Reiners, K.; Michels, M.; Hughes, R.; Heidenreich, F.; Zielasek, J.; Enders, U.; Toyka, K.V. Serum levels of soluble
E-selectin (ELAM-1) in immune-mediated neuropathies. Neurology 1994, 44, 1153. [CrossRef]
49. Enders, U.; Lobb, R.; Pepinsky, R.B.; Hartung, H.P.; Toyka, K.V.; Gold, R. The role of the very late antigen-4 and its counterligand
vascular cell adhesion molecule-1 in the pathogenesis of experimental autoimmune neuritis of the Lewis rat. Brain 1998, 121,
1257–1266. [CrossRef]
50. Trojano, M.; Avolio, C.; Ruggieri, M.; De Robertis, F.; Giuliani, F.; Paolicelli, D.; Livrea, P. Soluble intercellular adhesion molecule-I
(sICAM-I) in serum and cerebrospinal fluid of demyelinating diseases of the central and peripheral nervous system. Mult. Scler.
1998, 4, 39–44. [CrossRef]
51. Lund, H.; Pieber, M.; Parsa, R.; Han, J.; Grommisch, D.; Ewing, E.; Kular, L.; Needhamsen, M.; Espinosa, A.; Nilsson, E.; et al.
Competitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia-like cells. Nat. Commun.
2018, 9, 4845. [CrossRef] [PubMed]
52. Park, H.T.; Kim, Y.H.; Lee, K.E.; Kim, J.K. Behind the pathology of macrophage-associated demyelination in inflammatory
neuropathies: Demyelinating Schwann cells. Cell. Mol. Life Sci. 2020, 77, 2497–2506. [CrossRef] [PubMed]
53. Koike, H.; Katsuno, M.; Sobue, G. Deciphering the mechanism and spectrum of chronic inflammatory demyelinating polyneu-
ropathy using morphology. Clin. Exp. Neuroimmunol. 2018, 9, 35–46. [CrossRef]
54. Wiśniewski, H.; Terry, R.D.; Whitaker, J.N.; Cook, S.D.; Dowling, P.C. Landry-Guillain-Barré syndrome. A primary demyelinating
disease. Arch. Neurol. 1969, 21, 269–276. [CrossRef]
55. Carpenter, S. An ultrastructural study of an acute fatal case of the Guillain-Barré syndrome. J. Neurol. Sci. 1972, 15, 125–140.
[CrossRef]
56. Hafer-Macko, C.E.; Sheikh, K.A.; Li, C.Y.; Ho, T.W.; Cornblath, D.R.; McKhann, G.M.; Asbury, A.K.; Griffin, J.W. Immune attack
on the schwann cell surface in acute inflammatory demyelinating polyneuropathy. Ann. Neurol. 1996, 39, 625–635. [CrossRef]
[PubMed]
57. Berciano, J.; Figols, J.; García, A.; Calle, E.; Illa, I.; Lafarga, M.; Berciano, M.T. Fulminant Guillain-Barré syndrome with universal
inexcitability of peripheral nerves: A clinicopathological study. Muscle Nerve 1997, 20, 846–857. [CrossRef]
58. Raine, C.S.; Cannella, B.; Hauser, S.L.; Genain, C.P. Demyelination in primate autoimmune encephalomyelitis and acute multiple
sclerosis lesions: A case for antigen-specific antibody mediation. Ann. Neurol. 1999, 46, 144–160. [CrossRef]
59. Koike, H.; Katsuno, M. The role of macrophages in Guillain-Barré syndrome and chronic inflammatory demyelinating polyneu-
ropathy. Neurol. Clin. Neurosci 2021, in press. [CrossRef]
60. Lampert, P.W. Mechanism of demyelination in experimental allergic neuritis. Electron microscopic studies. Lab. Investig. 1969, 20,
127–138.
61. Schröder, J.M.; Krücke, W. Zur Feinstruktur der experimentell-allergischen Neuritis beim Kaninchen [Ultrastructure of experi-
mental allergic neuritis in the rabbit]. Acta Neuropathol. 1970, 14, 261–283. [CrossRef] [PubMed]
62. Lampert, P. Electron microscopic studies on ordinary and hyperacute experimental allergic encephalomyelitis. Acta Neuropathol.
1967, 9, 99–126. [CrossRef] [PubMed]
63. Lampert, P.W.; Kies, M.W. Mechanism of demyelination in allergic encephalomyelitis of guinea pigs. An electron microscopic
study. Exp. Neurol. 1967, 18, 210–223. [CrossRef]
64. Lassmann, H.; Wisniewski, H. Chronic relapsing experimental allergic encephalomyelitis: Morphological sequence of myelin
degradation. Brain Res. 1979, 169, 357–368. [CrossRef]
65. Ilyas, A.A.; Mithen, F.A.; Dalakas, M.C.; Chen, Z.W.; Cook, S.D. Antibodies to acidic glycolipids in Guillain-Barré syndrome and
chronic inflammatory demyelinating polyneuropathy. J. Neurol. Sci. 1992, 107, 111–121. [CrossRef]
Cells 2021, 10, 844 14 of 14

66. Kusunoki, S.; Chiba, A.; Hitoshi, S.; Takizawa, H.; Kanazawa, I. Anti-gal-C antibody in autoimmune neuropathies subsequent to
mycoplasma infection. Muscle Nerve 1995, 18, 409–413. [CrossRef]
67. Kuwahara, M.; Suzuki, S.; Takada, K.; Kusunoki, S. Antibodies to LM1 and LM1-containing ganglioside complexes in Guillain-
Barré syndrome and chronic inflammatory demyelinating polyneuropathy. J. Neuroimmunol. 2011, 239, 87–90. [CrossRef]
68. Devaux, J.J.; Odaka, M.; Yuki, N. Nodal proteins are target antigens in Guillain-Barré syndrome. J. Peripher. Nerv. Syst. 2012, 17,
62–71. [CrossRef]
69. Koike, H.; Ikeda, S.; Fukami, Y.; Nishi, R.; Kawagashira, Y.; Iijima, M.; Nakamura, T.; Kuwahara, M.; Kusunoki, S.; Katsuno,
M.; et al. Complement deposition and macrophage-induced demyelination in CIDP with anti-LM1 antibodies. J. Neurol. Sci. 2020,
408, 116509. [CrossRef]
70. Kuwahara, M.; Suzuki, H.; Samukawa, M.; Hamada, Y.; Takada, K.; Kusunoki, S. Clinical features of CIDP with LM1-associated
antibodies. J. Neurol. Neurosurg. Psychiatry 2013, 84, 573–575. [CrossRef]
71. Sato, D.K.; Callegaro, D.; Lana-Peixoto, M.A.; Waters, P.J.; Jorge, F.M.D.H.; Takahashi, T.; Nakashima, I.; Apostolos-Pereira, S.L.;
Talim, N.; Simm, R.F.; et al. Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders.
Neurology 2014, 82, 474–481. [CrossRef]
72. Cobo-Calvo, Á.; d’Indy, H.; Ruiz, A.; Collongues, N.; Kremer, L.; Durand-Dubief, F.; Rollot, F.; Casey, R.; Vukusic, S.; De Seze,
J.; et al. Frequency of myelin oligodendrocyte glycoprotein antibody in multiple sclerosis: A multicenter cross-sectional study.
Neurol. Neuroimmunol. Neuroinflamm. 2019, 7, e649. [CrossRef] [PubMed]
73. Misawa, S.; Kuwabara, S.; Sato, Y.; Yamaguchi, N.; Nagashima, K.; Katayama, K.; Sekiguchi, Y.; Iwai, Y.; Amino, H.; Suichi,
T.; et al. Safety and efficacy of eculizumab in Guillain-Barré syndrome: A multicentre, double-blind, randomised phase 2 trial.
Lancet. Neurol. 2018, 17, 519–529. [CrossRef]
74. Shen, D.; Chu, F.; Lang, Y.; Geng, Y.; Zheng, X.; Zhu, J.; Liu, K. Beneficial or Harmful Role of Macrophages in Guillain-Barré
Syndrome and Experimental Autoimmune Neuritis. Mediat. Inflamm. 2018, 2018, 4286364. [CrossRef] [PubMed]
75. Miron, V.E.; Boyd, A.; Zhao, J.-W.; Yuen, T.J.; Ruckh, J.M.; Shadrach, J.L.; Van Wijngaarden, P.; Wagers, A.J.; Williams, A.; Franklin,
R.J.; et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat. Neurosci. 2013,
16, 1211–1218. [CrossRef]