Biochimica et Biophysica Acta 1852 (2015) 658–666

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Biochimica et Biophysica Acta

journal homepage: www.elsevier.com/locate/bbadis

Review

Pathogenesis of immune-mediated neuropathies☆

Marinos C. Dalakas a,b,⁎
a
University of Athens Medical School, Athens, Greece
b
Thomas Jefferson University, Philadelphia, PA, USA

a r t i c l e i n f o a b s t r a c t

Article history: Autoimmune neuropathies occur when immunologic tolerance to myelin or axonal antigens is lost. Even though
Received 15 May 2014 the triggering factors and the underling immunopathology have not been fully elucidated in all neuropathy sub-
Accepted 9 June 2014 sets, immunological studies on the patients' nerves, transfer experiments with the patients' serum or intraneural
Available online 17 June 2014
injections, and molecular fingerprinting on circulating autoantibodies or autoreactive T cells, indicate that cellular
and humoral factors, either independently or in concert with each other, play a fundamental role in their cause.
Keywords:
Autoimmunity
The review is focused on the main subtypes of autoimmune neuropathies, mainly the Guillain–Barré syn-
Neuropathy drome(s), the Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), the Multifocal Motor Neuropathy
Ranvier (MMN), and the IgM anti-MAG-antibody mediated neuropathy. It addresses the factors associated with breaking
Immunotherapy tolerance, examines the T cell activation process including co-stimulatory molecules and key cytokines, and dis-
cusses the role of antibodies against peripheral nerve glycolipids or glycoproteins. Special attention is given to the
newly identified proteins in the nodal, paranodal and juxtaparanodal regions as potential antigenic targets that
could best explain conduction failure and rapid recovery. New biological agents against T cells, cytokines, B
cells, transmigration and transduction molecules involved in their immunopathologic network, are discussed
as future therapeutic options in difficult cases. This article is part of a Special Issue entitled: Neuromuscular
Diseases: Pathology and Molecular Pathogenesis.
© 2014 Elsevier B.V. All rights reserved.

1. Introduction agents are used. The review addresses the autoimmune pathways in-
volved in the pathogenesis of the most common autoimmune neuropa-
Autoimmune Peripheral Neuropathies (APN) develop when immu- thies and highlights the rationale for target-specific immunotherapies.
nologic tolerance to key antigenic sites on the myelin, axon, nodes of
Ranvier or ganglionic neurons is lost [1,2]. Current evidence supports
the notion that in APN the autoimmunity is mediated by antibodies di- 1.1. Main clinicopathologic features of common APN
rected against myelin antigens, along with autoreactive T cells and mac-
rophages that invade myelin sheath, axonal membranes or the nodes of The common autoimmune neuropathies include: 1) Acute Inflam-
Ranvier. In some APN the triggering factors have been identified and matory Polyneuropathy [the Guillain–Barré Syndrome(s)]; 2) Chronic
progress has been made in understanding the key players involved in inflammatory demyelinating polyneuropathy (CIDP) and its variants;
the immunopathogenic network; in several others however, the exact 3) Multifocal motor neuropathy with conduction block; and 4)
immunopathologic mechanisms remain still unclear, but autoimmunity Polyneuropathies associated with IgM monoclonal gammopathies and
is suspected based on the presence of antibodies, sensitized T cell infil- anti-MAG antibodies [1,2]. Other less common immune-mediated neu-
trates in the peripheral nerves, response to immunotherapies or coexis- ropathies that will not be addressed here because their pathogenesis is
tence with another autoimmune disease or viral infections. The APN are less clear include: the paraneoplastic neuropathies associated with anti-
clinically important because they respond to immunotherapies based Hu antibodies, vasculitic neuropathies due to isolated peripheral nerve
on controlled studies, or have the potential to respond if more effective vasculitis, certain diabetic demyelinating or inflammatory neuropathies
where an immune component appears prominent, and the neuropa-
thies associated with systemic autoimmune disorders.
☆ This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and As discussed below and elaborated previously [1,2], in some APN,
Molecular Pathogenesis. like certain GBS variants and the anti-MAG neuropathy, the main target
⁎ Corresponding author at: Neuroimmunology Unit, Dept. of Pathophysiology, National
University of Athens Medical School, 75 Mikras Asias Str., Athens, 11527 Greece. Tel.: +30
antigens have been identified and the antibodies against them are well
210 746 2616x2650; fax: +30 210 746 2664. characterized; in the most common neuropathies however, like the de-
E-mail address: mdalakas@med.uoa.gr. myelinating variant of GBS and the CIDP, the target antigens remain still

http://dx.doi.org/10.1016/j.bbadis.2014.06.013
0925-4439/© 2014 Elsevier B.V. All rights reserved.
 M.C. Dalakas / Biochimica et Biophysica Acta 1852 (2015) 658–666 659

elusive in spite of the progress made in understanding their molecular involvement remain unclear. Differences in the myelin composition,
immunopathology. leading to distinct antigenic specificities between motor and sensory fi-
The Guillain–Barré syndrome(s) (GBS) presents with an acute bers, have been implicated mainly because the ceramide content within
(within 1–3 weeks) ascending motor weakness, areflexia, and mild to the gangliosides differs between sensory and motor fibers [1,2,8]; the
moderate sensory abnormalities [1–5]. The neuropathy is inflammatory, reasons however may be more complex and relate to the uniqueness
with perivascular and endoneurial lymphoid cell infiltrates throughout of the targeted antigens not within the compact myelin but rather in
the nerves, roots or plexuses, and demyelinating with signs of segmental the nodal regions and axonal membrane at the nodes of Ranvier. Up
demyelination induced by complement-fixing antibodies and macro- to 50% of MMN patients have high IgM anti-GM1 antibody titers, but
phages as the final effector cells. GBS represents several syndromes – the pathogenic role of these antibodies remains unclear [1,2,17], in
or variants – according to whether the main clinicopathologic involve- spite of recent evidence that GM1 antibodies fix complement and may
ment is centered on motor or sensory nerve fibers and whether it affects induce a complement-mediated nodal dysfunction that reverses after
predominantly the myelin or the axon [1–4]. Accordingly, the GBS syn- IVIg therapy [18]. The suggestion that GM1 antibodies bind to GM1
dromes comprise the following subtypes: i) the acute inflammatory de- and interfere with saltatory conduction, has not been confirmed and
myelinating polyneuropathy (AIDP), where the main target appears to GM1-binding sites have not been co-localized with voltage-gated sodi-
be the myelin and accounts for the majority of GBS patients; ii) the um channels at the nodes of Ranvier. Even though the immunopatholo-
acute, motor axonal neuropathy (AMAN), where the primary pathology gy remains uncertain, MMN patients respond remarkably well to
is in the axon, either due to massive acute demyelination and inflamma- immunotherapy with IVIg.
tion, as occurs in experimental allergic neuritis when animals are im-
munized with a high dose of myelin antigens [1,2,6], or due to a 1.1.3. IgM MGUS polyneuropathies with anti-MAG or ganglioside antibodies
primary attack on the axons and the nodes of Ranvier mediated by mac- The majority of these patients present with a chronic, slowly pro-
rophages and antibodies. A number of these cases have high GM1 anti- gressive, large-fiber, sensory polyneuropathy of insidious onset, mani-
bodies and, as discussed later, report an antecedent infection with fested as sensory ataxia [1,2,19–21]. Other times, it presents as
Campylobacter jejuni [2,3,7]; iii) the acute motor–sensory axonal neurop- sensorimotor polyneuropathy with mixed features of demyelination
athy (AMSAN), which is like AMAN but with concurrent involvement of and axonal loss. Conduction velocity is slow with a rather characteristic
the sensory axons; iv) the Miller-Fisher syndrome, characterized by prolonged distal motor and sensory latencies consistent with distal de-
ophthalmoplegia, gait ataxia, and areflexia [1–5], a rather distinct vari- myelination. The serum protein electrophoresis shows a monoclonal
ant because of the unique clinical phenotype and the presence of IgG an- IgM spike that recognizes antigenic components on the compact mye-
tibodies against GQ1b ganglioside [1–4,7,8]; vi) the sensory ataxic GBS, lin, most of the times the Myelin Associated Glycoprotein (MAG) [21],
probably due to involvement of dorsal roots and ganglionic neurons; as discussed later. Sural nerve biopsy demonstrates diminished number
some of these patients have also IgG antibodies to GQ1b or GD1b gangli- of myelinated axons with a characteristic splitting of the outer myelin
oside and may be forming a continuum with Miller-Fisher syndrome or lamellae, linked to deposition of IgM that recognizes MAG in the same
share autoantibodies with the same sialic groups [1,2,8,9]; and vii) the area of the split myelin [1,2,21].
acute pandysautonomic neuropathy where the target antigen is probably
in the sympathetic ganglionic neurons [1,2]. 1.2. Immunopathogenesis

1.1.1. Chronic inflammatory demyelinating polyneuropathy (CIDP) In general, complement-fixing antibodies, macrophages and T cells
This is the most common APN with prevalence as high as 9/100,000 are the main effector mechanisms in all APN. In vitro and in vivo studies,
[2,10,11], and the most gratifying neuropathy because it is treatable in including immunization of animals with myelin proteins, disease trans-
the majority of the cases [2]. CIDP is viewed as the chronic counterpart fer experiments with the patients' serum or with intraneural injections,
of GBS [1,2] because it shares with GBS certain clinical, electrophysiolog- immunocytochemical studies on the patients' nerves, and T cell profil-
ic, histologic, laboratory and autoimmune features. It differs from GBS ing studies in the peripheral blood, have provided evidence that both
predominantly by its tempo, mode of evolution, prognosis, and respon- cellular and humoral factors, either independently or in concert with
siveness to steroids or immunosuppressants [1,2,10,12,16]. On electro- each other, play a central role in their pathogenesis [1,2].
physiological grounds, CIDP demonstrates features of demyelination in
motor and sensory fibers with slow conduction velocity, dispersion of 1.3. GBS
the compound muscle action potentials, conduction block in at least
one nerve, prolonged distal motor or sensory latencies and prolonged 1.3.1. Cellular factors
F wave latencies. On histological grounds, there is evidence of demyelin- In autopsy cases of GBS patients, perivascular and endoneurial in-
ation associated with macrophages, complement and activated T cells flammatory infiltrates are observed throughout the nerves, roots or
[10,12–16]. The demyelination in CIDP is also multifocal, like the one plexuses along with segmental demyelination mediated by macro-
seen in GBS, affecting spinal roots, plexuses and proximal nerve trunks phages, especially in areas with lymphoid infiltrates [1–4]. The macro-
[13–15], accounting for the variable distribution of symptoms and phages break through the basement membrane of healthy Schwann
signs, which are clinically expressed as CIDP variants [10]. The most cells and make direct contact with the outermost myelin lamellae, lead-
notable CIDP variables are the asymmetric, unifocal or multifocal motor– ing to destruction of the superficial myelin sheath [1–5]. Cytokines and
sensory form (the Lewis-Sumner syndrome); the pure motor form; the chemokines released by the activated T cells or complement activation,
pure sensory form; the sensory ataxic form; and the pure distal [1,2,10, may increase capillary permeability and facilitate transmigration of ad-
12,16]. ditional macrophages or T cells. Increased levels of IL-2 and soluble IL-2
receptors are also noted in the serum during the acute phase of GBS
1.1.2. Multifocal motor neuropathy (MMN) with conduction block suggesting ongoing T-cell activation [3]. Further, lymphocytes from
MMN has distinct clinical and electrophysiologic criteria, namely, GBS patients exert myelinotoxic activity when applied to cultures of
weakness in the distribution of individual motor nerves and multifocal myelinated axons [1,2]. The involvement of a T cell-mediated process
conduction block limited to motor but sparing the sensory nerves [1,2, in GBS has been strengthened by observations in the experimental aller-
17]. In contrast to CIDP, where conduction in the sensory nerves is gic neuritis (EAN) model induced in animals immunized with the whole
also affected and sensory responses may not be elicited, in MMN the human nerve or with various peripheral nerve myelin proteins, such as
sensory conduction remains normal across the nerve segments that Po, P2, or galactocerebroside. These animals develop EAN with segmen-
have the motor block. The reasons for such a selective motor tal demyelination and mononuclear cell infiltrates consisting of
660 M.C. Dalakas / Biochimica et Biophysica Acta 1852 (2015) 658–666

macrophages and T cells; the T cells are sensitized against myelin and reasons for different clinical syndromes in connection with specific
can passively transfer the disease to healthy animals [1–4]. gangliosides remain unclear, but distribution, accessibility, density and
conformation of ganglioside epitopes at different sites may be critical
factors [1,2,17]. For example, there is more GM1 in ventral than in dorsal
1.3.2. Humoral factors: the role of anti-ganglioside antibodies and molecular roots, hence the predominantly motor neuropathy seen with GM1 anti-
mimicry bodies, and more GQ1b in the ocular motor nerves which explains the
There is a stronger supporting evidence that circulating serum fac- ophthalmoplegia in Miller-Fisher syndrome.
tors play a role in the pathogenesis of GBS. On clinical grounds, this is
based on the beneficial effect of plasmapheresis that removes putative
pathogenic antibodies and other inflammatory mediators relevant to 1.3.2.1. Triggering factors and molecular mimicry. Current evidence sug-
demyelination and conduction block [1–5]; on laboratory grounds it is gests that antecedent infections with certain viral or bacterial infections
based on the variety of autoantibodies detected in the patients' serum. can break tolerance and trigger an autoimmune attack against myelin,
It has been known for years that serum from the acute phase of GBS in a phenomenon of molecular mimicry, when glycoconjugate epitopes
patients can demyelinate rodent dorsal root ganglionic extracts in a are shared between bacterial and myelin proteins [1,2]. Two-thirds of
complement-dependent manner. Further, GBS serum injected into rat patients with GBS give a history of a flu-like illness or acute dysenteric
sciatic nerves can cause demyelination and conduction block [1–5]. Im- episodes that precede the development of GBS by 1–3 weeks [1–3]. Vi-
munocytochemical studies on peripheral nerves from GBS patients have ruses, such as Cytomegalovirus, Epstein–Barr virus (EBV), herpes, hepatitis
shown deposits of IgG, IgM and membranolytic attack complex, imply- A and E, or HIV, and bacteria, such as Hemophilus influenza, Mycoplasma
ing complement-fixing antibodies against myelinated fibers [1–5]. Ad- pneumoniae and C. jejuni, are most commonly implicated. Among them,
ditionally, complement-fixing IgM antibodies against a peripheral infection with C. jejuni, which is the main culprit for certain GBS subsets,
nerve glycolipid that contains carbohydrate epitopes and various sulfat- has generated great interest because it provides the best example of
ed or acidic glycosphingolipids, have been detected in the serum of GBS molecular mimicry [1–3]. High titers of IgG or IgM C. jejuni-specific an-
patients [1–5,7–9]. tibodies are seen in up to 30% of patients with AMAN and 20% of patients
The interest has been focused on gangliosides as the more likely an- with Miller-Fisher syndrome and Campylobacter is isolated from the
tigenic targets because they are abundant in the peripheral nerve and stools early in acute GBS from 44% to 88% of the patients [1–3,8,9].
can elicit an immune response because their signature sugar residues C. jejuni is a common cause of a diarrheal illness worldwide but it is a
bearing one or more sialic acid molecules (such as ganglioside GM1 certain serotype, the Penner D:19 serogroup, that differs from the
that contains one sialic acid, GD1a with two, GT1a with three, or GQ1b other enteritis-causing common serotypes because it contains the
with four sialic acids), are exposed at the extracellular surface [1,2,7, genes for enzymes that synthesize sialic acid in the bacterial wall
19]. Different ganglioside antibodies associated with specific GBS sub- mimicking gangliosides GM1, GD1a or GQ1b [1–3,8,9,22]. Bacterial
types appear pathogenic [1,2,8,9]; for example, immunization of rabbits isolates from AMAN bear GM1-like or GD1a-like lipooligosaccharide,
with GM1 or GD1b induces an acute neuropathy with histological fea- while those from patients with Miller Fisher syndrome have
tures of AMAN, while GQ1b or GD1a antibodies may cause conduction lipooligosaccharides mimicking GQ1b [2,3,8,9,22]. Further, injection of
block at the motor nerve terminals in a mouse phrenic nerve preparation lipo-oligosaccharides extracted from C. jejuni into rabbits induces an
[1–3,8,9]. An inadvertent experiment in humans has strengthened the acute neuropathy with GM1 antibodies, identical to AMAN, [1–3,22].
pathogenic role of GM1 as a triggering factor because patients who re- Accordingly, a classic example of molecular mimicry takes place when
ceived ganglioside injections for various maladies, developed AMAN infection by C. jejuni carrying GM1-like or GD1a-like lipooligosaccharide
with GM1 antibodies [20]. Overall, IgG antibodies that react with GM1, induces antibodies to GM1 or anti-GD1a, which are expressed in motor
GD1a, GalNAc-GD1a and GM1b are found in 80% of patients with the ax- nerves, resulting clinically in AMAN [2,3,8,9]; in contrast, infection by
onal forms of GBS (AMAN and AMSAN); in contrast, in the most common C. jejuni bearing GQ1b-mimicking lipooligosaccharide, generates anti-
GBS subtype, the AIDP, anti-ganglioside antibodies are infrequent and GQ1b antibodies which, by binding to GQ1b expressed in oculomotor
the antigenic targets remain still elusive. One ganglioside that clearly nerves and muscle spindles, cause Miller Fisher syndrome [2,3,8,9].
correlates with a specific clinical syndrome is the GQ1b because IgG- Cross-reactivity between epitopes in the lipo-oligosaccharide of the
anti-GQ1b antibodies are specifically associated with the Miller-Fisher bacterial wall and the gangliosides on the peripheral nerve results in
variant and they are detected in more than 90% of these patients [1,2,8, sensitization of autoreactive T cells, production of complement-fixing
9]. In contrast, anti-GQ1b antibodies of the IgM class are found in some anti-ganglioside antibodies and upregulation of cytokines and transmi-
patients with chronic IgM paraproteinemic polyneuropathies [1,2,19], gration molecules on the endothelial cell wall facilitating the entrance of
as discussed later. Anti-GQ1b IgG antibodies are also found in post- more activated T cells to the endoneurial parenchyma [21]. The molec-
infectious ophthalmoplegias and in GBS patients with ophthalmoplegia, ular mimicry phenomenon as a triggering factor and the main immune
but not in GBS patients without ophthalmoplegia [1], probably because players involved in the pathogenesis of GBS are diagrammatically
GQ1b is present in the paranodal regions of oculomotor nerves III, IV, depicted in Fig. 1A.
and VI and the generated anti-GQ1b antibodies block impulse genera- Molecular mimicry may be also involved with other bacteria.
tion at the nodes of Ranvier resulting in conduction block. Many patients Hemophilus influenzae, which is a triggering factor in 5% of GBS patients,
with antibodies to GQ1b also have antibodies to GD1a [1,2,8,9]. The carries GM1 and GQ1b epitopes in its bacterial wall and may cross-react

Fig. 1. A: The main factors in the immunopathology of autoimmune peripheral neuropathies and the concept of molecular mimicry. The immune attack begins when tolerance is broken by
infections, such as Campylobacter jejuni, in a concept of molecular mimicry when glycoconjugate epitopes are shared between Campylobacter and peripheral myelin resulting in sensiti-
zation of cross-reactive T cells and production of antibodies against myelin glycolipids. These antibodies by fixing complement on the nerve or by binding to the Fc receptors on macro-
phages lead to demyelination and conduction block. Macrophages act as effector cells and via co-stimulatory molecules, lead to clonal expansion of T-cells, release of cytokines,
upregulation of adhesion molecules (ICAM, VCAM, and MMP) on endothelial cells and transmigration of T-cells to myelin sheath. Cytokines IL-4, IL-6 enhance B-cell-activation and anti-
body production. B. Targets of action of new biological agents as future immunotherapies in APN. Biological agents currently on the market for various autoimmune diseases target the
following: 1) T cell activation and intracellular signaling pathways, such as Alemtuzumab directed against the CD52 molecule; Daclizumab an IL-2 receptor antagonist; and Tofacitinib,
an oral Janus Kinase inhibitor, that inhibits interleukin-2-dependent differentiation of Th17 helper T cells; 2) B cells, such as Belimumab (Benlysta) against the B cell trophic factor Blys;
rituximab, ocrelizumab, ofatumumab (Arzera) and obinutuzumab (Gazyva), against CD20 molecules on B cells causing peripheral B cell depletion; 3) Complement, represented by the
drug Eculizumab, a monoclonal antibody against C5; 4) T cells and key Cytokines, such as Tocilizumab, an IL6 receptor antagonist; Brodalumab and Ixekizumab, both monoclonal antibodies
directed against IL17; and Ustekinumab, a human monoclonal antibody against the p40 subunit of IL12/1L-23; and 5) Cell adhesion and T cell migration, such as Natalizumab, that blocks
transmigration and Fingolimod, that traps lymphocytes in the lymphoid organs.
 M.C. Dalakas / Biochimica et Biophysica Acta 1852 (2015) 658–666 661

with the corresponding myelin antigens. Mycoplasma pneumoniae, 1.4. CIDP

which precedes GBS in 5% of cases, is another agent because it stimu-
lates antibodies against human carbohydrate antigens, including 1.4.1. Cellular factors
galactocerebrocide, the main glycolipid antigen in the peripheral The role of autoimmune cells is becoming increasingly compelling in
nerve [1–3,21]. GBS triggered by CMV infection has been also associated the mechanism of CIDP. Although defined as an “inflammatory
with the presence of IgM anti-GM2 antibodies [1,2] polyneuropathy”, the sural nerve biopsies from CIDP patients show
662 M.C. Dalakas / Biochimica et Biophysica Acta 1852 (2015) 658–666

only minimal signs of T cell infiltrates, at least at the time nerve biopsies from entering the germinal centers to become IgG-positive plasma
are performed [1,2,10,20,22]. The predominant lymphoid cells consist of cells [47], if confirmed, may further support the role of B cells in the
macrophages, found scattered or in clusters around endoneurial vessels disease.
[2,13–15,22,23]. Macrophages constitute the final effector cells associat- In contrast to GBS where molecular mimicry with bacterial or viral
ed with demyelination because they express activation markers, proba- antigens triggers the disease in some patient subsets, there is no con-
bly induced by cytokines released by autoreactive T cells in situ or in the vincing evidence that viral infections are antecedent events in CIDP. Of
circulation [2,10–16,24,25], penetrate the basement membrane of the interest is the observation that the incidence of CIDP is higher in pa-
Schwann cell, displace the cytoplasm, split the myelin lamellae and tients with melanoma or after vaccination with melanoma lysates
result in focal destruction of the myelin sheath (macrophage-mediated [48]. Because several carbohydrate epitopes, such as GM3, GM2, GD3,
demyelination). The macrophages, but also the Schwann cells, play a are shared between myelin and melanoma cells and the serum of one
role in local antigen presentation because they express the co- such patient recognized GM2 epitopes on her own melanomatous
stimulatory molecules B7-1, B7-2, while their counter-receptors CTLA- tumor, we have inferred that molecular mimicry may be a triggering
4 and CD28 are expressed on the rare endoneurial CD4 + T cells [26, factor in such clinical settings [49]. Overall, the immunopathogenetic
27]. The role of B7-1/B7-2 is further supported by the development of scheme presented in Fig. 1A summarizing the proposed role of T cells,
a spontaneous autoimmune polyneuropathy in a strain of non-obese di- cytokines, B cells and autoantibodies for GBS, is also relevant in CIDP.
abetic mice deficient in B7-2 co-stimulation that demonstrate clinical,
electrophysiological and immunopathological features similar to 1.4.2.1. Emerging target antigens in the nodal regions: an explanation for
human CIDP [28]. Preliminary data in a small series of patients, indicate conduction block and rapid recovery. In spite of the progress made in
that the few CD8+ and CD4+ T cells found in the nerve biopsies of CIDP the field, the target antigen(s) in CIDP and in the commonest form of
patients, have monoclonal or oligoclonal restrictions in their T-cell re- GBS, the acute inflammatory demyelinating polyneuropathy (AIDP), re-
ceptor repertoire that overlap with those found in the same patients' main still elusive. Recent studies however suggest that molecules not in
peripheral blood lymphocytes, implying an antigen-driven T-cell the compact myelin as we have been so far focused on, but rather within
response against peripheral nerve antigens [29]. After successful treat- the nodal or paranodal regions and the Schwann cell/axonal interac-
ment with IVIg in a few of these patients, the oligoclonal expansions tions may be probable candidate targets of the immune attack [2,50] be-
of CD4+ and CD8+ populations appear reduced [30]; if these findings cause dysfunction in these regions can best explain the rapid changes in
are confirmed in more prospectively studied patients and correlate with clinical symptomatology seen in CIDP patients after treatment with
the clinical response, changes in Vβ elements of the T cell receptors plasmapheresis or IVIg. Such a recovery is often noticeable within
might become interesting markers of CIDP responsiveness to IVIg [31]. days after treatment which cannot be explained on the basis of
Higher number of Th17-positive cells is also observed in the periph- remyelination but rather by the presence of a functional, “minute-to-
eral blood and CSF of CIDP patients with increased levels of circulating minute”, blockade induced by humoral factors against molecules associ-
interleukin-17 which augments the induction of co-stimulatory mole- ated with saltatory conduction at the nodes of Ranvier [2,10]. The same
cules and enhances further the immune process [32]. The noted is true for the worsening seen at the end of treatment effect, often pre-
dysfunction of immunoregulatory T cells may also play a role by affect- dictable at 3–5 weeks, which cannot be due to an another predictable
ing the local inflammatory microenvironment and sustaining the ongo- demyelinating episode but rather due to reappearance of the conduc-
ing immune response [2,10,31–34]. Soluble adhesion molecules, tion block across the nodes. Electron microscopy studies have now re-
chemokines, cytokines and metalloproteinases are increased in the pa- vealed multiple alterations in the nodal and paranodal regions in the
tients' sera, endothelial cells and CSF, facilitating T cell transmigration Schwann cells of CIDP nerves compared to disease controls [51]. The
across the blood–nerve barrier [34–38]. Gene array studies have con- distribution of KCNQ2, a potassium channel subunit present in nodal re-
firmed the upregulation of genes for various inflammatory mediators gions was found diminished in CIDP nerves, while paranodin, known as
not only in the sural nerve biopsies [39] but also in the small nerve fibers CASPR, an axonal membrane glycoprotein highly enriched at the
of the skin [40]. The skin biopsy is emerging as a powerful and accessible paranodes, was more widespread in CIDP than in controls extending
tool to further explore the molecular events associated with the inflam- along the axon in the internodes [51]. Analogous alterations were ob-
matory process directly on the intradermal nerve fibers and monitor the served in the demyelinated sciatic nerves of mice that exhibited in-
changes over time or after therapies. creased levels of paranodin/CASPR and increased density of ankyrin G
clusters [51]. Additionally, in mice with EAN disruption of sodium chan-
1.4.2. Humoral factors nel clusters at the nodes of Ranvier was associated with loss of adhesion
Humoral factors play a more fundamental role in CIDP owing to the molecules gliomedin and neurofascin, that started before the loss of
beneficial effect of plasmapheresis that removes putative pathogenic sodium channels and the onset of paranodal demyelination, and was ac-
antibodies or other inflammatory mediators [1,2,10]. It is the fast re- companied by antibodies to gliomedin and neurofascin [52]. According-
sponse of patients to plasmapheresis that implicates a circulating factor ly, molecules in the nodal, paranodal or juxtaparanodal regions, as
– probably an antibody – responsible for demyelination and conduction depicted in Fig. 2, may be target antigens in human demyelinating
block. In contrast to GBS however, where ganglioside antibodies play a neuropathies that could best explain the conduction block. As depicted
causative role in the axonal and ataxic variants as discussed above, no in Fig. 2, some of the putative antigenic proteins within these regions in-
specific antibody has yet been identified as the causative factor in clude: at the node the neurofascin (NF186), gliomedin, sodium channels,
CIDP, in spite of the compelling indirect evidence. The first indication ankyrin G or spectrin; at the paranode the neurofascin 155, contactin/
that antibodies are involved in CIDP was the presence of complement- Caspr 1 and connexins Cx31.3, Cx3232, Cx31.3, or 29; and at the
fixing IgG and IgM deposits on the patient's myelin sheath [41]; the juxtaparanode the Transient Axonal Glycoprotein-1 (TAG-1)/CASPR 2
presence of a band, probably IgG, in their CSF provided further credence and potassium channels [52,53]. Immune responses against such mole-
[42]. Antibodies to glycolipids LM1, GM1, or GD1b were subsequently cules may change the fine structure at the nodes and induce conduction
detected in some patients, but less frequently detected than in GBS, al- failure that would best explain the rapid recovery seen after therapy [2,
though more frequently detected than in controls [43,44]. Passive trans- 50].
fer experiments have then demonstrated that serum IgG can induce A number of laboratories including ours, are actively searching for
conduction block in the rat nerves [45] implicating a 28 kDa myelin pro- antibodies against such targets. In one study, 43% of patients with GBS
tein Po as a putative antigen, but only in 20% of the tested patients [46]. and 30% of patients with CIDP showed IgG fixation at the nodes of
The recent observation that B cells from CIDP patients exhibit reduced Ranvier in an in vitro system; in eight of these patients IgG antibodies
expression of FcγRIIB, an inhibitory receptor that prevents B cells recognized the native extracellular domain of neurofascin NF186,
 M.C. Dalakas / Biochimica et Biophysica Acta 1852 (2015) 658–666 663

Fig. 2. Proteins in the nodal, paranodal and juxtaparanodal regions of myelinated fibers as target antigens in acquired demyelinating neuropathies with conduction block. Contactin 1, Na
+ channel, Ankyrin G, and Neurofascin 186 are the most common putative antigens in the nodal region; Neurofascin 155, CASPR 1/contactin 1 in the paranodal region; and contactin 2/
CASPR2 and K + channel in the juxtaparanodal region. Additional ones (see text) include gliomedin, connexin, NCAM, cadherin and others. Part of the figure was adapted from Susuki [53]
with permission.

gliomedin, or contactin [54]. In three other studies, high titer antibodies 1.5. IgM-MGUS neuropathy with anti-mag or SGPG antibodies
to neurofascin have been observed in some patients with CIDP and AIDP
but not in controls [55–57]. Although these antibodies were detected in Among patients with paraproteinemias, the best characterized
a small number of patients, there is evidence that they may be patho- antibody-mediated neuropathy is the one associated with IgM
genic [57]. In another series, 4 of 46 (8.6%) CIDP patients reacted with monoclonal gammopathy. The sera from approximately 50% of these
hippocampal neurons and paranodal structures on teased nerves, patients react with myelin-associated glycoprotein (MAG), a 100-kDa
while three of them (6.5%) had antibodies to contactin-1 and one to glycoprotein of the central and peripheral nerve myelin, as well as
contactin-associated protein 1 (CASPR 1) [58]. Of interest, the CASPR- other glycoproteins or glycolipids that share antigenic determinants
positive patients had poor response to IVIg, more axonal involvement with MAG [1,2,64–68]. The antigenic determinant of MAG resides in
and aggressive course. The same group has also found in 4 other CIDP the carbohydrate component of the molecule because after deglycosyl-
patients who had predominant distal weakness, poor response to IVIg ation of MAG the IgM reactivity is lost [67]. Most importantly, the anti-
and a disabling tremor, IgG4 antibodies to neurofascin-155; these pa- MAG IgM paraproteins always react with an acidic glycolipid in the gan-
tients' serum immunoreacted with paranodes in teased-nerve fibers glioside fraction of the human peripheral nerve that we had identified
and with the neuropil of rat cerebellum, brain, and brainstem [59]. It as a sulfoglucuronyl glycosphingolipid (SGPG) [68]. SGPG is more rele-
is likely that different antibodies at the nodal region may identify differ- vant in the pathogenesis of the neuropathy because, in contrast to MAG
ent CIDP phenotypes. Polymorphisms in the TAG-1 molecule have been which is mostly present in the CNS myelin, SGPG is found exclusively in
also noted in CIDP patients and it was suggested that TAG-1 may be a the peripheral nerve. In addition, animals we immunized with SGPG
target antigen [60]. We have tested 15 CIDP patients for TAG-1 antibod- develop an ataxic neuropathy similar to the one seen in IgM-MGUS
ies using a cell-based assay in our laboratory, but we did not identify patients. More than half of the IgM paraproteins in patients with neu-
any positive sera [61]. Further, testing for reactivity to CASPR 2, which ropathy recognize MAG and SGPG, while 75% of the rest recognize
is localized in the juxtaparanodal region (Fig. 2), using a sensitive cell- other ganglioside antigens, most commonly those that contain either
based assay also failed to detect antibodies [62]. A more recent screen a disialosyl moiety, such as GD1b, GQ1b, GT1b, the GalNac-GM1b and
of 45 CIDP patients for contactin-2/TAG1, Connexins Cx31.3 and Cx32, GalNAc-GD1a, or two gangliosides that share epitopes with GM2, or a
as well as CASPR 2 was still disappointing except for one patient that combination of GM2 and GM1, GM1 and GD1b [1,19,69,70]. Acidic gly-
recognized a heretofore-unidentified antigen at the node in a teased colipids are therefore, the most common antigenic epitopes in IgM-
nerve fiber preparation [63]. In spite of the very small number of posi- MGUS patients [1,19,69,70].
tive sera, the plethora of proteins in the nodal regions, open the way Because anti-MAG-reacting sera always recognize the SGPG glyco-
to explore other candidate target antigens, especially against proteins lipid, the assay is often performed using SGPG as antigen instead of pu-
with an extracellular domain, in an effort to identify distinct patient rified human MAG [1]. It should be noted however that IgM binds to
subsets. MAG 10–100 times more strongly than to SGPG, and checking for
664 M.C. Dalakas / Biochimica et Biophysica Acta 1852 (2015) 658–666

SGPG instead of MAG may potentially miss some very low-affinity anti- but after IVIg the FcγRIIB protein expression was upregulated; whether
MAG antibodies [1,2]. such an upregulatory effect of IVIg on FcγRIIB of B cells predicts respon-
There is strong evidence that MAG/SGPG antibodies are causatively siveness to IVIg, remains to be proven [84].
related to the neuropathy because: a) IgM and complement are depos-
ited on the myelinated fibers in the patient's sural nerve biopsies sug- 1.5.2. Emerging biological agents as new targeted therapies
gesting that activated complement is fixed in situ by the antibodies There is a need for more effective and specific therapies for all APN
[71]; b) the patients' IgM recognizes the neural cell adhesion molecule because: a) a number of patients with GBS or CIDP do not adequately
NCAM and co-localizes with MAG on the areas of the split myelin impli- respond to the available therapies and left with significant disability;
cating a myelin disadhesion process induced by the circulating anti- b) there is a need for steroid and IVIg-sparing effect in CIDP to diminish
MAG IgM [72]; c) in skin biopsies from the patients, there is deposition the long-term steroid-related side effects and reduce the high cost of
of IgM, complement and MAG on the intradermal myelinated fibers monthly IVIg maintenance; c) a number of patients with MMN do not
with a concurrent loss of nerve fibers suggesting IgM-induced adequately respond to IVIg or the efficacy wanes with time; and d)
fiber loss [72]; d) intraneural injections of the patients' serum supple- very few patients with anti-MAG neuropathy respond only to Rituxi-
mented with fresh complement into peripheral nerve of cats results in mab [80,86]. Emerging therapeutic agents in the form of monoclonal
a complement-dependent demyelination with conduction block, 2–9 antibodies or fusion proteins offer target-specific therapy and are cur-
days after the injection; the injected serum also caused splitting of the rently used in other autoimmune disorders, as discussed [87,88].
outer layer of the myelin sheath resembling the human pathology These agents may be of value as future therapies in all APN because
[73]; d) systemic transfusion of anti-MAG IgM paraproteins causes seg- they target key molecules involved in immunopathology of the disease
mental demyelination in chickens with deposition of IgM to the outer from the early T and B cell activation to the final induction of cytotoxic-
layers of the myelin sheath and splitting of the myelin lamellae similar ity including cytokines, complement, and adhesion or transmigration
to the one seen in the patients' nerves [74]; and e) immunization of molecules, as depicted in Fig. 1B [2,10,87,88]. As emphasized [2], these
cats with SGPG causes sensory ataxia, as seen in patients with anti- drugs may be considered as future therapeutic options, provided that
MAG neuropathy, and an inflammatory ganglionopathy with dorsal they are tested in control trials and the rare but potentially catastrophic
root involvement consistent with the clinical signs of sensory ataxia side effects are being monitored. The new biological agents target the
[75]. following.

1.5.1. Current therapies and emerging disease biomarkers

1.5.2.1. T cell intracellular signaling pathways. This group includes: a)
The autoimmune neuropathies are clinically important because they
Alemtuzumab, a monoclonal antibody against the CD52 transduction
respond to treatment with various immunomodulating or chemothera-
molecule, that causes long-lasting lymphocyte depletion. Alemtuzumab
peutic agents. Randomized clinical trials have shown that intravenous
has been effective in multiple sclerosis and seems promising in CIDP [2,
immunoglobulin (IVIg) and plasma exchange are equally effective in
10,9,87,88] where a controlled trial is ready to begin; b) Daclizumab, a
GBS [76], although some patients do not adequately respond for reasons
monoclonal antibody against CD25 (IL-2 receptor antagonist) that in-
that remain still unclear. In CIDP, corticosteroids, IVIg and plasma ex-
hibits T cell proliferation. The drug is well tolerated, has been approved
change exert a short- or long-term meaningful clinical improvement
for leukemia, and is very promising in patients with Multiple Sclerosis in
in the majority of the patients, but maintenance therapy is required
two phase III clinical trials; c) Tofacitinib, an oral Janus Kinase inhibitor,
[2,10,77,78]. In MMN, the only effective therapy is IVIg but remains
that inhibits interleukin-2-dependent differentiation of type 2 and type
curious why this neuropathy does not respond to any other immuno-
17 helper T cells and attenuates signaling by proinflammatory cyto-
therapy and worsens with corticosteroids. Anti-MAG neuropathy is re-
kines, such as interleukin-6 and interferon-γ. Blockade of Janus kinases
fractory to available therapies [1,79], but a small number of patients
suppresses both T and B cells and maintains Regulatory T-cell function.
respond very well to Rituximab [80]. Immunosuppressants, such as aza-
The drug has been effective in ulcerative colitis and rheumatoid arthritis
thioprine, cyclosporine, mycophenolate, or cyclophosphamide are vari-
[87,88].
ably used as steroid- or IVIg-sparing agents in all APN [80], but their
efficacy is overall disappointing. Controlled trials with β-interferon
and methotrexate were ineffective in CIDP [81–83]. Because some 1.5.2.2. B cells and B cell trophic factors. They include: i) Belimumab
CIDP patients respond only to steroids, while others with pure motor (Benlysta), a human monoclonal antibody against B-lymphocyte stimu-
disease worsen with steroids and still others respond only to plasma- lator (BLyS) that has been approved for lupus; ii) rituximab, a chimeric
pheresis or IVIg [10,84], biomarkers predicting response to therapies monoclonal antibody directed against CD20, a membrane-associated
from the outset are needed [84]. phosphoprotein present on B cells, causes peripheral B cell depletion
Pharmacokinetic studies in 174 GBS patients treated with IVIg have [87–90]. Rituximab is given in two, 1 g each infusions, 15 days apart in-
shown that patients with a lower increase in serum IgG (DeltaIgG) re- travenously or in 4 weekly infusions each at 375 mg/m2; up to 50% of
covered more slowly and fewer of them reached the ability to walk un- the treated patients with CIDP seem to improve after 2–12 months
aided at six months, concluding that a low DeltaIgG was independently [91] but controlled studies are needed. Rituximab also helps a number
associated with poor outcome [85]. If confirmed, this would suggest that of patients with anti-MAG neuropathy, 6–8 months after one 2 gram in-
patients might benefit from a higher dosage or from a second IVIg infu- fusion [80,86]; iii) ocrelizumab, the humanized version of rituximab; iv)
sion early in the disease course. Serum IgG levels after IVIg infusions do ofatumumab (Arzera) that targets different CD20 epitopes and can be
not seem to play a role in predicting responsiveness of CIDP to IVIg. Two given subcutaneously; and v) Obinutuzumab (Gazyva), another mono-
potential biomarkers, the TAG-1 (Transient Axonal Glycoprotein-1), an clonal antibody against CD20 that causes more profound B cell deple-
adhesion molecule involved in axonal maintenance, and the expression tion and has been approved for chronic lymphocytic leukemia.
of inhibitory FcγRIIB receptors on B cells [59,47], seem promising in
conferring responsiveness to IVIg. Single nucleotide polymorphisms 1.5.2.3. Complement. Eculizumab, a monoclonal antibody against C5 in-
and haplotype studies in 100 Japanese patients, revealed an association tercepts the terminal formation of membranolytic attack complex
between IVIG responsiveness and TAG-1 polymorphism [59], suggest- (MAC) and blocks the generation of proinflammatory molecules [92,
ing that response to IVIg may be even genetically determined. The in- 93]. The agent, approved for paroxysmal hemoglobinuria, is of interest
hibitory FcγRIIB receptors on B cells transduce inhibitory signals and in CIDP and GBS where complement is activated and deposited on the
prevent their transformation into IgG-producing plasma cells [47]. Pa- nerves. The drug was effective in an EAN model, showed some promise
tients with CIDP were found to have lower FcγRIIB on naive B cells, in a small uncontrolled trial in MMN patients, and was effective in a
 M.C. Dalakas / Biochimica et Biophysica Acta 1852 (2015) 658–666 665

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