J Neurol (2011) 258:533–548
DOI 10.1007/s00415-010-5836-5
REVIEW
The role of cytokines in Guillain–Barré syndrome
Ming-Ou Lu • Jie Zhu
Received: 7 June 2010 / Revised: 13 October 2010 / Accepted: 9 November 2010 / Published online: 23 November 2010
Ó Springer-Verlag 2010
Abstract Cytokines play an important role in the patho-
genesis of autoimmune diseases including Guillain–Barré
syndrome (GBS) and its animal model experimental auto-
immune neuritis (EAN). In this article, we reviewed the
current knowledge of the role of cytokines such as TNF-a,
IFN-c, IL-1b, IL-6, IL-12, IL-18, IL-23, IL-17, IL-10, IL-4
and chemokines in GBS and EAN as unraveled by studies
both in the clinic and the laboratory. However, these
studies occasionally yield conflicting results, highlighting
the complex role that cytokines play in the disease process.
Efforts to modulate cytokine function in GBS and other
autoimmune disease have shown efficiency indicating that
cytokines are important therapeutic targets.
Keywords Cytokine
Guillain–Barré syndrome

Experimental autoimmune neuritis
Autoimmunity
T cell
Introduction
Guillain–Barré syndrome (GBS) is a common cause of
acute neuromuscular paralysis with an annual incidence of
M.-O. Lu
J. Zhu
Department of Neurology, The First Hospital, Jilin University,
Xinmin Street No.17, Changchun, China
M.-O. Lu
Department of Neurology, The First Hospital, Dalian Medical
University, Zhongshan Road 222, Dalian, China
J. Zhu (&)
Division of Neurodegeneration (NOVUM, plan 5),
Department of Neurobiology, Care Sciences and Society,
Karolinska Institute, Karolinska University Hospital
in Huddinge, 141 86 Stockholm, Sweden
e-mail: jie.zhu@ki.se
1.2–2.3 per 100,000 throughout the world [1]. It is a
clinical syndrome whose pathological substrate may be
acute inflammatory demyelinating polyradiculoneuropathy
(AIDP) or acute axonal motor (AMAN) or motor and
sensory axonal neuropathy (AMSAN) [2], acute sensory
neuronopathy, acute pandysautonomia and the Fisher syn-
drome [3]. In two-thirds of GBS cases, the disease is
regarded as a post-infectious autoimmune disease that may
involve molecular mimicry triggered by many antecedent
pathogens [4], [5]. Both cellular and humoral immunity
may participate. The different patterns of GBS are probably
due to the diverse interplay between antibodies and T cells
of differing specificities [6]. Experimental evidence
implicated that axonal subgroups of GBS and Fisher syn-
drome are more related to auto-antibodies against gangli-
oside, while AIDP more involves CD4? T cell induced
macrophage associated demyelination, although some
studies showed the importance of humoral immunity
especially in early stages of AIDP [1, 5, 7, 8]. Due to the
remarkable similarities in clinic and pathology, experi-
mental autoimmune neuritis (EAN) is considered to be an
animal model of AIDP, the most common form of GBS [9].
Current therapies for GBS such as plasma exchange
(PE) and intravenous immunoglobulin (IVIg) mainly focus
on the humoral immunity. Although results of international
randomized trials have shown equivalent efficacy of PE
and IVIg, but not corticosteroids, in hastening recovery
from GBS, IVIg is usually used because of its greater
convenience and availability [1, 10, 11]. However, none of
the treatments significantly reduced mortality. Since
*20% of patients die or have persistent disability despite
immunotherapy, more studies are needed to identify better
treatment regimens and new therapeutic strategies [8].
Cytokines are polypeptides that act as signal molecules
in a paracrine or autocrine fashion between the cells of the
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immune system and also in other area including psycho-
neuroimmunological interactions. Cytokines play a key
role in initiating, propagating and regulating tissue-specific
autoimmune injury. The analysis of cytokine production is
increasingly important in defining the mechanism of
autoimmune responses and in evaluating specific therapies
of autoimmune diseases. This review will focus on the role
of cytokines in GBS and EAN in recent years, to better
understand the mechanism and treatment of GBS.
Cytokine in GBS and EAN
Cellar immunity is likely involved in the pathogenesis of
the GBS and some forms of EAN. The inflammatory cells
infiltrating in the peripheral nervous system (PNS) of both
diseases are composed of lymphocytes and cells of the
macrophage lineage, exerting most of their effects through
immuno-regulatory cytokines [12] (Fig. 1). Pro-inflamma-
tory cytokines such as IL-1b, IL-6, IL-12, IL-17, IL-18,
IL-23, TNF-a, IFN-c and chemokines are thought to sig-
nificantly contribute to disease development by recruiting
effecter cells to the PNS and by enabling in situ release of
other products toxic for Schwann cells (SCs) and myelin
such as free radicals, oxygen intermediates and nitric oxide
(NO) [12–16]. Anti-inflammatory cytokines from Th2 and
Th3 cells such as IL-4, IL-10 and TGF-b may suppress the
Fig. 1 The role of cytokines in
EAN and GBS
APC
Th2
B cell
Plasma cell
Th3
enhancement
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disease by playing an important anti-inflammatory role
[17–19]. More recently, IL-17 producing Th17 cells has
been found playing an important role in many autoimmune
diseases including experimental autoimmune encephalo-
myelitis (EAE), an analogous disease of the central nervous
system (CNS), while thymic regulatory T (Treg) cells have
a suppressive role, although their roles need to be further
investigated in EAN and GBS [20, 21]. Actually, increased
levels of activated T cells and reduced levels of CD4/
CD25? cells (Treg cells) were found in peripheral blood of
acute stage of GBS, but marked improvement of Tregs in
stable-stage of GBS after IVIg treatment [22, 23]. Single
cytokine in EAN and GBS would be discussed as below.
IFN-c
IFN-c is mainly produced by T cells and natural killer (NK)
cells [24]. It is typically produced by Th1 cells and is the
principal marker of a Th1 response. The effects of IFN-c
are induced and regulated by IL-12, and also suppressed
markedly by apoptotic cells as evidenced in stimulated
human peripheral mononuclear cells [25]. Its functions
include activation of macrophages, differentiation of T
cells to Th1 phenotype, induction of MHC I and MHC II
expression, B cell class switching, apoptosis of T cells and
other cell types, enhancement of other cytokine production
such as TNF-a, IL-1b, IL-6, and receptor activator of
Cell migration
BNB breakdown
Increase BNB permeability
Th1
Adhesion molecules,
IL-1, 6,TNF-α, MCP-
1,MIP-1a, β, IP-10,
RANTES,CCR2
IL-18
TGF-β (-)
IL-6,
TGF-β
TNF-α
(-)
IL-12, sIL-6R
probably (-) inhibition
J Neurol (2011) 258:533–548
nuclear factor-kB (NF-kB) ligand, as well as up-regulation
of metalloproteinases, chemokines and adhesion mole-
cules. IFN-c also up-regulates cytokine inducible NO
synthase (iNOS)-specific mRNA in SCs and precipitates
release of nitrite in a dose-dependent manner [26]. More-
over, IFN-c promotes SCs to present exogenous P2 protein
to P2-specific neurogenic T cell line cells [27].
In EAN, the level of IFN-c producing cells in blood
lymph node and PNS tissue roughly parallel clinical
symptoms. Systemic administration of recombinant rat
IFN-c (rrIFN-c) worsens EAN rats and IFN-c receptor
deficient mice showed a suppression of EAN [28]. In GBS
patients, serum IFN-c was found elevated [29]. Although a
significantly increased antigen specific peripheral blood
mononuclear cells (PBMC) proliferation was not shown,
PBMC secreting IFN-c spontaneously elevated in 25% of
patients of GBS, which indicated a role of T cells in the
immunopathology of GBS [30]. Moreover, neutralizing
auto-antibodies to IFN-c are significantly correlated with
down-regulation of IFN-c producing cells and with
improved clinical disability in GBS patients [31].
However, IFN-c has also been evidenced to have a
protective role in autoimmunity since some other autoim-
mune disease aggravated either in the anti-IFN-c treatment
or gene knock out animal models such as EAE, collagen
induced arthritis (CIA) and experimental autoimmune
uveitis (EAU) [32–34]. Exogenous IFN-c prevents auto-
immune diabetes both in BB rats and NOD mice [35–37].
Also in patients with rheumatoid arthritis (RA), various
studies described protective effects for the use of recom-
binant IFN-c [38, 39], although one report established
beneficial effects for the antibody treatment [40].
The main protective roles of IFN-c in recent findings
included as below: inhibit on neutrophil trafficking [41,
42]; convert CD4?CD25- cells into CD4? Treg cells
[43]; suppress the differentiation and effector function of
the pro-inflammatory Th17 cells [44, 45]; microglia acti-
vated by IFN-c or IL-4 can protect neutrons and support
both neurogenesis and oligodendrogenesis [46–48]. In
2008, Foulds et al. [49] reported IFN-c plays a critical role
for controlling all stages of Th1 differentiation and mem-
ory formation. At first, IFN-c controls T cell expansion by
direct caspase induction and causing apoptosis. Later,
IFN-c mediates the death of Th1 cells indirectly through
induction of numerous factors, such as NO, Indoleamine
2,3-dixoygenase (IDO), and TNF-a receptors. Therefore,
Kelchtermans [41] suggests that endogenous IFN-c can be
considered as a process with bidirectional immune-regu-
lation and often resulting in moderation of pathology.
To date, most researches indicate that IFN-c plays a
crucial inflammatory role in EAN and GBS while recent
study reveals that IFN-c can convert peripheral
CD4(?)CD25(-) T cells to CD4(?)CD25(?) regulatory T
535
cells in GBS [50]. Thus, IFN-c might have a dual role in
this disease and the protective role needs to be further
investigated.
TNF-a
TNF-a is produced by many cells including macrophage, T
cells, SCs and so on [51]. Membrane-bound or soluble
TNF-a signals through TNF-a receptor 1 (TNFR1, p55)
and TNF-a receptor 2 (TNFR2, p75), mainly TNFR1, to
elicit a wide variety of signals in many different cell types
[52, 53].
In immune response, TNF-a induced matrix metallo-
proteinase (MMP-9) promotes macrophage recruitment
into injured peripheral nerve [54]. Induction of TNF-a by
lipopolysaccharide (LPS) in SC is regulated by mitogen-
activated protein kinase (MAPK) signals [55] and inhibi-
tion of TNF-a-initiated p38MAPK pathway enhances
axonal regeneration [56]. This indicates that MAPK might
be an important pathway that leads TNF production and its
action on the peripheral nerve. Moreover, it is also revealed
that TNF-a inhabits SC proliferation and mediates SC
death by up-regulating Src-suppressed protein kinase C
substrate and p75NTR expression separately [57, 58]. More
recently, TNFR1 is found as a positive T cell costimulatory
molecule that is important for T cell activation and effector
cytokine production and the development of primary
immune responses in mice [59].
TNF-a has a pivotal role in the pathogenesis of EAN and
GBS. In GBS, serum TNF-a, correlated to TNF-a two
allele, was elevated and associated with the disease
severity [60, 61]. TNF-a converting enzyme (TACE),
processing of membrane-bound inactive pro-TNF-a into
the active soluble cytokine TNF-a, is up-regulated during
EAN and expressed in nerves of GBS patients and thus
may contribute to the pathogenesis of inflammatory
demyelination of the PNS [62]. Moreover, TNF-a and
TNFR1 decreased while sTNFR1, an antagonist of TNF-a,
increased correlated to the neurological recovery in GBS
patients treated with IVIg [60, 63, 64]. This might be due to
the down-regulation of TNF-a production and sustained
buffering of TNF-a by sTNF-Rs, particularly sTNFR1, and
IVIg could selectively induce this gene transcription and
secretion of anti-inflammatory cytokines as evidenced in
cultured human lymphocyte [65].
In EAN, TNFR1 deficiency reduces antigen-presenting
capacity of SCs and ameliorates EAN in mice [66]. Pro-
phylaxis with sTNFR1 treatment delayed the onset, which
was accompanied by inhibition of blood-nerve-barrier
(BNB) permeability and inflammation, however, after EAN
established, sTNFR1 cannot affect the course of the dis-
ease, indicating that TNF plays a role in BNB permeability
[67]. Through activation of caspase-3, TNF-a seemed
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implicated in SC apoptosis in the natural course of EAN
[55]. On the other hand, hypersensitivity of pain in rats
with EAN accompanied by pronounced autoimmune
inflammation in peripheral nerve and SC-derived TNF-a is
a major mediator of this hyper-algesia [68, 69]. Indeed,
TNF-a contributing to neuropathic pain has been shown in
many recent studies [70].
Although release of sTNF-Rs appear to be protective
since they can buffer TNF-a biological activities [71],
TNF-a itself might have a beneficial role in EAN. The
inhibition of TNF-a leads to a decrease of T cell apoptosis
during high dose antigen therapy in AT-EAN rats, making
TNF-a the principal candidate for mediating some of the
effects of antigen therapy [72]. Moreover, previous study
showed that TNFR1 deficient mice in EAN exhibited a
more severe clinical signs (Fig. 2), in parallel with
enhanced numbers of inflammatory infiltrating cells in
peripheral nerves and splenic P0-reactive T cell prolifera-
tion, as well as increased MHCII and CCR3 expression on
the macrophages in cauda equina [73]. However, this result
is contrary to our previous study, mentioned above, that
TNFR1 deficiency ameliorates EAN in mice. The con-
flicting results may be due to the different P0 protein
peptide applied or differential timing, location and quantity
of TNF-a expressed and released [66]. We suppose that the
exacerbation of EAN in TNFR1 deficient mice might be by
altering antigen-presenting cell (APC) function, increasing
T cell receptor signaling, and decreasing apoptosis of
potentially auto-reactive T cells. Further, this protective
role of TNF-a/TNFR1 was also demonstrated in our pre-
vious data in kainic acid-induced hippocampal injury in
mice [74]. Similarly, TNF-a antagonist exacerbate the
disease in multiple sclerosis (MS), another autoimmune
demyelinating disease in CNS [75].
In addition, TNFR2 might also have a protective role as
demonstrated in another study from our group that TNF
Fig. 2 Effect of TNFR1 deficiency on the outcome of EAN. The
wild type mice (n = 22) and TNFR1-/- mice (n = 23) were
immunized with P0 peptide 180–199 in Freund’s complete adjuvant
(FCA) twice, at day 0 and day 7, and monitored for the development
of clinical EAN. The results are presented as mean values ± SD of
clinical scores P \ 0.05, P \ 0.01. Data are representative of four
separate experiments
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and TNFR2 increased after IVIg treatment in patients with
AMAN [64]. Interaction of TNF with TNFR2 promotes
expansion and function of mouse CD4?CD25? Tregs
[76]. More recently, TNF is found as an activator of
CD4?FoxP3?TNFR2? Tregs, which help terminate
immune response [77]. Moreover, TNF activates a NF-kB
regulated cellular program in human CD45RA-Tregs that
modulates their suppressive function [78].
Taken together, it seems that TNF-a might also have a
dual role in EAN and GBS. TNFR1 exerts most of the
inflammatory effects, while both TNFR1 and TNFR2 may
have protective effects, though the mechanism is not quite
clear.
IL-12 and IL-23
IL-12, mainly produced by phagocytes and dentric cells
(DC), is critical for the differentiation of Th1 cells. IL-12 is
a disulfide-linked heterodimer p70 complex composed of
p40 and p35 subunit. By promoting IFN-c production,
proliferation, and proliferation and cytolytic activity of NK
and T cells, IL-12 mediates cellular immunity [64, 79].
More recently it is found that Il-12p40 homodimer suppress
Treg cells via NO [80].
Additional treatment of EAN in mice and rats with
mouse recombinant IL-12 (mrIL-12) prolonged the course
of EAN characterized by earlier clinical signs and delayed
recovery stage [81, 82]. IL-12p40 deficient mice showed a
delayed onset, reduced incidence and severity of EAN.
Fewer IFN-c and TNF-a producing cells but more cells
secreting IL-4 were found in sciatic nerve from IL-12
deficient EAN mice.
In human, although numbers of IL-12p70 secreting
PBMCs were not affected over the course of GBS [83],
increased IL-12 and IL-12R on PBMCs were found in
serum of AIDP patients and decreased IL-12R after the
IVIg treatment [64].
These results indicate IL-12 has a major role in the
initiation, enhancement and perpetuation of pathogenic
events in EAN and GBS by promoting a Th1 cell-mediated
immune response and suppressing the Th2 response [16].
IL-23, a newly identified heterodimeric pro-inflamma-
tory cytokine and a novel IL-12 family member comprising
the p40 subunit of IL-12 but a different p19 subunit, has
been reported to preferentially act on memory T cells and
play an important role during cellular immune responses.
Recent evidence suggested that IL-23 rather than IL-12 is
critically involved in the pathogenesis of various immune-
mediated disorder including EAE [84, 85]. IL-23 induces a
population of IL-17-producing cells that is more critically
involved in EAE pathogenesis than Th1 cells [86].
IL-23 may play an essential role during the early ef-
fecter phase in immune-mediated demyelination of the
J Neurol (2011) 258:533–548
peripheral nerve [87]. IL-23p19 RNA increased prior to the
onset of first clinical symptoms and peaked expression
levels preceding maximum clinical disease during EAN. In
GBS patients, IL-23p19 protein was detectable in cere-
brospinal fluid (CSF) samples [87].
Recently, IL-27 and IL-35 belong to IL-12 family have
also been investigated. IL-27 not only induces Th1 dif-
ferentiation but also suppresses immune responses by
inhibition of Th17 cells development and induction of
IL-10 production. Administration of IL-27 or augmentation
of IL-27 signaling suppresses some autoimmune disease
such as RA, systemic lupus erythematosus (SLE) [88].
IL-35, composed of the IL-12p35 and EBI3, has been
newly identified as an anti-inflammatory cytokine [89].
However, roles of these two cytokines need to be explored
in EAN and GBS.
IL-1b
IL-1b is a member of the IL-1 gene family and synthesized
by MNC, mainly macrophages. It is also produced by SCs
in PNS [90]. Expression of IL-1b mRNA in lymph node
MNC and sciatic nerve section was observed prior to
clinical EAN, indicating IL-1b participate in initiating the
autoimmune response of EAN [13]. IL-1b can induce both
apoptosis and proliferation in cultured SCs, showing IL-1b
is not only involved in destruction of nerve, but also in the
regeneration [91]. Moreover, IL-1b might also contribute
to the neuropathic pain since impairment of IL-1 signaling
attenuates neuropathic pain, autotomy and spontaneous
ectopic neuronal activity, following nerve injury in mice
[92].
In GBS, increased expression of IL-1b was immune-
localized on SC membranes in sural nerve biopsies [93].
IL-1b could be detected in CSF of GBS [94], however,
serum IL-1b principally produced by macrophage, has
been observed in solely a minority of GBS patients [95].
IL-18
IL-18, is a member of the IL-1 family of pro-inflammatory
cytokines [96]. IL-18 enhances the IL-12-driven Th1
immune responses, but it can also stimulate Th2 immune
responses in the absence of IL-12 [97]. IL-18 serum levels
have been found to be increased in GBS patients and IL-18
was up-regulated in the nerve roots of EAN rats [98]. EAN
mice treated with anti-IL-18 monoclonal antibody exhib-
ited a reduced clinical severity of disease and impaired Th1
response in inflamed nerves [14]. However, our recent
study showed that IL-18 deficiency inhibit IFN-c, TNF-a
and IL-10 production but not the clinical symptoms in
EAN, suggesting IL-18 may act as a co-inducer of both
Th1 and Th2 cytokines in EAN and possibly in GBS [99].
537
IL-6
Mononuclear phagocytes, T cells, vascular endothelial
cells, SCs and other cells synthesize IL-6 in response IL-1
and/or, TNF-a IL-6 acts by binding to the IL-6 receptor
(IL-6-R), which can also exist as a soluble protein (sIL-6R).
The pleiotropic effects of IL-6 include inhibiting apoptosis
of auto-reactive T cells [100], BNB disturbance [13], reg-
ulating macrophage infiltration [101], B cell stimulation
[102]. Trans-signaling into T cells via the sIL-6R com-
pletely abrogates the generation of Treg cells [103, 104].
Like TNF-a and IL-1, IL-6 also contributes in neuropathic
pain [105].
Overproduction of IL-6 within the PNS or systemically
were found in EAN and IL-6 is up-regulated in serum and
CSF of GBS patients [94, 102, 106]. Intra-neural injection
of recombinant rat IL-6 (rrIL-6) into the sciatic nerve
induces high inflammation and severe demyelination in
EAN [107]. Clinical trials of tocilizumab, a humanized
anti-IL-6RmAb that blocks IL-6 signaling, have demon-
strated dramatic therapeutic benefit in RA [108, 109]. The
IL-6/sIL-6R complex has been seen as a novel target for
therapeutic approaches in inflammatory, autoimmune dis-
eases as well as cancer [110]. However, IL-6 might also
have an anti-inflammatory role in chronic EAN since nasal
administration of rrIL-6 in the initial phase decreased the
severity and the duration of clinical symptoms, accompa-
nied by reduced auto-antigen reactivity of T cells as well as
TNF-a production [18].
This potential neuro-protective action of IL-6 is also
shown in some other condition such as diabetes related
neuropathy [111]. Furthermore, IL-6 can enhance PMP22
production in SC via a JAK2-dependent pathway by
probably activating STAT3 and thus may contribute to
myelination [112]. IL-6R might be importantly involved in
not only SC proliferation but also re-myelination of the rat
sciatic nerve [113]. sIL-6R, besides acting as an agonist of
IL-6, has been found some other properties such as IL-6-
antagonistic effects, [114].
Consequently, IL-6, besides its pro-inflammatory role in
EAN and GBS, might have protective effects by reducing
TNF, IL-1 and remyelination and, etc.
IL-17 and IL-21
Currently, it appears that IL-17-producing T cells are
responsible for many of the inflammatory and autoimmune
responses once attributed to Th1 cells [115]. IL-17A, a pro-
inflammatory cytokine, was shown to be the hallmark
cytokine of this new T helper subset termed ‘‘Th17’’ [116].
A combination of TGFb1 and IL-6, together with IL-23
leads to generation of this CD4? T cell subtype. IL-17
might enhance TNF-a signaling by regulating TNF
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receptor [117]. It also protects B cells from apoptosis,
thereby increasing the number of autoantibody-producing
cells [118]. IL-17A deficiency or neutralization in vivo
attenuates EAE [119]. Th17-associated cytokines such as
IL-21 has been on spot as well. It might increase the Tregs
numbers and function, and also up-regulate the IL-10
expression. [120, 121].
But so far, the function of Th17 and its related cytokines
such as IL-17, IL-21 needs to be explored in EAN and GBS.
TGF-b
TGF-b family consists of TGF-b1, TGF-b2, TGF-b3, with
TGF-b1 being the predominant form expressed in the
immune system [122]. The potential principal cell sources
of TGF-b include Treg cells, APCs, leukocytes and B cells
[123].
The pivotal function of TGF-b is to maintain tolerance
via the regulation of lymphocyte proliferation, differenti-
ation, and survival. It also controls inflammatory response
by regulating chemotaxis, activation and survival of NK
cells, DCs and macrophages, etc. [124]. Furthermore, TGF-
b-driven APC exhibited the morphology, phenotypes and
functions of tolerogenic immature DC, and had lower
capacity to stimulate T cells [125, 126].
Recently TGF-b has been in spot because of its
emerging role in Treg and Th17 cells [20, 21]. TGF-b
production by Treg cells has also been suggested as an
important (if controversial) mechanism of suppression in
autoimmune response [21]. Actually, TGF-b1, by inducing
Treg cells, has potential clinical application in treating SLE
[127]. Local but not systemic antibody blockade of TGF-b
prevented Th17 cell differentiation and the onset of EAE
[128]. However, it has been suggested that the differenti-
ation of human Th17 cells is not associated with TGF-b,
even suppressed by TGF-b, thus differs fundamentally
from that in mice. TGF-b enhanced expression of Th17
transcription factor RORgammat but simultaneously
inhibited its ability to induce IL-17 expression [129, 130].
In peripheral tissues, similarly, TGF-b inhibits T cell
proliferation, activation and effecter T cells differentiation
and maintains Treg cells, thereby might contributing to
prevent the autoimmune disease. In fact, TGF-b1 in plasma
were decreased in the first days of the disease and associ-
ated with a loss of immune-regulatory function [131],
however, both TGF-b1 cytokine and mRNA level
increased during the recovery of GBS [132]. This switch in
the cytokine profile may instead precede the reversal of
clinical symptoms, which was also as noted in EAN [133,
134]. Accordingly, the level of TGF-b1 in serum of GBS
peaked in the plateau phase, i.e. before onset of recovery
and declined during recovery phase but still higher than
patients with non-inflammatory neurological diseases and
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healthy subjects [135]. Moreover, number of cells secreting
TGF-b is elevated in all phase of GBS, but was statistically
significant only in the acute phase [132].
The temporal relationship between increased levels of
TGF-b and the end of the progressive phase indicates that
TGF-b might have a role in terminating the pathological
immune response in GBS.
IL-10
IL-10 is produced by monocytes, macrophages, B cells,
Th2 cells and various subsets of CD4? and CD8? T cells.
Its dominant role is to be as an immunosuppressive cyto-
kine by inhibiting macrophage and DC function, including
cytokine production such as IL-1 and TNF-a, co-stimula-
tors and MHC expression, general APC function. IL-10 can
also inhibit T cell proliferation and promote humoral
immune responses enhancing class II expression on B cells
and Ig production including IgA [136]. Moreover, IL-10
plays a crucial role for Treg cell development [136].
Pathways leading to IL-10 production by different T cell
populations have been recently revealed and it is becoming
clear that some pro-inflammatory cytokines directly induce
IL-10, allowing immune responses to be inherently self-
regulating [137].
Administration of a low-dose of IL-10 permits better
regeneration of damaged axons [138]. SCs produce IL-10
that might counterbalance the pro-inflammatory cytokines
in reducing the neuropathic pain [139, 140]. Intrathecal
IL-10 gene therapy attenuates paclitaxel-induced mechan-
ical allodynia and pro-inflammatory cytokine expression in
dorsal root ganglia in rats [140].
In EAN, up-regulation of IL-10 mRNA expression was
seen in lymph node MNC and sciatic nerve on the onset of
EAN, and maximal expression at onset of clinical recovery
[13]. Treatment with IL-10 ameliorates the inflammatory
responses in EAN [19]. Amino acid copolymer-specific
IL-10-secreting Treg cells could ameliorate EAN [141].
In GBS, although serum IL-10 is un-elevated [29],
IL-10-secreting BMNC increased during the acute phase,
which may account for the self-limited clinical course of
GBS [29, 83]. On the other hand, Myhr et al. [142] reported
that GBS is related to IL-10 promoter polymorphisms and
IL-10 worsens the disease via enhancing the ganglioside
antibody production probably.
Altogether, the anti-inflammatory cytokine IL-10 has a
role in terminating the EAN and GBS, however, might also
worsen the disease by promoting the ganglioside antibody.
IL-4
IL-4 is produced by CD4? Th2 cells and participates in the
differentiation and growth of B cells. IL-4 promotes Th
J Neurol (2011) 258:533–548 539

cells towards a differentiation into Th2 phenotype through
intra-signaling factor STAT6. IL-4 inhibits the activation
of Th1 cells and this in turn, decreases the production of
IL-1 and TNF-a.
Increase of IL-4 in the recovery phase was shown by
detection of cytokine mRNA expression in EAN [133].
Nasal administration of rrIL-4 ameliorates ongoing EAN
and inhibits demyelination [107]. Self-limitation of acute
EAN may owe to the rising levels of IL-4 and IL-10 [143].
Serum IL-4 were also elevated during acute and recovery
stage of GBS [29, 144].
Thus, the anti-inflammatory cytokine IL-4 may have a
role in terminating EAN and GBS.
Chemokines
Chemokines are small cytokines that are involved in the
directed migrations (chemotaxis) and the activation of
cells, especially phagocytes and lymphocytes, and thereby
play a central role in inflammatory responses [145–147].
Chemokines such as MIP-1a, MCP-1, CCR2, RANTES
and IP-10 play an important role in the recruitment of
MNC into the PNS of EAN rats and GBS patients [148–
151]. Patients examined in the acute phase of GBS prior to
treatment with IVIg had elevated CSF levels of MCP-1 and
IP-10 [152]. The expression of CX3CL1 (fractalkine) and
its receptor CX3CR1 were also higher in EAN than in
control dorsal horns suggesting spinal microglia and
CX3CL1/CX3CR1 may play a role in the pain-like
behavior [153].
Therapies on cytokines in EAN and GBS (Table 1)
Modulation of cytokine pathway
IL-12 activated Th1 cells via the JAK2/STAT4 pathway,
whereas IL-4 activated Th2 cells via JAK1-3/STAT6 [154–
156]. Suppressors of cytokine signaling (SOC) act in a
negative feedback loop to suppress further JAK/STAT
signaling [157–159]. NF-kB and MAPK transcriptions are
also important in cytokine expression. The new anti-
depression drugs treated the sickness behavior’s animal
models and the patients suffered from depression can
inhibit inflammatory markers and SAPK/MAPK and/or
JAK/STAT signaling in vitro [160]. Many drugs targeting
NF-kB have been recently thought a promising molecular
therapy in autoimmune disease such as RA [161].
Administered at the time of immunization and on day 14th
post-immunization, immunosuppressive agent cyclophos-
phamide (CY) prevents clinical EAN and also reduces
cytokine and NF-kBp65 expression [162]. Inhibition of
ERK MAPK suppresses IL-23- and IL-1-driven IL-17
production and attenuates autoimmune disease [163]. More
recently, the signaling AKT axis becomes attractive for
therapeutic targeting in autoimmune disease [164].

Table 1 Possible therapies on EAN and GBS

Possible therapies intervention in GBS and EAN
Modulation of CK pathway JAK/STAT, NF-kB, MAPK, AKT axis
mAb and fusion protein sTNFR1, Anti-TNF-a mAb
IL-1bR antagonist
Anti-IL-6RmAb
Blocking IL-12/23
Blocking IFN-c
Neuroprotections Induce auto-reactive T cell apoptosis IFN-c, TNF-a, IL-6
Maintain Treg cell IFN-c, TGF-b, IL-10
Induce SC proliferation IFN-c, IL-1 b, IL-6
Reduce the neuropathic pain, enhance nerve repair IL-10
Counteract Th1 cells IL-10, IL-4
Increased GM1 specific T cell reactivity; down-regulation of macrophage function
Compounds applied in EAN Rolipram: down-regulate antigen-driven T cell proliferation, suppress TNF-a/b production
ABR-215062: regulation of Th1/Th2 cytokine balance, inhibited migration of inflammatory cells into the PNS
VPA: suppressed mRNA levels of IFN-c, TNF-a, IL-1b, IL-4, IL-6 and IL-17 in the lymph nodes
Minocycline: inhibit mRNA expressions of MMP-9, iNOS and proinflammatory cytokines IL-1b and TNF-a in
EAN sciatic nerves
Compound A: depressed Th1 and Th17 cytokines, but increased Th2 cytokine and Foxp3 expression in lymph
nodes of EAN rats
MS-275: suppressing inflammatory T cells, macrophages and cytokines

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Table 2 Cytokine type, cellular origin and pathogenetic relevance, role as biomarker in EAN and GBS
Cytokine Origin Function Biomarker in EAN and GBS
Inflammation Anti-inflammation EAN GBS

IFN-r T, NK cells Mø activation T cell apoptosis IFN-c producing cells Serum IFN-c was
T differentiation to Th1 Inhibit neutrophil trafficking parallel clinical EAN elevated
MHC I/II induction Convert CD4?CD25- cells Systemic administration of Auto-Abs to IFN-c are
into CD4? Treg cells rrIFN-c worsens EAN correlated with down-
B cell class switching regulation of IFN-c
Suppress the differentiation IFN-cR-/- mice showed a
Enhance CK suppression of EAN producing cells and
production such as and effector function of with improved clinical
TNF-a, IL-1b, IL-6, Th17 cells disability
as well as Microglia activated by IFN-
Convert peripheral
metalloproteinases, c or IL-4 can protect CD4?CD25- T cells
chemokines and neutrons and support both to CD4?CD25? Treg
adhesion molecules neurogenesis and cells
Up-regulates CK oligodendrogenesis
iNOS-specific mRNA
in SCs
TNF-a Mø, T cells, SCs, etc. Promotes macrophage Might decrease APC Might have effect on BNB Serum TNF-a was
recruitment function TNFR1-/- reduces APC elevated
Inhabits SC Might down-regulate T cell function of SCs and TNF-a converting
proliferation and receptor signaling ameliorates EAN enzyme increased
mediates SC death Might increase apoptosis of Implicated in SC apoptosis sTNFR1 increased while
TNFR1, a positive T- auto-reactive T cells in EAN TNF-a and TNFR1
cell costimulatory Activator of SC-derived TNF-a, a major decreased following
molecule for T cell CD4?FoxP3?TNFR2? mediator of hyper-algesia treatment
activation Tregs, which help TNF and TNFR2
TNFR1-/- EAN mice
terminate immune showed more severe increased after IVIg
response clinical signs, with treatment
enhanced infiltrating TNF–TNFR2 promotes
inflammatory cells, T expansion and function
proliferation, and MHC of mouse Tregs
and CCR 3 expression on
Mø
IL-12 Mainly phagocytes Differentiation of Th1 mrIL-12 treatment Increased IL-12 and IL-
and DC cells prolonged EAN course 12R on PBMCs were
Promoting IFN-c IL-12p40-/- mice showed found in serum of
production, a delayed onset, reduced AIDP patients and
proliferation incidence and severity of decreased IL-12R after
EAN the IVIg treatment;
Proliferation and
cytolytic activity of Fewer IFN-c and TNF-a
NK and T cells producing cells, but more
IL-12p40 homodimer cells secreting IL-4 were
suppress Treg cells found in IL-12-/- EAN
via nitric oxide mice
IL-23 A novel IL-12 family Act on memory T cells IL-23p19 RNA increased IL-23p19 protein was
member and play an important prior to the onset of detectable in CSF
role during cellular clinical symptoms and
immune responses peaked preceding
May play an important maximum clinical disease
role during the early
effecter phase in
immune-mediated
demyelination of the
peripheral nerve
IL-1b MNC, mainly Mø, also Induce SC apoptosis Induce SC proliferation IL-1b mRNA in lymph node IL-1b could be detected
SC Contribute to the MNC and sciatic nerve in CSF
neuropathic pain section was observed prior Increased IL-1b was
to clinical EAN immunolocalized on
SC membranes in sural
nerve biopsies

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Table 2 continued
Cytokine Origin Function Biomarker in EAN and GBS
Inflammation Anti-inflammation EAN GBS

IL-18 A member of the IL-1 Enhances the IL-12- IL-18 was up-regulated Serum IL-18 increased
family of pro- driven Th1 responses, Anti-IL-18 Ab reduced
inflammatory CK, as well as Th2 clinical severity and Th1
produced in many responses in the response
cells including Mø, absence of IL-12
endothelial cells, DC, IL-18-/- inhibit IFN-c,
etc. TNF-a and IL-10
production but not clinical
symptoms
IL-6 Mononuclear Inhibites apoptosis of Enhance PMP22 production Overproduction of IL-6 IL-6 is up-regulated in
phagocytes, T cells, auto-reactive T-cells in SC, thus may contribute within the PNS or serum and CSF of
vascular endothelial BNB disturbance to myelination systemically patients
cells, SCs and other IL-6R might be involved in Nasal administration of rrIL-
cells Regulates Mø
infiltration SC proliferation and re- 6 in initial EAN decreased
myelination of the rat severity and duration; but
B cell stimulation; sciatic nerve intra-neural injection of
contributes in rrIL-6 into the sciatic
neuropathic pain sIL-6R, also have IL-6-
antagonistic effects nerve induced high
IL-6/sIL-6R complex inflammation and
abrogates the demyelination
generation of Treg
cells
TGF-b Treg cells, APCs, Maintain tolerance by Decreased in the initial Decreased in the initial
leukocytes and B regulating differentiation, stage, TGF-b1 cytokine stage, TGF-b1
cells survival of lymphocyte, as and mRNA level increased cytokine and mRNA
well as NK cells, DCs, Mø during the recovery level increased during
and chemotaxis the recovery, peaked in
TGF-b-driven APC plateau phase
exhibited lower capacity to Number of cells
stimulate T cells secreting TGF-b is
Human Th17 cells are not elevated in all phase,
associated with TGF-b, but significant in acute
even suppressed by it stage
IL-10 Monocytes, Mø, B Inhibit Mø and DC function, Up-regulation of IL-10 Serum IL-10 is un-
cells, Th2 cells, including CK production mRNA expression was elevated, however, IL-
various subsets of such as IL-1 and TNF-a, seen on the onset and 10-secreting BMNC
CD4? and CD8? T co-stimulators and MHC maximal expression at increased during the
cells expression, general APC onset of clinical recovery acute phase
function Treatment with IL-10 IL-10 worsens the
Inhibit T cell proliferation ameliorates EAN disease via enhancing
and promote humoral Amino acid copolymer- the ganglioside Ab
immune responses specific IL-10-secreting production probably
enhancing class II Treg cells ameliorate EAN
expression on B cells and Ig
production including IgA
Treg cell development
Administration of a low-
dose of IL-10 permits
better regeneration of
axons
SCs produce IL-10 reducing
the neuropathic pain
Intrathecal IL-10 gene
therapy attenuates
paclitaxel-induced
mechanical allodynia and
pro-inflammatory CK
expression in dorsal root
ganglia in rats

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Table 2 continued
Cytokine Origin Function Biomarker in EAN and GBS
Inflammation Anti-inflammation EAN GBS

IL-4 CD4? Th2 cells Promotes Th cells towards a mRNA expression of IL-4 is Serum IL-4 were
differentiation into Th2 shown in the recovery elevated during acute
Inhibits the activation of phage of EAN and recovery stage
Th1 and decreases the Nasal administration of rrIL-
production of IL-1 and 4 ameliorates EAN and
TNF-a inhibits demyelination
Mø, macrophage; -/-, knockout; CK cytokine

Neutralization of cytokines 3. Valproic acid (VPA): a short-chain branched fatty,

Blockade of cytokine by monoclonal antibody or fusion
proteins have been investigated. Exogenous sTNFR1
ameliorates murine EAN [52]. Anti-TNF-a mAb and
sTNFR, IL-1bR antagonist, anti-IL-6RmAb have effi-
ciency in treatment of autoimmune disease such as RA
[165]. Drugs such as ABT-84, Apilimod, CNTO-1275 that
block IL12/IL23 are being tested clinically in disease such
as Crohn’s disease, psoriasis, RA, MS [166–168]. Although
absence of IFN-c causes worse EAE in some studies [169,
170], antibody to IFN-c not TNF-a showed significantly
improvement in MS [171]. Skurkovich [172] indicated that
cytokines act in an interrelated immune cascade with IFN-c
playing a central role, blocking IFN-c is the safest and most
effective method of treatment of Th1-mediated autoim-
mune diseases, although blocking other cytokines in the
cascade may lead to some therapeutic effects as well.
Cytokines for neuroprotection and regeneration
IFN-c, TNF-a, IL-6 induce auto-reactive T cell apoptosis;
IFN-c, TGF-b, IL-10 maintain Treg cell; IL-1, IL-6, IFN-c
induce SC proliferation; IL-10 reduces the neuropathic
pain, enhance nerve repair, etc. More recently, patients
with increased anti-GM1 T cell reactivity were signifi-
cantly less severe than those without such reactivity. This
raises the possibility that increased GM1 specific T cell
reactivity and its related cytokine might have an immune-
regulatory or neuro-protective role [173].
Reagents applied in EAN treatment
1. Rolipram: markedly down-regulate antigen-driven T
cell proliferation and suppress TNF-a/b production in
vitro and in vivo, which have led to its use in the
treatment of EAE and EAN [174, 175].
2. ABR-215062: immune regulator derived from Lino-
mide, could suppress EAN by regulation of Th1/Th2
cytokine balance and inhibited migration of inflam-
matory cells into the PNS [176].
effectively suppress inflammation in EAN [177]. VPA
administration to EAN rats significantly suppressed
mRNA levels of IFN-c, TNF-a, IL-1b, IL-4, IL-6 and
IL-17 in the lymph nodes. In peripheral blood and
sciatic nerves of EAN rats, Foxp3(?) cells increased
but IL-17(?) cells decreased during VPA treatment.
4. Minocycline: obviously inhibit mRNA expressions of
MMP-9, iNOS and proinflammatory cytokines IL-1b
and TNF-a in EAN sciatic nerves. It is very clear that
Minocycline could effectively apply in the conditions
with the peripheral and spinal inflammation to improve
outcome and attenuated mechanical allodynia in EAN
rats [178].
5. Compound A: a plant-derived phenyl aziridine pre-
cursor, depressed Th1 and Th17 cytokines, but
increased Th2 cytokine and Foxp3 expression in
lymph nodes of EAN rats [179].
6. MS-275: a potent histone deacetylase inhibitor, could
effectively suppress inflammation in EAN, through
suppressing inflammatory T cells, macrophages and
cytokines [180].
Conclusions
Cytokines in EAN and GBS have been extensively studied
these years and sometimes the conflicting results make it
more complicated (Table 2). Besides the complexity of the
cytokines themselves, this is partly due to the different
methods used and aspects of cytokines observed in the
animal model and clinical studies. Agents that block the
egress of T cells across the BNB and agents that antagonise
T cell cytokine-induced priming of macrophages may prove
efficacious [5]. However, in recent years, the traditional
inflammatory cytokines such as IFN-c, TNF-a, IL-6 and IL-1
are also found to have a protective role in EAN and GBS,
although the exact mechanism remain elusive. They might
exert their dual roles through different signal ways in vari-
ous conditions. Therefore, therapies on cytokines especially

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by regulating their pathways are important and promising.
Treg cells are becoming increasingly attentive due to their
suppressive roles in EAN and GBS. Moreover, Th17 and
some cytokines such as IL-17, 21, 27, 35 are on spot pres-
ently in autoimmune diseases, though their possible roles in
GBS need to be further explored.
Acknowledgments The studies of the authors referred to in this
review were supported by grants from the Swedish Research Council
(K2007-62X-13133-09-3) and from ALF-project grant of Karolinska
Institute University Hospital, Stockholm, Sweden and grant from
Swedish Medical Association.
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