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Mediators of Inflammation
Volume 2015, Article ID 564098, 12 pages
http://dx.doi.org/10.1155/2015/564098
Review Article

Biomarkers of Guillain-Barré Syndrome: Some Recent Progress, More Still to Be Explored

1Neuroscience Center, Department of Neurology, The First Hospital of Jilin University, Changchun 130000, China
2Department of Neurology, Heilongjiang Provincial Hospital, Harbin, China
3Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden

Received 28 June 2015; Revised 23 August 2015; Accepted 24 August 2015

Academic Editor: Jagadeesh Bayry

Copyright © 2015 Ying Wang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Guillain-Barré syndrome (GBS), the axonal subtype of which is mainly triggered by C. jejuni with ganglioside-mimicking lipooligosaccharides (LOS), is an immune-mediated disorder in the peripheral nervous system (PNS) accompanied by the disruption of the blood-nerve barrier (BNB) and the blood-cerebrospinal fluid barrier (B-CSF-B). Biomarkers of GBS have been extensively explored and some of them are proved to assist in the clinical diagnosis and in monitoring disease progression as well as in assessing the efficacy of immunotherapy. Herein, we systemically review the literature on biomarkers of GBS, including infection-/immune-/BNB, B-CSF-B, and PNS damage-associated biomarkers, aiming at providing an overview of GBS biomarkers and guiding further investigations. Furthermore, we point out further directions for studies on GBS biomarkers.

1. Introduction

Guillain-Barré Syndrome. Guillain-Barré syndrome (GBS) is an immune-mediated disorder in peripheral nervous system (PNS) and experimental autoimmune neuritis (EAN) serves as a main animal model of GBS. GBS is typically triggered by antecedent infections and C. jejuni is blamed for at least one-third of these infections. Nevertheless, only one in 1,000–5,000 patients with Campylobacter enteritis will develop GBS [1, 2] and GBS patients with the same type of infection can have distinct clinical manifestations. Thus, both infection and host factors may influence the pathogenesis and the development of GBS.

The cardinal step in the development of GBS is exerted by the immune response. A subset of C. jejuni strains contains lipooligosaccharides (LOS), a kind of carbohydrate structure located on the outer membrane, which mimic the gangliosides in human. Autoantibodies that cross-react with gangliosides are provoked by antecedent infections and attack the PNS by activating complements [3]. Furthermore, the unbalance of Th1/Th2/Th17/Treg and M1/M2 is observed in both GBS and EAN [4]. Cytokines, chemokines, complements, and other immune- and inflammatory-associated factors are also proved to play an essential role in GBS and EAN [5]. Nerve biopsy studies demonstrate segmental demyelination and axonal degeneration as well as infiltration of macrophages, lymphocytes, and mast cells in the endoneurium of nerves in the PNS [6].

Damage to the PNS and the barriers, including the blood-nerve barrier (BNB) and the blood-cerebrospinal fluid barrier (B-CSF-B), is the pathological feature of GBS. BNB and B-CSF-B are barriers between blood and nerve/CSF that maintain a relatively stable environment to nerve/CSF. Distinct types of peripheral nerves damage address GBS as a highly diverse spectrum of clinical manifestations. A rapidly progressive, symmetrical weakness of the limbs in combination with hyporeflexia of areflexia is the clinical character of GBS [3]. Some of the GBS patients are also accompanied by cranial nerve involvement, sensory deficits and ataxia and may suffer from pain and autonomic dysfunction [3]. GBS is divided into two major subtypes: acute inflammatory demyelinating polyneuropathy (AIDP) and axonal subtypes including acute motor axonal degeneration neuropathy (AMAN) and acute motor and sensory axonal neuropathy (AMSAN). Nerve conduction studies (NCS) can help discriminate these subtypes of GBS in clinic.

Overview of Biomarkers for GBS. A biomarker is a characteristic that can be objectively measured and evaluated as an indicator of a physiological as well as a pathological process or pharmacological response to a therapeutic intervention. The diagnosis of the GBS is still challenging due to the lack of a single specific diagnostic test, which in some cases leads to a delay in the correct diagnosis and hence in the initiation of immunomodulatory treatment against GBS. The diagnosis of GBS is rather based on a combination of clinical features, NCS and analysis of the CSF at present [3]. However, the variety of clinical manifestations as mentioned above may mislead the diagnosis and NCS/CSF examination fails to show the abnormity at an early stage of the disease [3]. Lack of specific biomarkers that could eventually assist in the clinical diagnosis and in monitoring disease progression as well as the efficacy of immunotherapy has been a serious problem in GBS.

Serum, CSF, and peripheral nerve tissue are the main sources of biomarkers for GBS. It is noteworthy that the CSF is the most important source of biomarkers. Proximal nerve roots located in the subarachnoid region are floating freely in CSF and are in close contact with CSF. Therefore, the altered protein content of CSF could mirror the damage within the tissue of the nervous system [7]. Moreover, the dysfunction of B-CSF-B and BNB also permits CSF to serve as an essential source of biomarkers. B-CSF-B damage results in an alteration of CSF flow rate that modulates the protein content in CSF [8] and BNB lesion leads to the influx of serum proteins into the CSF [7]. Furthermore, the intrathecal synthesis of proteins also contributes to the changes of protein content in CSF.

At present, a growing number of studies focus on biomarkers in GBS. Although Johannes Brettschneider et al. first systemically reviewed the studies of GBS biomarkers published until October 2007, they only took CSF biomarkers into consideration. A panoramic review of biomarkers in GBS is still lacking. Herein, we summarize the studies of infection-, immune-, and BNB, B-CSF-B, and PNS damage-associated biomarkers in GBS to provide an outlook of GBS biomarkers.

2. Biomarkers of GBS (Table 1)

2.1. Infection-Associated Biomarkers

Only a subset of C. jejuni strains containing ganglioside-mimicking LOS could trigger GBS and the synthesis of LOS is controlled by a set of polymorphic genes and enzymes that vary greatly between different C. jejuni strains [3].

Table 1: Biomarkers in GBS.
2.1.1. LOS, Serotype, and Sequence Type of Campylobacter as Biomarkers

The gene contents of LOS loci are divided into eight classes (classes A to H). The expression of classes A, B, C, E, F, and H loci was found in GBS-associated C. jejuni [9, 10]. The Thr51 variant of C. jejuni cst-II gene that determined the structure of LOS was associated with the occurrence of GBS while the Asn51 variant was associated with MFS [11]. Moreover, Campylobacter strains with Penner heat-stable (HS) serotypes, including HS:1, HS:2, HS:4, HS:19, HS:23, and HS:41, were overrepresented among the strains isolated from GBS patients [2, 12, 13]. Furthermore, relatedness between sequence type 22 complex and GBS isolates was suggested [14].

2.1.2. C. jejuni DNA-Binding Protein from Starved Cells (C-Dps)

A high level of C-Dps is produced to protect bacterial DNA from damage under the condition of oxidative or nutritional stress via specifically binding to the sulfatide that is important for the maintenance of the ion channels on myelinated axons and for paranodal junction formation. Recently, C-Dps was elucidated as a potential contributor to the peripheral nerve insult in GBS. After C-Dps was injected into the rat sciatic nerves, it densely binds to the myelin sheath and the nodes of Ranvier. And NCS disclosed a compound muscle action potential amplitude reduction [15]. Anti-C-Dps IgG was detected in C. jejuni-related GBS patients but not in healthy controls (HCs) or in patients with OIND. The frequency of production of anti-C-Dps IgG in C. jejuni-related GBS patients was significantly higher than that in C. jejuni enteritis patients without GBS (62.5% versus 9%). C-Dps was also found in serum of some C. jejuni-related GBS patients (14.8%) [16].

2.2. Immune-Associated Biomarkers

LOS of C. jejuni activates the innate immune response via interacting with immunoglobulin-like receptor LMIR5, TLR 4, and sialic acid-specific receptors which are involved in the DC-mediated Th cell differentiation and B cell proliferation [1719]. Furthermore, an intricate immune network has been addressed with a crucial role in the pathogenesis and the development of GBS [4] (Figure 1).

Figure 1: Axonal damage type of GBS is triggered by a subset of C. jejuni containing ganglioside-mimicking LOS on outer membrane. Immune response to C. jejuni induces the unbalance of Th1/Th2/Th17/Treg and cytokines that is crucial for the development of GBS. Chemokines are responsible for the infiltration of immune cells and complements activated by antibodies could mediate PNS lesion. Damage of barriers and PNS permits CSF to serve as an important source of biomarkers. Structural molecules of PNS, including myelin sheath molecules and neuron molecules, are released to CSF due to the damage of PNS and may provoke further immune response. Disturbance of BNB also results in an alteration of protein content in CSF due to blood protein influx.
2.2.1. Gene Polymorphisms

FcγR is a family of cell-surface molecules linking humoral and cell-mediated responses. It is expressed on almost all immune cells and plays a key role in defending against pathogens. It showed that the leukocyte degranulation and phagocytosis in GBS could be induced/blocked by anti-GM1 IgG/IVIg via FcγR that are localized on Schwann cells (SCs) and perineurial cells [20, 21]. Several studies have documented the relationship between FcγR/FcRL gene polymorphism and GBS. Among others, human leukocyte FcγR genes are divided into three classes: FcγRI, FcγRII, and FcγRIII. FcγRIIa, FcγRIIb, FcγRIIIa, and FcγRIIIb were found to be associated with the severity of GBS [22, 23]. The frequencies of expression of FcRL3-3-169C, FcRL3-6 intron 3A, and FcRL3-8 exon 15G alleles were significantly higher in GBS patients compared with HCs [24].

Studies on the relationship between the gene polymorphism of human leukocyte antigen (HLA) complex and GBS have elucidated that the frequencies of DQbeta 060x, DR03:01, DR07:01, DR01:01, DRB14/DQB05, and DRB13/DQB03 HLA genotypes were increased in GBS patients while the frequency of DR6 HLA genotype was elevated in control group [2527]. Furthermore, HLA-DRB01, HLA-DQA0301, and HLA-DQA0302/HLA-DQB03 were found to be related to mechanical ventilation, anti-GM1 IgG levels, and recent C. jejuni infection, respectively [2830]. DQBRLD55–57/E epitopes, DRβE9V11H13 epitopes, and HLA-DRB1301 allele were found to be associated with the development of AIDP while the DQβRPD55–57 epitopes were found to be associated with the protection from AIDP [31, 32]. In AMAN patients, the frequencies of HLA-DRB1301-03 and HLA-DRB1312, taken collectively, were increased [32].

Gene polymorphisms of other important molecules in GBS were studied as well. It has been documented that CD101/02 and CD101/02 genotypes, A(-670)G single nucleotide polymorphism in the promoter region of CD95, TNF-α308 G/A and 857 C/T polymorphisms, mannose-binding lectin H allele/HY promoter haplotype/HYA haplotype, macrophage mediators SNPs, TCR Vβ and Vδ genes, CD95 A(-670)G SNP, TLR 4 Asp299Gly polymorphism, killer-immunoglobulin-like receptor genotype, and glucocorticoid receptor genotype were related to GBS [28, 3339].

2.2.2. Cytokines

Cytokines are polypeptides that play a fundamental role in initiating, propagating, and regulating tissue-specific autoimmune injury (Figure 1). They act as signal molecules in an autocrine or paracrine fashion between cells of the immune system.

IFN-γ has a dual role in GBS. On the one hand, to date, most studies have addressed IFN-γ with a proinflammatory role in EAN and GBS. Clinical disability of GBS patients was positively correlated with the elevated serum level of IFN-γ and was improved after treatment with intravenous immunoglobulin (IVIg) [40]. On the other hand, recent evidence that IFN-γ could convert peripheral CD4(+)CD25 T cells to CD4(+)CD25(+) regulatory T cells in GBS [41] and IFN-γ deficiency exacerbated EAN via upregulating Th17 cells despite a mitigated systemic Th1 immune response [42] defined an anti-inflammatory role for IFN-γ.

It seems that TNF-α plays a dual role in GBS as well. The proinflammatory function of TNF-α was identified by the association between the increased serum TNF-α levels and the severity of GBS [40]. In addition, treatment with IVIg significantly reduced the levels of plasma TNF-α and TNFR1 while enhancing the levels of sTNFR1—an antagonist of TNF-α [40, 43]. However, TNFR2 might have a protective role in GBS as well. As demonstrated in another study, serum TNFR2 was increased after IVIg treatment in patients with AMAN [44]. It was demonstrated that TNF-α secretion was associated with the altered balance of different subtypes of macrophages in EAN [45].

IL-17 and IL-22 secreted by Th17 cells play a critical role in inflammatory disease and mucosal host defense. In GBS, plasma IL-17A and IL-22 levels were markedly elevated during the acute phase and the IL-17A concentration was reduced after IVIg therapy [46]. Both plasma and CSF IL-17A levels were positively correlated with the GBS disability scale scores [40]. In EAN, IL-17A expressed in the sciatic nerves was significantly downregulated by AUY954 treatment [47]. Administration of recombinant IL-17A provoked the infiltration of inflammatory cells into the sciatic nerves and induced more severe demyelination in EAN [48].

IL-18 was overexpressed in the nerve roots of EAN animals [49]. EAN mice exhibited attenuated clinical severity and impaired Th1 response in inflamed nerves when treated with anti-IL-18 monoclonal antibody [50]. However, more recent study elucidated that IL-18 deficiency in EAN inhibited the production of IFN-γ, TNF-α, and IL-10 but not the clinical severity. It indicated that IL-18 may act as a coinducer of Th1 and Th2 cytokines in EAN [51]. Preliminary data support elevation of IL-18 levels in serum of GBS patients [49].

For other cytokines, IL-1β was immunolocalized on the membranes of SCs in sural nerves [52] and IL-1β was detected in the CSF of GBS patients. For anti-inflammatory cytokine IL-4, its upregulation in the recovery phase defined it with a role in terminating EAN and GBS [53, 54]. Similarly, IL-10 also helped terminate GBS/EAN; however, it might worsen the disease by promoting the generation of anti-ganglioside antibodies [5557]. IL-6 was found to be upregulated in serum and CSF of GBS patients [58, 59]. Intraneural injection of recombinant rat IL-6 induced high inflammation and severe demyelination in EAN [60]. IL-12 was reported to have a major role in the initiation, enhancement, and perpetuation of pathogenic events in both EAN and GBS by promoting Th1 cell-mediated immune response while suppressing the Th2 response [44, 61]. IL-16 was suggested to be a pathological contributor to EAN due to a strong correlation of IL-16+ cell accumulation with local demyelination in perivascular areas of sciatic nerves [62]. IL-23 might play a cardinal role during the early and acute phase of EAN. IL-23 was detectable in CSF samples of GBS patients [5]. The plasma and CSF levels of IL-37 in GBS patients at the acute phase were significantly higher than HCs, and treatment with IVIg significantly reduced the serum levels of IL-37 [40]. Interestingly, TGF-β1 levels in plasma were decreased at the onset of GBS [63] while they were increased during the recovery phase [64]. However, the number of TGF-β secreting cells was elevated in all phases of GBS [64].

Additionally, some cytokines such as IL-21, IL-27, and IL-35 that play an important role in other autoimmune diseases may be the biomarkers for GBS. Further studies are needed to explore their possible roles in GBS.

2.2.3. Complements

Complements are another group of candidates for GBS biomarkers (Figure 1). In the presence of complements, serum from GBS patients exhibited demyelinating activity both in vitro and in vivo [65, 66]. A growing body of evidence pointed out that complements activated by the anti-ganglioside autoantibodies disrupted sodium channel clusters, paranodal axoglial junctions, the nodal cytoskeleton, and microvilli of SCs in GBS [67]. Furthermore, the blockade of complements activation by IVIg treatment or anti-complements antibodies prevented the formation of membrane attack complex (C5b-9) and the emergence of clinical signs [68, 69].

The presence of C3 in PNS was observed in both GBS and EAN. A proteomic study addressed an enhanced C3 level in CSF [70]. Complement activation marker C3d was localized on the outer surface of the SCs in GBS patients and C3d-positive fibers were found with vesicular changes on the outermost myelin lamellae [71]. C3d binds to the nodal axolemma of motor fibers in AMAN and to the myelinated internodes in more severe cases [72]. Similar results appeared in animal studies [73]. C5b-9 activated by anti-ganglioside antibodies mediated a direct injury to peripheral nerves. SC5b-9, an inactive isoform of C5b-9, was detected in both serum and CSF of GBS patients [74, 75]. Deposits of C5b-9 on SCs, myelin sheaths, macrophages, and endothelial cells were shown in GBS and EAN as well [76]. Notably, deleterious effects of complements could be prevented by eculizumab which blocked the formation of human C5a and C5b-9 [68].

2.2.4. Chemokines

Chemokines are low-molecular-weight (8–14 kDa) cytokines that are involved in the directed migrations (chemotaxis) across concentration gradients and the activation of immune cells. Chemokines are classified into 4 subfamilies based on the organization of two conserved cysteine residues: CC, CXC, CX3C, and C subfamilies. Multiple lines of evidence point out that the chemokines are involved in the immune response of GBS patients.

CCL2 was expressed on SCs, infiltrating cells and blood vessels with its receptor CCR2 expressed on macrophages and lymphocytes. CCL2, the secretion of which was stimulated by TNF-α, was postulated to facilitate the trafficking of autoreactive leucocytes across the BNB in GBS [77]. High expression of CCL2 and CCR2 was observed in the sciatic nerves of severe EAN [78]. In GBS, the circulating CCL2 levels were elevated at the acute phase and peaked at the time of plateau but normalized at the recovery stage [79].

The peak number of CCL3 positive cells was seen in the sciatic nerves of EAN 14 days after onset and was correlated with the severe clinical presentations. Anti-CCL3 antibody was demonstrated to attenuate the severity of EAN and inhibit the inflammation and demyelination in sciatic nerves. CCR1 and CCR5 expressed by endoneurial macrophages with CCL5 colocalizing to axons were increased on sciatic nerves of EAN and GBS [78, 80]. The levels of CX3CL1/CX3CR1 were higher in dorsal horns of EAN and CX3CL1 CSF/serum ratios were observed to be elevated in GBS [81, 82]. The number of CXCL2 positive cells reached a maximum of 21 days after immunization; however, anti-CXCL2 antibody failed to diminish the clinical severity of EAN [83]. CXCL10 was localized on the endoneurial endothelial cells and within the endoneurial interstitium, with its receptor CXCR3 on lymphocytes [78]. CXCL10/CXCR3 levels were significantly increased in the sciatic nerves of EAN [78] and the enhanced CSF levels of CXCL10 were measured in GBS patients [84]. The median CSF concentrations of CCL7, CCL27, CXCL9, and CXCL12 were also higher in GBS [84].

Additionally, other immune-related biomarkers are listed in Supplementary Table (in Supplementary Material available online at http://dx.doi.org/10.1155/2015/564098).

2.3. BNB, B-CSF-B, and PNS Damage-Associated Biomarkers
2.3.1. BNB and B-CSF-B Damage-Associated Biomarkers

The protein content in CSF is altered in GBS patients due to B-CSF-B/BNB disturbance and intrathecal synthesis of proteins. 80% of the proteins in CSF are blood derived with the other 20% being brain derived. There are mainly three types of brain-derived proteins in CSF with different sources, including protein originating from neurons and glial cells, proteins released from leptomeninges, and proteins with a nonnegligible blood-derived fraction in CSF [8]. A reduced CSF flow rate caused by B-CSF-B dysfunction influences the molecular flux in CSF [8]. BNB insults permit circulation proteins influx into CSF. Intrathecal synthesis of proteins obviously contributes to the protein content alteration in CSF and it could be measured with CSF index of protein x. CSF index of protein x is calculated as (CSF level of protein x/plasma level of protein x)/(CSF level of albumin/plasma level of albumin). Although the alterations of many biomarkers mentioned above and PNS damage-associated biomarkers discussed in the next subtitle are also due to the damage of barrier, we will review some other barriers damage-associated biomarkers in this section.

(1) Brain-Derived Proteins. A combination of elevated total protein (TP) level and normal cell counts in the CSF may be regarded as the first CSF biomarker for GBS. The elevation was directly associated with the time point of performing lumbar puncture [85].

Prealbumin is synthesized predominantly by parenchymal cells of the liver and then secreted into the plasma. However, the prealbumin in CSF originates mainly (90%) from the choroid plexus in the ventricles. The levels of the prealbumin in both plasma and CSF were elevated in patients with GBS; nevertheless, the CSF index of prealbumin was decreased [86]. In contrast, another study elucidated that CSF prealbumin levels were reduced at admission and were associated with greater clinical severity [87]. Transthyretin, the former prealbumin, in CSF originates predominantly from the choroid plexus; however, a small blood-derived fraction of about 10% can be calculated to contribute to the concentration in CSF. The study of transthyretin in CSF showed controversial results. Proteome study demonstrated downregulated levels of transthyretin [70] while ELISA analysis reported upregulated levels [88].

S100B is a calcium-binding protein originating from glial cells. It was reported to be upregulated in the CSF of GBS patients and was correlated with the GBS disability scale scores in AIDP as well as with months to recovery [89, 90]. Cystatin C is produced by all nucleated cells and is primarily secreted from choroid plexus into CSF. Cystatin C in CSF can be regarded as brain derived with no more than 1% from serum. It was proved by both ELISA and proteome study that cystatin C levels were decreased in CSF of GBS patients [91, 92]. Prostaglandin D(2) synthase is an abundant brain protein in CSF and it is tied closely with inflammatory processes. The concentration of prostaglandin D(2) synthase was significantly increased in the CSF, whereas the intrathecal synthesis was significantly decreased in AIDP patients [93]. Hypocretin-1 is a hypothalamic originated neuropeptide. The levels of hypocretin-1 were moderately downregulated in early stage of GBS and were associated with central nervous system abnormalities [94].

(2) Blood-Derived Proteins. Haptoglobin is a plasma protein with haemoglobin-binding capacity and is a positive acute-phase protein that functions as an inhibitor of prostaglandin synthesis and angiogenesis. Proteomic study revealed that the expression of haptoglobin was enhanced in CSF of GBS patients [91]. This result was consistent with the result of another study using ELISA [86]. Fibrinogen is a plasma glycoprotein involved primarily in the blood clotting cascade. Preliminary data of fibrinogen concentration in CSF was contradictory. One study demonstrated decreased concentrations of fibrinogen [95], whereas the other reported elevated levels with decreased CSF index of fibrinogen [86]. Additionally, proteomic studies also demonstrated enhanced Apo A-IV, ApoH, vitamin D-binding protein, and α-1-antitrypsin levels in CSF of GBS patients [70, 91, 95].

2.3.2. PNS Damage-Associated Biomarkers (Figure 1)

(1) Myelin Sheath-Associated Markers. Gangliosides are a group of glycosphingolipids characterized by the presence of one or more sialic acid residues in the oligosaccharide chain. Anti-ganglioside antibodies are often closely associated with clinical phenotypes and specific clinical signs of GBS. This association is likely to depend upon the diverse distribution of ganglioside antigens in the PNS. The antigens targeted are located at or near the nodes of Ranvier in AMAN and on myelin sheath in AIDP. The antibodies can activate complements that provoke the formation of C5b-9. Interestingly, excepting antibodies against single gangliosides, patients can also have antibodies against the combination of epitopes from ganglioside complexes (GSCs). Such complexes are located in specialized microdomains or “lipid rafts” in the cell membranes [3]. In total, IgG and IgM were the most frequent types of antibodies to ganglioside [109]. Seropositive patients were more frequently involved with preceding diarrhea and pure motor neuropathy [109, 110]. IgG1 was related to diarrhea and poor outcomes while both IgG1 and IgG3 were related to upper respiratory tract infections and better outcomes [110]. Associations between antecedent infections, subtypes of GBS, clinical manifestations, and the types of antibodies to ganglioside are listed in Table 2.

Table 2: Autoantibodies to gangliosides and their association with GBS.

Neurofascin and gliomedin are neuronal cell adhesion molecules that play a central role in the formation of nodes of Ranvier and are considered as novel target antigens in GBS. Investigations reported the detectable autoantibodies to neurofascin and gliomedin in both GBS and EAN [111, 112]. In EAN, it is pointed out that the immunity to neurofascin and gliomedin was prior to the demyelination. They also induced progressive neuropathy characterized by the deposition of autoimmune antibodies and the defects of conduction [112, 113].

P2, P0, PMP22, and connexin 32 are peripheral myelin proteins, and both P2 and P0 are used to induce EAN. Antibodies to P0, PMP22, P214–25, and connexin 32 were detected in GBS patients [114116]. α6β4 is a laminin receptor that mediates the recognition and attachment to extracellular matrix proteins in SCs and myelin. α6β4 immunoreactivity was detected in 66% of GBS patients [117]. Anti-phospholipid antibodies were detected in GBS patients and were downregulated by IVIg [118]. Patients with Gal-C-GBS were more frequently involved with sensory deficits, autonomic dysfunctions, and antecedent Mycoplasma pneumonia infections [119].

(2) Neuron-Component-Associated Biomarkers. Neurofilaments are cytoskeletal proteins that are particularly abundant in large myelinated axons. Their release into the CSF addressed them as a promising biomarker for neurodegeneration. The CSF neurofilaments levels were increased in GBS patients, positively correlated with the GBS disability scale scores in AMAN, and predicted the clinical/electrophysiological outcomes of GBS [89, 120]. Moreover, enhanced neurofilament levels were seen in the corresponding serum samples as well [121].

Tau proteins modulate assembly and stability in axonal damage marker. Tau concentrations in CSF from GBS patients were enhanced. The elevated tau levels were correlated with the GBS disability scale scores in AMAN and predicted poor clinical outcomes [89]. 14-3-3 proteins are highly conserved acidic polypeptides that are particularly abundant in the nervous system. 14-3-3 protein assay showed that 14-3-3 expressed by mononuclear inflammatory infiltrates and SCs was detected as early as 12 to 48 hours after disease onset [108]. Neuron-specific enolase is a glycolytic enzyme predominantly presenting in neurons and neuroendocrine cells. Neuron-specific enolase was significantly elevated in CSF of GBS patients and was correlated with months to recovery [90].

Additionally, other biomarkers that have not been included above but are related to GBS are presented in Supplementary Table .

3. Concluding Remarks

Specific biomarkers are still lacking to help make exact diagnosis and predict the outcomes of GBS. A growing number of studies focus on the biomarkers of GBS and address infection-, immune-, and BNB, B-CSF-B. and PNS damage-associated molecules as potential biomarkers for GBS. Serum, CSF, and peripheral nerves are the main sources of biomarkers. Many of these biomarkers are proved to be associated with the pathogenesis, development, and recovery of GBS. IVIg treatment, inhibiting the Fc-mediated activation of immune cells as well as the binding of autoimmune antibodies to their targets, is one of the first-line immunotherapies of GBS. IVIg downregulated Th17, Th22, IL-17, and IL-22 in GBS patients and mediated expansion of regulatory T cells [46, 122]. Clinical improvement with prominent peripheral mobilization of HLA-DCD13CXCR immature plasma cells was also observed in GBS patients. Further studies are warranted to explore more therapeutic biomarkers in GBS [123]. However, the related studies and the using of biomarkers have limitations. Firstly, several biomarkers, described as “predisposition” or “susceptibility indicators,” such as gene polymorphisms, may not be used in clinic as a basis for predictive testing, because they are found too frequently in healthy populations and may not develop the suspected diseases, although they may have a higher statistical probability that a disease may occur. Secondly, some biomarkers are discovered by flawed methods and their clinical value is negligible. A standard protocol to measure the biomarkers has not been established yet and the studies using distinct methods casually acquire conflicting results. The disease-related proteins in CSF may be produced intrathecally; regretfully, most of the studies fail to use CSF index to evaluate the intrathecal synthesis. Furthermore, the annual incidence of GBS is as low as 1-2/100,000 and most of the investigations have a relative small sample size. Numbers of GBS patients included are generally too low to permit a final verdict. Last but not the least, the clinical applications of many biomarkers may be withdrawn by expensive methods, invasive examinations, low sensitivity/specificity, and so forth. Further investigations are needed to continue searching for new biomarkers and studying existing biomarkers for GBS.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgments

The work was supported by grants from the National Natural Science Foundation of China (nos. 81241147, 81271294, 81271293, and 81471216), the Young Scholars Program of Norman Bethune Health Science Center of Jilin University (no. 2013205035), the Young Scholars Program of the First Hospital of Jilin University (no. JDYY42013003), and the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry (3C113BK734).

References

  1. C. C. Tam, L. C. Rodrigues, I. Petersen, A. Islam, A. Hayward, and S. J. O'Brien, “Incidence of Guillain-Barré syndrome among patients with Campylobacter infection: a general practice research database study,” Journal of Infectious Diseases, vol. 194, no. 1, pp. 95–97, 2006. View at Publisher · View at Google Scholar · View at Scopus
  2. I. Nachamkin, B. M. Allos, and T. Ho, “Campylobacter species and Guillain-Barré syndrome,” Clinical Microbiology Reviews, vol. 11, no. 3, pp. 555–567, 1998. View at Google Scholar · View at Scopus
  3. B. van den Berg, C. Walgaard, J. Drenthen, C. Fokke, B. C. Jacobs, and P. A. van Doorn, “Guillain-Barré syndrome: pathogenesis, diagnosis, treatment and prognosis,” Nature Reviews Neurology, vol. 10, no. 8, pp. 469–482, 2014. View at Publisher · View at Google Scholar · View at Scopus
  4. H.-L. Zhang, X.-Y. Zheng, and J. Zhu, “Th1/Th2/Th17/Treg cytokines in Guillain-Barré syndrome and experimental autoimmune neuritis,” Cytokine and Growth Factor Reviews, vol. 24, no. 5, pp. 443–453, 2013. View at Publisher · View at Google Scholar · View at Scopus
  5. M.-O. Lu and J. Zhu, “The role of cytokines in Guillain-Barré syndrome,” Journal of Neurology, vol. 258, no. 4, pp. 533–548, 2011. View at Publisher · View at Google Scholar · View at Scopus
  6. R. A. C. Hughes and D. R. Cornblath, “Guillain-Barré syndrome,” The Lancet, vol. 366, no. 9497, pp. 1653–1666, 2005. View at Publisher · View at Google Scholar · View at Scopus
  7. J. Brettschneider, A. Petzold, S. Süssmuth, and H. Tumani, “Cerebrospinal fluid biomarkers in Guillain-Barré syndrome—where do we stand?” Journal of Neurology, vol. 256, no. 1, pp. 3–12, 2009. View at Publisher · View at Google Scholar · View at Scopus
  8. H. Reiber, “Dynamics of brain-derived proteins in cerebrospinal fluid,” Clinica Chimica Acta, vol. 310, no. 2, pp. 173–186, 2001. View at Publisher · View at Google Scholar · View at Scopus
  9. Z. Islam, A. van Belkum, J. A. Wagenaar et al., “Comparative genotyping of Campylobacter jejuni strains from patients with Guillain-Barré syndrome,” PLoS ONE, vol. 4, no. 9, Article ID e7257, 2009. View at Publisher · View at Google Scholar · View at Scopus
  10. H. Jiang, M.-J. Zhang, R.-C. Liu, X.-Y. Tian, Y.-X. Gu, and J.-Z. Zhang, “Characteristics of lipo-oligosaccharide loci of Campylobacter jejuni isolates associated with Guillain-Barré syndrome from Hebei, China,” International Journal of Molecular Sciences, vol. 11, no. 3, pp. 1155–1161, 2010. View at Publisher · View at Google Scholar · View at Scopus
  11. P. C. R. Godschalk, M. L. Kuijf, J. Li et al., “Structural characterization of Campylobacter jejuni lipooligosaccharide outer cores associated with Guillain-Barré and Miller Fisher syndromes,” Infection and Immunity, vol. 75, no. 3, pp. 1245–1254, 2007. View at Publisher · View at Google Scholar · View at Scopus
  12. S. Fujimoto, B. M. Allos, N. Misawa, C. M. Patton, and M. J. Blaser, “Restriction fragment length polymorphism analysis and random amplified polymorphic DNA analysis of Campylobacter jejuni strains isolated from patients with Guillain-Barré syndrome,” Journal of Infectious Diseases, vol. 176, no. 4, pp. 1105–1108, 1997. View at Publisher · View at Google Scholar · View at Scopus
  13. T. M. Wassenaar and D. G. Newell, “Genotyping of Campylobacter spp.,” Applied and Environmental Microbiology, vol. 66, no. 1, pp. 1–9, 2000. View at Publisher · View at Google Scholar · View at Scopus
  14. L. N. Nielsen, S. K. Sheppard, N. D. McCarthy, M. C. J. Maiden, H. Ingmer, and K. A. Krogfelt, “MLST clustering of Campylobacter jejuni isolates from patients with gastroenteritis, reactive arthritis and Guillain-Barré syndrome,” Journal of Applied Microbiology, vol. 108, no. 2, pp. 591–599, 2010. View at Publisher · View at Google Scholar · View at Scopus
  15. H. Piao, M. Minohara, N. Kawamura et al., “Induction of paranodal myelin detachment and sodium channel loss in vivo by Campylobacter jejuni DNA-binding protein from starved cells (C-Dps) in myelinated nerve fibers,” Journal of the Neurological Sciences, vol. 288, no. 1-2, pp. 54–62, 2010. View at Publisher · View at Google Scholar · View at Scopus
  16. N. Kawamura, H. Piao, M. Minohara et al., “Campylobacter jejuni DNA-binding protein from starved cells in Guillain-Barré syndrome patients,” Journal of Neuroimmunology, vol. 240-241, pp. 74–78, 2011. View at Publisher · View at Google Scholar · View at Scopus
  17. M. Bax, M. L. Kuijf, A. P. Heikema et al., “Campylobacter jejuni lipooligosaccharides modulate dendritic cell-mediated T cell polarization in a sialic acid linkage-dependent manner,” Infection and Immunity, vol. 79, no. 7, pp. 2681–2689, 2011. View at Publisher · View at Google Scholar · View at Scopus
  18. R. Huizinga, W. van Rijs, J. J. Bajramovic et al., “Sialylation of Campylobacter jejuni endotoxin promotes dendritic cell-mediated B cell responses through CD14-dependent production of IFN-beta and TNF-alpha,” Journal of Immunology, vol. 191, no. 11, pp. 5636–5645, 2013. View at Publisher · View at Google Scholar · View at Scopus
  19. V. Phongsisay, “Campylobacter jejuni targets immunoglobulin-like receptor LMIR5,” Molecular Immunology, vol. 63, no. 2, pp. 574–578, 2015. View at Publisher · View at Google Scholar · View at Scopus
  20. M. C. Dalakas, “Mechanisms of action of IVIg and therapeutic considerations in the treatment of acute and chronic demyelinating neuropathies,” Neurology, vol. 59, pp. S13–S21, 2002. View at Publisher · View at Google Scholar · View at Scopus
  21. N. M. Van Sorge, L. H. Van Den Berg, K. Geleijns et al., “Anti-GM1 IgG antibodies induce leukocyte effector functions via Fcγ receptors,” Annals of Neurology, vol. 53, no. 5, pp. 570–579, 2003. View at Publisher · View at Google Scholar · View at Scopus
  22. W.-L. van der Pol, L. H. van den Berg, R. H. M. Scheepers et al., “IgG receptor IIa alleles determine susceptibility and severity of Guillain-Barré syndrome,” Neurology, vol. 54, no. 8, pp. 1661–1665, 2000. View at Publisher · View at Google Scholar · View at Scopus
  23. N. M. van Sorge, W.-L. van der Pol, M. D. Jansen et al., “Severity of Guillain-Barré syndrome is associated with Fc gamma Receptor III polymorphisms,” Journal of Neuroimmunology, vol. 162, no. 1-2, pp. 157–164, 2005. View at Publisher · View at Google Scholar · View at Scopus
  24. D. Sang, Q. Chen, X. Liu et al., “Fc receptor like 3 in Chinese patients of Han nationality with Guillain-Barré syndrome,” Journal of Neuroimmunology, vol. 246, no. 1-2, pp. 65–68, 2012. View at Publisher · View at Google Scholar · View at Scopus
  25. N. Fekih-Mrissa, M. Mrad, A. Riahi et al., “Association of HLA-DR/DQ polymorphisms with Guillain-Barré syndrome in Tunisian patients,” Clinical Neurology and Neurosurgery, vol. 121, pp. 19–22, 2014. View at Publisher · View at Google Scholar · View at Scopus
  26. Z. N. Hasan, H. H. Zalzala, H. R. Mohammedsalih et al., “Association between human leukocyte antigen-DR and demylinating guillain-barré syndrome,” Neurosciences, vol. 19, no. 4, pp. 301–305, 2014. View at Google Scholar · View at Scopus
  27. S. Sinha, K. N. Prasad, D. Jain, K. K. Nyati, S. Pradhan, and S. Agrawal, “Immunoglobulin IgG Fc-receptor polymorphisms and HLA class II molecules in Guillain-Barré syndrome,” Acta Neurologica Scandinavica, vol. 122, no. 1, pp. 21–26, 2010. View at Publisher · View at Google Scholar · View at Scopus
  28. K. Geleijns, G. M. T. Schreuder, B. C. Jacobs et al., “HLA class II alleles are not a general susceptibility factor in Guillain-Barré syndrome,” Neurology, vol. 64, no. 1, pp. 44–49, 2005. View at Publisher · View at Google Scholar · View at Scopus
  29. H. Li, J. Yuan, H. Hao, Z. Yan, and S. Wang, “HLA alleles in patients with Guillain-Barre syndrome,” Chinese Medical Journal, vol. 113, no. 5, pp. 429–432, 2000. View at Google Scholar · View at Scopus
  30. J. H. Rees, R. W. Vaughan, E. Kondeatis, and R. A. C. Hughes, “HLA-class II alleles in Guillain-Barré syndrome and Miller Fisher syndrome and their association with preceding Campylobacter jejuni infection,” Journal of Neuroimmunology, vol. 62, no. 1, pp. 53–57, 1995. View at Publisher · View at Google Scholar · View at Scopus
  31. E. E. Magira, M. Papaioakim, I. Nachamkin et al., “Differential distribution of HLA-DQβ/DRβ epitopes in the two forms of Guillain-Barré syndrome, acute motor axonal neuropathy and acute inflammatory demyelinating polyneuropathy (AIDP): identification of DQβ epitopes associated with susceptibility to and protection from AIDP,” Journal of Immunology, vol. 170, no. 6, pp. 3074–3080, 2003. View at Publisher · View at Google Scholar · View at Scopus
  32. D. S. Monos, M. Papaioakim, T. W. Ho, C. Y. Li, and G. M. McKhann, “Differential distribution of HLA alleles in two forms of Guillain-Barré syndrome,” Journal of Infectious Diseases, vol. 176, no. 6, pp. S180–S182, 1997. View at Publisher · View at Google Scholar · View at Scopus
  33. S. Blum, P. Csurhes, S. Reddel, J. Spies, and P. McCombe, “Killer immunoglobulin-like receptor and their HLA ligands in Guillain-Barré Syndrome,” Journal of Neuroimmunology, vol. 267, no. 1-2, pp. 92–96, 2014. View at Publisher · View at Google Scholar · View at Scopus
  34. L.-Y. Wu, Y. Zhou, C. Qin, and B.-L. Hu, “The effect of TNF-alpha, FcgammaR and CD1 polymorphisms on Guillain-Barré syndrome risk: evidences from a meta-analysis,” Journal of Neuroimmunology, vol. 243, no. 1-2, pp. 18–24, 2012. View at Publisher · View at Google Scholar · View at Scopus
  35. K. K. Nyati, K. N. Prasad, A. Verma et al., “Association of TLR4 Asp299Gly and Thr399Ile polymorphisms with Guillain-Barré syndrome in Northern Indian population,” Journal of Neuroimmunology, vol. 218, no. 1-2, pp. 116–119, 2010. View at Publisher · View at Google Scholar · View at Scopus
  36. M. L. Kuijf, K. Geleijns, N. Ennaji, W. van Rijs, P. A. van Doorn, and B. C. Jacobs, “Susceptibility to Guillain-Barré syndrome is not associated with CD1A and CD1E gene polymorphisms,” Journal of Neuroimmunology, vol. 205, no. 1-2, pp. 110–112, 2008. View at Publisher · View at Google Scholar · View at Scopus
  37. K. Geleijns, M. Emonts, J. D. Laman et al., “Genetic polymorphisms of macrophage-mediators in Guillain-Barré syndrome,” Journal of Neuroimmunology, vol. 190, no. 1-2, pp. 127–130, 2007. View at Publisher · View at Google Scholar · View at Scopus
  38. K. Geleijns, A. Roos, J. J. Houwing-Duistermaat et al., “Mannose-binding lectin contributes to the severity of Guillain-Barré syndrome,” Journal of Immunology, vol. 177, no. 6, pp. 4211–4217, 2006. View at Publisher · View at Google Scholar · View at Scopus
  39. C. M. Caporale, F. Papola, M. A. Fioroni et al., “Susceptibility to Guillain-Barré syndrome is associated to polymorphisms of CD1 genes,” Journal of Neuroimmunology, vol. 177, no. 1-2, pp. 112–118, 2006. View at Publisher · View at Google Scholar · View at Scopus
  40. C. Li, P. Zhao, X. Sun, Y. Che, and Y. Jiang, “Elevated levels of cerebrospinal fluid and plasma interleukin-37 in patients with Guillain-Barré syndrome,” Mediators of Inflammation, vol. 2013, Article ID 639712, 9 pages, 2013. View at Publisher · View at Google Scholar · View at Scopus
  41. S. Huang, L. Li, S. Liang, and W. Wang, “Conversion of peripheral CD4+CD25- T cells to CD4+CD25+ regulatory T cells by IFN-γ in patients with Guillain-Barré syndrome,” Journal of Neuroimmunology, vol. 217, no. 1-2, pp. 80–84, 2009. View at Publisher · View at Google Scholar · View at Scopus
  42. H.-L. Zhang, S. Azimullah, X.-Y. Zheng et al., “IFN-γ deficiency exacerbates experimental autoimmune neuritis in mice despite a mitigated systemic Th1 immune response,” Journal of Neuroimmunology, vol. 246, no. 1-2, pp. 18–26, 2012. View at Publisher · View at Google Scholar · View at Scopus
  43. V. V. Radhakrishnan, M. G. Sumi, S. Reuben, A. Mathai, and M. D. Nair, “Serum tumour necrosis factor-α and soluble tumour necrosis factor receptors levels in patients with Guillain-Barré syndrome,” Acta Neurologica Scandinavica, vol. 109, no. 1, pp. 71–74, 2004. View at Publisher · View at Google Scholar · View at Scopus
  44. H. Deng, X. Yang, T. Jin et al., “The role of IL-12 and TNF-α in AIDP and AMAN,” European Journal of Neurology, vol. 15, no. 10, pp. 1100–1105, 2008. View at Publisher · View at Google Scholar · View at Scopus
  45. H.-L. Zhang, M. Y. Hassan, X.-Y. Zheng et al., “Attenuated EAN in TNF-alpha deficient mice is associated with an altered balance of M1/M2 macrophages,” PLoS ONE, vol. 7, no. 5, Article ID e38157, 2012. View at Publisher · View at Google Scholar · View at Scopus
  46. S. Li, T. Jin, H.-L. Zhang et al., “Circulating Th17, Th22, and Th1 cells are elevated in the guillain-barré syndrome and downregulated by IVIg treatments,” Mediators of Inflammation, vol. 2014, Article ID 740947, 10 pages, 2014. View at Publisher · View at Google Scholar · View at Scopus
  47. Z.-Y. Zhang, Z. Zhang, C. Zug, B. Nuesslein-Hildesheim, D. Leppert, and H. J. Schluesener, “AUY954, a selective S1P1 modulator, prevents experimental autoimmune neuritis,” Journal of Neuroimmunology, vol. 216, no. 1-2, pp. 59–65, 2009. View at Publisher · View at Google Scholar · View at Scopus
  48. S.-H. Pelidou, L.-P. Zou, G. Deretzi, C. Oniding, E. Mix, and J. Zhu, “Enhancement of acute phase and inhibition of chronic phase of experimental autoimmune neuritis in Lewis rats by intranasal administration of recombinant mouse interleukin 17: potential immunoregulatory role,” Experimental Neurology, vol. 163, no. 1, pp. 165–172, 2000. View at Publisher · View at Google Scholar · View at Scopus
  49. S. Jander and G. Stoll, “Interleukin-18 is induced in acute inflammatory demyelinating polyneuropathy,” Journal of Neuroimmunology, vol. 114, no. 1-2, pp. 253–258, 2001. View at Publisher · View at Google Scholar · View at Scopus
  50. S. Yu, Z. Chen, E. Mix et al., “Neutralizing antibodies to IL-18 ameliorate experimental autoimmune neuritis by counter-regulation of autoreactive Th1 responses to peripheral myelin antigen,” Journal of Neuropathology and Experimental Neurology, vol. 61, no. 7, pp. 614–622, 2002. View at Google Scholar · View at Scopus
  51. R.-S. Duan, X.-M. Zhang, E. Mix, H. C. Quezada, A. Adem, and J. Zhu, “IL-18 deficiency inhibits both Th1 and Th2 cytokine production but not the clinical symptoms in experimental autoimmune neuritis,” Journal of Neuroimmunology, vol. 183, no. 1-2, pp. 162–167, 2007. View at Publisher · View at Google Scholar · View at Scopus
  52. R. Hayashi, W. Xiao, M. Kawamoto, O. Yuge, and G. J. Bennett, “Systemic glucocorticoid therapy reduces pain and the number of endoneurial Tumor Necrosis Factor-alpha (TNFα)-positive mast cells in rats with a painful peripheral neuropathy,” Journal of Pharmacological Sciences, vol. 106, no. 4, pp. 559–565, 2008. View at Publisher · View at Google Scholar · View at Scopus
  53. C. Dahle, C. Ekerfelt, M. Vrethem, M. Samuelsson, and J. Ernerudh, “T helper type 2 like cytokine responses to peptides from P0 and P2 myelin proteins during the recovery phase of Guillain-Barré syndrome,” Journal of the Neurological Sciences, vol. 153, no. 1, pp. 54–60, 1997. View at Publisher · View at Google Scholar · View at Scopus
  54. W. Yun, W. Hua-bing, and W. Wei-zhi, “A study of associated cell-mediated immune mechanisms in experimental autoimmune neuritis rats,” Journal of Neuroimmunology, vol. 185, no. 1-2, pp. 87–94, 2007. View at Publisher · View at Google Scholar · View at Scopus
  55. K. Hohnoki, A. Inoue, and C.-S. Koh, “Elevated serum levels of IFN-gamma, IL-4 and TNF-alpha/unelevated serum levels of IL-10 in patients with demyelinating diseases during the acute stage,” Journal of Neuroimmunology, vol. 87, no. 1-2, pp. 27–32, 1998. View at Publisher · View at Google Scholar · View at Scopus
  56. R. Press, V. Ozenci, M. Kouwenhoven, and H. Link, “Non-T(H)1 cytokines are augmented systematically early in Guillain-Barré syndrome,” Neurology, vol. 58, no. 3, pp. 476–478, 2002. View at Publisher · View at Google Scholar · View at Scopus
  57. K.-M. Myhr, K. S. Vågnes, T. H. Marøy, J. H. Aarseth, H. I. Nyland, and C. A. Vedeler, “Interleukin-10 promoter polymorphisms in patients with Guillain-Barré syndrome,” Journal of Neuroimmunology, vol. 139, no. 1-2, pp. 81–83, 2003. View at Publisher · View at Google Scholar · View at Scopus
  58. S. Sivieri, A. M. Ferrarini, F. Lolli et al., “Cytokine pattern in the cerebrospinal fluid from patients with GBS and CIDP,” Journal of the Neurological Sciences, vol. 147, no. 1, pp. 93–95, 1997. View at Publisher · View at Google Scholar · View at Scopus
  59. J. Zhu, H. Link, S. Weerth, C. Linington, E. Mix, and J. Qiao, “The B cell repertoire in experimental allergic neuritis involves multiple myelin proteins and GM1,” Journal of the Neurological Sciences, vol. 125, no. 2, pp. 132–137, 1994. View at Publisher · View at Google Scholar · View at Scopus
  60. G. Deretzi, S. H. Pelidou, L. P. Zou, C. Quiding, and J. Zhu, “Local effects of recombinant rat interleukin-6 on the peripheral nervous system,” Immunology, vol. 97, no. 4, pp. 582–587, 1999. View at Publisher · View at Google Scholar · View at Scopus
  61. L. Bao, J. U. Lindgren, P. van der Meide, S. W. Zhu, H.-G. Ljunggren, and J. Zhu, “The critical role of IL-12p40 in initiating, enhancing, and perpetuating pathogenic events in murine experimental autoimmune neuritis,” Brain Pathology, vol. 12, no. 4, pp. 420–429, 2002. View at Google Scholar · View at Scopus
  62. Z.-Y. Zhang, Z. Zhang, U. Fauser, and H. J. Schluesener, “Expression of interleukin-16 in sciatic nerves, spinal roots and spinal cords of experimental autoimmune neuritis rats,” Brain Pathology, vol. 19, no. 2, pp. 205–213, 2009. View at Publisher · View at Google Scholar · View at Scopus
  63. A. Creange, L. Belec, B. Clair, J.-D. Degos, J.-C. Raphael, and R. K. Gherardi, “Circulating transforming growth factor beta 1 (TGF-β1) in Guillain-Barre syndrome: decreased concentrations in the early course and increase with motor function,” Journal of Neurology Neurosurgery and Psychiatry, vol. 64, no. 2, pp. 162–165, 1998. View at Publisher · View at Google Scholar · View at Scopus
  64. L. M. Ossege, E. Sindem, B. Voss, and J. P. Malin, “Expression of TNFalpha and TGFbeta1 in Guillain-Barré syndrome: correlation of a low TNFalpha-/TGFbeta1-mRNA ratio with good recovery and signs for immunoregulation within the cerebrospinal fluid compartment,” European Journal of Neurology, vol. 7, pp. 17–25, 2000. View at Google Scholar
  65. T. Saida, K. Saida, R. P. Lisak, M. J. Brown, D. H. Silberberg, and A. K. Asbury, “In vivo demyelinating activity of sera from patients with Guillain-Barre syndrome,” Annals of Neurology, vol. 11, no. 1, pp. 69–75, 1982. View at Publisher · View at Google Scholar · View at Scopus
  66. S. Sawant-Mane, M. B. Clark, and C. L. Koski, “In vitro demyelination by serum antibody from patients with Guillain-Barré syndrome requires terminal complement complexes,” Annals of Neurology, vol. 29, no. 4, pp. 397–404, 1991. View at Publisher · View at Google Scholar · View at Scopus
  67. S. Kuwabara and N. Yuki, “Axonal Guillain-Barré syndrome: concepts and controversies,” The Lancet Neurology, vol. 12, no. 12, pp. 1180–1188, 2013. View at Publisher · View at Google Scholar · View at Scopus
  68. S. K. Halstead, F. M. P. Zitman, P. D. Humphreys et al., “Eculizumab prevents anti-ganglioside antibody-mediated neuropathy in a murine model,” Brain, vol. 131, no. 5, pp. 1197–1208, 2008. View at Publisher · View at Google Scholar · View at Scopus
  69. M. C. Dalakas, “The use of intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: evidence-based indications and safety profile,” Pharmacology and Therapeutics, vol. 102, no. 3, pp. 177–193, 2004. View at Publisher · View at Google Scholar · View at Scopus
  70. S. D'Aguanno, D. Franciotta, S. Lupisella et al., “Protein profiling of Guillain-Barrè syndrome cerebrospinal fluid by two-dimensional electrophoresis and mass spectrometry,” Neuroscience Letters, vol. 485, no. 1, pp. 49–54, 2010. View at Publisher · View at Google Scholar · View at Scopus
  71. C. E. Hafer-Macko, K. A. Sheikh, C. Y. Li et al., “Immune attack on the Schwann cell surface in acute inflammatory demyelinating polyneuropathy,” Annals of Neurology, vol. 39, no. 5, pp. 625–635, 1996. View at Publisher · View at Google Scholar · View at Scopus
  72. C. Hafer-Macko, S.-T. Hsieh, C. Yan Li et al., “Acute motor axonal neuropathy: an antibody-mediated attack on axolemma,” Annals of Neurology, vol. 40, no. 4, pp. 635–644, 1996. View at Publisher · View at Google Scholar · View at Scopus
  73. K. Susuki, N. Yuki, D. P. Schafer et al., “Dysfunction of nodes of Ranvier: a mechanism for anti-ganglioside antibody-mediated neuropathies,” Experimental Neurology, vol. 233, no. 1, pp. 534–542, 2012. View at Publisher · View at Google Scholar · View at Scopus
  74. M. E. Sanders, C. L. Koski, D. Robbins, M. L. Shin, M. M. Frank, and K. A. Joiner, “Activated terminal complement in cerebrospinal fluid in Guillain-Barré syndrome and multiple sclerosis,” Journal of Immunology, vol. 136, no. 12, pp. 4456–4459, 1986. View at Google Scholar · View at Scopus
  75. C. L. Koski, M. E. Sanders, P. T. Swoveland et al., “Activation of terminal components of complement in patients with Guillain-Barré syndrome and other demyelinating neuropathies,” The Journal of Clinical Investigation, vol. 80, no. 5, pp. 1492–1497, 1987. View at Publisher · View at Google Scholar · View at Scopus
  76. G. A. Putzu, D. Figarella-Branger, C. Bouvier-Labit, A. Liprandi, N. Bianco, and J. F. Pellissier, “Immunohistochemical localization of cytokines, C5b-9 and ICAM-1 in peripheral nerve of Guillain-Barre Syndrome,” Journal of the Neurological Sciences, vol. 174, no. 1, pp. 16–21, 2000. View at Publisher · View at Google Scholar · View at Scopus
  77. K. A. Langert, C. L. Von Zee, and E. B. Stubbs Jr., “Tumour necrosis factor α enhances CCL2 and ICAM-1 expression in peripheral nerve microvascular endoneurial endothelial cells,” ASN Neuro, vol. 5, no. 1, Article ID e00104, 2013. View at Publisher · View at Google Scholar · View at Scopus
  78. R. H. Xia, N. Yosef, and E. E. Ubogu, “Selective expression and cellular localization of pro-inflammatory chemokine ligand/receptor pairs in the sciatic nerves of a severe murine experimental autoimmune neuritis model of Guillain-Barré syndrome,” Neuropathology and Applied Neurobiology, vol. 36, no. 5, pp. 388–398, 2010. View at Publisher · View at Google Scholar · View at Scopus
  79. D. Orlikowski, B. Chazaud, A. Plonquet et al., “Monocyte chemoattractant protein 1 and chemokine receptor CCR2 productions in Guillain-Barré syndrome and experimental autoimmune neuritis,” Journal of Neuroimmunology, vol. 134, no. 1-2, pp. 118–127, 2003. View at Publisher · View at Google Scholar · View at Scopus
  80. B. C. Kieseier, M. Tani, D. Mahad et al., “Chemokines and chemokine receptors in inflammatory demyelinating neuropathies: a central role for IP-10,” Brain, vol. 125, no. 4, pp. 823–834, 2002. View at Publisher · View at Google Scholar · View at Scopus
  81. L. Luongo, M. Sajic, J. Grist, A. K. Clark, S. Maione, and M. Malcangio, “Spinal changes associated with mechanical hypersensitivity in a model of Guillain-Barré syndrome,” Neuroscience Letters, vol. 437, no. 2, pp. 98–102, 2008. View at Publisher · View at Google Scholar · View at Scopus
  82. S. Kastenbauer, U. Koedel, M. Wick, B. C. Kieseier, H.-P. Hartung, and H.-W. Pfister, “CSF and serum levels of soluble fractalkine (CX3CL1) in inflammatory diseases of the nervous system,” Journal of Neuroimmunology, vol. 137, no. 1-2, pp. 210–217, 2003. View at Publisher · View at Google Scholar · View at Scopus
  83. L.-P. Zou, S.-H. Pelidou, N. Abbas et al., “Dynamics of production of MIP-1α, MCP-1 and MIP-2 and potential role of neutralization of these chemokines in the regulation of immune responses during experimental autoimmune neuritis in Lewis rats,” Journal of Neuroimmunology, vol. 98, no. 2, pp. 168–175, 1999. View at Publisher · View at Google Scholar · View at Scopus
  84. P. P. Sainaghi, L. Collimedaglia, F. Alciato et al., “The expression pattern of inflammatory mediators in cerebrospinal fluid differentiates Guillain-Barré syndrome from chronic inflammatory demyelinating polyneuropathy,” Cytokine, vol. 51, no. 2, pp. 138–143, 2010. View at Publisher · View at Google Scholar · View at Scopus
  85. C. Fokke, B. van den Berg, J. Drenthen, C. Walgaard, P. A. van Doorn, and B. C. Jacobs, “Diagnosis of Guillain-Barré syndrome and validation of Brighton criteria,” Brain, vol. 137, no. 1, pp. 33–43, 2014. View at Publisher · View at Google Scholar · View at Scopus
  86. H.-L. Zhang, X.-M. Zhang, X.-J. Mao et al., “Altered cerebrospinal fluid index of prealbumin, fibrinogen, and haptoglobin in patients with Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy,” Acta Neurologica Scandinavica, vol. 125, no. 2, pp. 129–135, 2012. View at Publisher · View at Google Scholar · View at Scopus
  87. A. Gonzalez-Quevedo, R. F. Carriera, Z. L. O'Farrill, I. S. Luis, R. M. Becquer, and R. S. Luis Gonzalez, “An appraisal of blood-cerebrospinal fluid barrier dysfunction during the course of Guillain Barré syndrome,” Neurology India, vol. 57, no. 3, pp. 288–294, 2009. View at Publisher · View at Google Scholar · View at Scopus
  88. H.-L. Chiang, R.-K. Lyu, M.-Y. Tseng et al., “Analyses of transthyretin concentration in the cerebrospinal fluid of patients with Guillain-Barré syndrome and other neurological disorders,” Clinica Chimica Acta, vol. 405, no. 1-2, pp. 143–147, 2009. View at Publisher · View at Google Scholar · View at Scopus
  89. X.-K. Wang, H.-L. Zhang, F.-H. Meng et al., “Elevated levels of S100B, tau and pNFH in cerebrospinal fluid are correlated with subtypes of Guillain-Barré syndrome,” Neurological Sciences, vol. 34, no. 5, pp. 655–661, 2013. View at Publisher · View at Google Scholar · View at Scopus
  90. K. Mokuno, K. Kiyosawa, K. Sugimura et al., “Prognostic value of cerebrospinal fluid neuron-specific enolase and S-100b protein in Guillain-Barre syndrome,” Acta Neurologica Scandinavica, vol. 89, no. 1, pp. 27–30, 1994. View at Google Scholar · View at Scopus
  91. Y.-R. Yang, S.-L. Liu, Z.-Y. Qin et al., “Comparative proteomics analysis of cerebrospinal fluid of patients with Guillain-Barré syndrome,” Cellular and Molecular Neurobiology, vol. 28, no. 5, pp. 737–744, 2008. View at Publisher · View at Google Scholar · View at Scopus
  92. A. Nagai, Y. Murakawa, M. Terashima et al., “Cystatin C and cathepsin B in CSF from patients with inflammatory neurologic diseases,” Neurology, vol. 55, no. 12, pp. 1828–1832, 2000. View at Publisher · View at Google Scholar · View at Scopus
  93. Y.-C. Huang, R.-K. Lyu, M.-Y. Tseng et al., “Decreased intrathecal synthesis of prostaglandin D2 synthase in the cerebrospinal fluid of patients with acute inflammatory demyelinating polyneuropathy,” Journal of Neuroimmunology, vol. 206, no. 1-2, pp. 100–105, 2009. View at Publisher · View at Google Scholar · View at Scopus
  94. S. Nishino, T. Kanbayashi, N. Fujiki et al., “CSF hypocretin levels in Guillain-Barré syndrome and other inflammatory neuropathies,” Neurology, vol. 61, no. 6, pp. 823–825, 2003. View at Publisher · View at Google Scholar · View at Scopus
  95. T. Jin, L.-S. Hu, M. Chang, J. Wu, B. Winblad, and J. Zhu, “Proteomic identification of potential protein markers in cerebrospinal fluid of GBS patients,” European Journal of Neurology, vol. 14, no. 5, pp. 563–568, 2007. View at Publisher · View at Google Scholar · View at Scopus
  96. N. Shahrizaila, N. Kokubun, S. Sawai et al., “Antibodies to single glycolipids and glycolipid complexes in Guillain-Barré syndrome subtypes,” Neurology, vol. 83, no. 2, pp. 118–124, 2014. View at Publisher · View at Google Scholar · View at Scopus
  97. J. K. Kim, J. S. Bae, D.-S. Kim et al., “Prevalence of anti-ganglioside antibodies and their clinical correlates with Guillain-Barré syndrome in Korea: a nationwide multicenter study,” Journal of Clinical Neurology, vol. 10, no. 2, pp. 94–100, 2014. View at Publisher · View at Google Scholar · View at Scopus
  98. C. W. Ang, N. Yuki, B. C. Jacobs et al., “Rapidly progressive, predominantly motor Guillain-Barre syndrome with anti-GalNAc-GD1a antibodies,” Neurology, vol. 53, no. 9, pp. 2122–2127, 1999. View at Publisher · View at Google Scholar · View at Scopus
  99. S. Hitoshi, S. Kusunoki, K. Kon et al., “A novel ganglioside, 9-O-acetyl GD1b, is recognized by serum antibodies in Guillain-Barré syndrome,” Journal of Neuroimmunology, vol. 66, no. 1-2, pp. 95–101, 1996. View at Publisher · View at Google Scholar · View at Scopus
  100. M. Koga, N. Yuki, T. Ariga, and K. Hirata, “Antibodies to GD3, GT3, and O-acetylated species in Guillain-Barré and Fisher's syndromes: their association with cranial nerve dysfunction,” Journal of the Neurological Sciences, vol. 164, no. 1, pp. 50–55, 1999. View at Publisher · View at Google Scholar · View at Scopus
  101. K. Kaida, K. Kamakura, G. Ogawa et al., “GD1b-specific antibody induces ataxia in Guillain-Barré syndrome,” Neurology, vol. 71, no. 3, pp. 196–201, 2008. View at Publisher · View at Google Scholar · View at Scopus
  102. A. Chiba, S. Kusunoki, H. Obata, R. Machinami, and I. Kanazawa, “Serum anti-GQ(1b) IgG antibody is associated with ophthalmoplegia in Miller Fisher syndrome and Guillain-Barré syndrome: clinical and immunohistochemical studies,” Neurology, vol. 43, no. 10, pp. 1911–1917, 1993. View at Publisher · View at Google Scholar · View at Scopus
  103. M. Kuwahara, S. Suzuki, K. Takada, and S. Kusunoki, “Antibodies to LM1 and LM1-containing ganglioside complexes in Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy,” Journal of Neuroimmunology, vol. 239, no. 1-2, pp. 87–90, 2011. View at Publisher · View at Google Scholar · View at Scopus
  104. K. Kaida, D. Morita, M. Kanzaki et al., “Anti-ganglioside complex antibodies associated with severe disability in GBS,” Journal of Neuroimmunology, vol. 182, no. 1-2, pp. 212–218, 2007. View at Publisher · View at Google Scholar · View at Scopus
  105. K.-I. Kaida, D. Morita, M. Kanzaki et al., “Ganglioside complexes as new target antigens in Guillain-Barré syndrome,” Annals of Neurology, vol. 56, no. 4, pp. 567–571, 2004. View at Publisher · View at Google Scholar · View at Scopus
  106. G. Ogawa, K.-I. Kaida, M. Kuwahara, F. Kimura, K. Kamakura, and S. Kusunoki, “An antibody to the GM1/GalNAc-GD1a complex correlates with development of pure motor Guillain-Barré syndrome with reversible conduction failure,” Journal of Neuroimmunology, vol. 254, no. 1-2, pp. 141–145, 2013. View at Publisher · View at Google Scholar · View at Scopus
  107. S. Rinaldi, K. M. Brennan, G. Kalna et al., “Antibodies to heteromeric glycolipid complexes in guillain-barré syndrome,” PLoS ONE, vol. 8, no. 12, Article ID e82337, 2013. View at Publisher · View at Google Scholar · View at Scopus
  108. A. Bersano, M. Fiorini, S. Allaria et al., “Detection of CSF 14-3-3 protein in Guillain-Barré syndrome,” Neurology, vol. 67, no. 12, pp. 2211–2216, 2006. View at Publisher · View at Google Scholar · View at Scopus
  109. Y. Sekiguchi, A. Uncini, N. Yuki et al., “Antiganglioside antibodies are associated with axonal Guillain-Barré syndrome: a Japanese-Italian collaborative study,” Journal of Neurology, Neurosurgery & Psychiatry, vol. 83, no. 1, pp. 23–28, 2012. View at Publisher · View at Google Scholar · View at Scopus
  110. B. C. Jacobs, M. Koga, W. van Rijs et al., “Subclass IgG to motor gangliosides related to infection and clinical course in Guillain-Barré syndrome,” Journal of Neuroimmunology, vol. 194, no. 1-2, pp. 181–190, 2008. View at Publisher · View at Google Scholar · View at Scopus
  111. J. J. Devaux, M. Odaka, and N. Yuki, “Nodal proteins are target antigens in Guillain-Barré syndrome,” Journal of the Peripheral Nervous System, vol. 17, no. 1, pp. 62–71, 2012. View at Publisher · View at Google Scholar · View at Scopus
  112. J. J. Devaux, “Antibodies to gliomedin cause peripheral demyelinating neuropathy and the dismantling of the nodes of ranvier,” The American Journal of Pathology, vol. 181, no. 4, pp. 1402–1413, 2012. View at Publisher · View at Google Scholar · View at Scopus
  113. W. Yan, T. Nguyen, N. Yuki et al., “Antibodies to neurofascin exacerbate adoptive transfer experimental autoimmune neuritis,” Journal of Neuroimmunology, vol. 277, no. 1-2, pp. 13–17, 2014. View at Publisher · View at Google Scholar · View at Scopus
  114. C. M. Gabriel, N. A. Gregson, and R. A. C. Hughes, “Anti-PMP22 antibodies in patients with inflammatory neuropathy,” Journal of Neuroimmunology, vol. 104, no. 2, pp. 139–146, 2000. View at Publisher · View at Google Scholar · View at Scopus
  115. A. Makowska, J. Pritchard, L. Sanvito et al., “Immune responses to myelin proteins in Guillain-Barré syndrome,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 79, no. 6, pp. 664–671, 2008. View at Publisher · View at Google Scholar · View at Scopus
  116. H. R. Inglis, P. A. Csurhes, and P. A. McCombe, “Antibody responses to peptides of peripheral nerve myelin proteins P0 and P2 in patients with inflammatory demyelinating neuropathy,” Journal of Neurology, Neurosurgery & Psychiatry, vol. 78, no. 4, pp. 419–422, 2007. View at Publisher · View at Google Scholar · View at Scopus
  117. G. Sessa, R. Nemni, N. Canal, and P. C. Marchisio, “Circulating fragments of myelin-associated α6β4 integrin in guillain-barre syndrome,” Journal of Neuroimmunology, vol. 80, no. 1-2, pp. 115–120, 1997. View at Publisher · View at Google Scholar · View at Scopus
  118. G. Nakos, E. Tziakou, L. Maneta-Peyret, C. Nassis, and M. E. Lekka, “Anti-phospholipid antibodies in serum from patients with Guillain-Barré syndrome,” Intensive Care Medicine, vol. 31, no. 10, pp. 1401–1408, 2005. View at Publisher · View at Google Scholar · View at Scopus
  119. M. Samukawa, Y. Hamada, M. Kuwahara et al., “Clinical features in Guillain-Barré syndrome with anti-Gal-C antibody,” Journal of the Neurological Sciences, vol. 337, no. 1-2, pp. 55–60, 2014. View at Publisher · View at Google Scholar
  120. I. Dujmovic, M. P. Lunn, M. M. Reilly, and A. Petzold, “Serial cerebrospinal fluid neurofilament heavy chain levels in severe Guillain-Barré syndrome,” Muscle & Nerve, vol. 48, no. 1, pp. 132–134, 2013. View at Publisher · View at Google Scholar · View at Scopus
  121. J. Gaiottino, N. Norgren, R. Dobson et al., “Increased neurofilament light chain blood levels in neurodegenerative neurological diseases,” PLoS ONE, vol. 8, no. 9, Article ID e75091, 2013. View at Publisher · View at Google Scholar · View at Scopus
  122. M. S. Maddur, J. Trinath, M. Rabin et al., “Intravenous immunoglobulin-mediated expansion of regulatory T cells in autoimmune patients is associated with increased prostaglandin E2 levels in the circulation,” Cellular & Molecular Immunology, vol. 12, no. 5, pp. 650–652, 2014. View at Publisher · View at Google Scholar
  123. C. Galeotti, S. V. Kaveri, and J. Bayry, “Molecular and immunological biomarkers to predict IVIg response,” Trends in Molecular Medicine, vol. 21, pp. 145–147, 2015. View at Publisher · View at Google Scholar · View at Scopus