Pathogenesis Of Guillain-Barré Syndrome Research Articles

Correlations between microRNA-146a and immunoglobulin and inflammatory factors in Guillain-Barré syndrome.

ObjectiveTo study correlations between expression of microRNA-146a (miR-146a) and immunoglobulin and inflammatory cytokines in serum of patients with Guillain–Barré syndrome (GBS).MethodsEighty-four patients with GBS were selected as the experimental group and 50 healthy individuals as controls. Reverse transcription-PCR was used to detect expression of miR-146a in peripheral blood of all participants. Immunoturbidometric assay was used to detect immunoglobulins (Ig)G, IgA, and IgM in peripheral blood of all participants. The levels of interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor α (TNF-α) were measured by ELISA in peripheral blood. The expression of miR-146a was compared between the two groups and Pearson correlation analysis was used to analyze correlations between miR-146a and immunoglobulin and inflammatory factors.ResultsExpression of miR-146a was higher in the GBS group than in controls. Expression of IL-6, CRP, TNF-α, and IgG was significantly higher in the GBS group than in controls. miR-146a was significantly and positively correlated with IL-6, CRP, TNF-α, and IgG but not with IgA and IgM.ConclusionThe expression profile of miR-146a in patients with GBS differs from that in healthy individuals. Thus, miR-146a may participate in the pathogenesis of GBS by regulating immune and inflammatory responses.

Efektivitas Immunoterapi Dalam Tatalaksana Guillain-Barré Syndrome Pada Anak

Guillain-Barré Syndrome (GBS) merupakan suatu kelainan mediator imun dari sistem saraf perifer dimana respon autoimun menjadi aktif dan menargetkan saraf perifer. Patogenesis GBS dipercaya sebagai sebuah respon imun yang abnormal terhadap sebuah kejadian yang terjadi sebelumnya, paling sering didahului oleh suatu infeksi, dan pada sebagian kecil kasus dilaporkan pasca imunisasi terutama untuk pasien anak-anak. Manifestasi klinis GBS berupa kelemahan ekstremitas bilateral progresif yang cepat dan bersifat ascending. Terapi yang masih digunakan dan dianggap efektif untuk saat ini yaitu immunoglobulin intravena (IVIg), dan plasmaferesis. Modalitas terapi baru seperti Interferon-β (IFN-β), Siklofosfamid, dan antibodi monoklonal manusia masih memerlukan penelitian lebih lanjut terkait efektivitas dan efek samping yang bisa terjadi. Prognosis GBS anak didapatkan lebih baik, mortalitas juga ditemukan lebih rendah yaitu sekitar 1-2% pada anak dengan GBS, dan hanya 4% dari seluruh pasien anak yang membutuhkan alat bantu pernapasan selama perawatan.

The effects of IVIg therapy on serum levels of neuropeptide Y and cytokines in Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is a common acute immune-mediated inflammatory disorder affecting the peripheral nervous system (PNS) of humans. Studies in humans and in animal models revealed that neuropeptide Y (NPY) levels are altered in some neurodegenerative and neuroimmune disorders. Herein, we investigated the levels of NPY and cytokines in the serum of GBS patients and explored the roles of NPY in the disease severity and its short-term prognosis. Twenty patients with GBS (case group) and twenty healthy individuals (control group) were enrolled in this study. NPY levels were analyzed by enzyme-linked immunosorbent assay (ELISA). The levels of pro- and anti-inflammatory cytokines (including interferon-γ (IFN-γ), interleukin (IL)-4, IL-10, IL-12p70, IL-17A, and tumor necrosis factor-α (TNF-α)) were analyzed using cytometric beads array (CBA). The clinical characteristics, disease severity, and short-term prognosis were compared between the two groups. Compared with the control group, the levels of NPY and cytokines were significantly increased in the serum of patients with GBS. NPY levels in the serum of GBS patients were correlated with the disease severity. Our results suggest that NPY and cytokines are involved in the pathogenesis of GBS. The levels of NPY can help to predict the severity of the disease.

Human Schwann cells are susceptible to infection with Zika and yellow fever viruses, but not dengue virus

Zika virus (ZIKV) is a re-emerged flavivirus transmitted by Aedes spp mosquitoes that has caused outbreaks of fever and rash on islands in the Pacific and in the Americas. These outbreaks have been associated with neurologic complications that include congenital abnormalities and Guillain-Barré syndrome (GBS). The pathogenesis of ZIKV-associated GBS, a potentially life-threatening peripheral nerve disease, remains unclear. Because Schwann cells (SCs) play a central role in peripheral nerve function and can be the target for damage in GBS, we characterized the interactions of ZIKV isolates from Africa, Asia and Brazil with human SCs in comparison with the related mosquito-transmitted flaviviruses yellow fever virus 17D (YFV) and dengue virus type 2 (DENV2). SCs supported sustained replication of ZIKV and YFV, but not DENV. ZIKV infection induced increased SC expression of IL-6, interferon (IFN)β1, IFN-λ, IFIT-1, TNFα and IL-23A mRNAs as well as IFN-λ receptors and negative regulators of IFN signaling. SCs expressed baseline mRNAs for multiple potential flavivirus receptors and levels did not change after ZIKV infection. SCs did not express detectable levels of cell surface Fcγ receptors. This study demonstrates the susceptibility and biological responses of SCs to ZIKV infection of potential importance for the pathogenesis of ZIKV-associated GBS.

Time Course of Axon and Myelin Degeneration in Peripheral Nerves in Experimental Autoimmune Neuritis Rats

Experimental autoimmune neuritis (EAN) is an animal model for Guillain-Barré syndrome (GBS), which results in neurological symptoms and histopathological changes in peripheral nerves. In this model, the correlation between the progression of the disease and the histopathological changes is not clear. To further examine histopathological changes in peripheral nerves in EAN rats, sciatic nerves were sampled at onset (day 10), peak (day 16), and recovery (days 22 and 25) of neurological symptoms in P2(57-81)-peptide-administered rats. Axon and myelin degeneration was observed by light microscopy at onset, degeneration became severe at peak, and persisted at recovery. Densities of myelinated nerve fibers and myelin areas decreased from day 10 to a minimum on day 22. Slight axon and myelin degeneration, such as accumulation of vesicles in axons and focal myelin splitting and folding, was observed by transmission electron microscopy at onset; severe degeneration, such as axonal loss, myelin ovoid, and demyelination, increased at peak; and regenerative changes, such as remyelination and enlargement of Schwann cell cytoplasm, occurred at recovery. These results suggest that EAN rats have histopathological similarities to some types of GBS patients and that EAN rats are a useful model to understand the pathogenesis of GBS.

Autoimmunity and cytokines in Guillain-Barré syndrome revisited: review of pathomechanisms with an eye on therapeutic options.

Guillain-Barré syndrome (GBS) is the most common cause of acute paralysis in the United States. Campylobacter jejuni is a common trigger for GBS, igniting autoimmunity as a result of molecular mimicry between C.jejuni lipooligosaccharide (LOS) and host gangliosides. Evidence also suggests an active role for cell-mediated and innate immunity in pathogenesis of GBS. Infection alone is not enough for GBS to develop, infection with the same strain might yield different outcomes in different patients. C.jejuni strains with low to absent molecular mimicry to self-antigens can cause full-blown GBS with positive autoantibodies. A role for T helper 17 and IL-17 in acute phase of GBS is also identified. Currently, no biological treatment is validated for severe, ventilation-dependent patients with GBS, who might not benefit from either IVIG or plasma exchange therapy. Use of biologic agents in treatment-resistant GBS, especially anti-IL-17 agents, such as secukinumab, ixekizumab, and brodalumab, is to be hoped. This review covers up-to-date knowledge on autoimmune mechanisms responsible in different subtypes of GBS: acute inflammatory demyelinating polyneuropathy and acute motor axonal neuropathy; as well as the experimental autoimmune neuritis (EAN), a commonly used animal model of GBS.

Dynamic thiol-disulphide homeostasis in patients with Guillain-Barre Syndrome

ABSTRACT Objective: The aim of this study was to evaluate dynamic thiol-disulphide homeostasis as a novel oxidative stress parameter in patients with Guillain-Barre syndrome (GBS). Methods: A total of 130 participants were included in this study, 70 of whom were diagnosed with GBS. Total thiol (-SH+-S-S-) and native thiol (-SH) levels in serum were measured in all patients and healthy individuals. Amount of dynamic disulphide bond were calculated from these values. In the GBS patients, disability status was determined by the Hughes and Medical Research Center (MRC) sum scores at the time of admission and 3 months thereafter. Results: Total and native thiol levels were significantly lower in patients with GBS compared with healthy individuals. There was no statistically significant difference in the number of dynamic disulphide bonds between groups. There was a negative correlation between total thiol levels in patients with GBS and Hughes scores at month 3. Discussion: Oxidative stress is among the molecular changes underlying the pathogenesis of GBS. In this study, we have investigated the dynamic thiol-disulfide homeostasis in patients with epilepsy using a new method in the literature. Also, functional recovery in Guillain-Barré syndrome patients could be promoted by increasing antioxidant activity.

Experimental approach in research of Guillain–Barré syndrome: A range of pathogeneses mediated by molecular mimicry

AbstractMolecular mimicry between microbial antigens and host tissue is a highly attractive explanation for the pathogenesis of many autoimmune diseases. Among them, Guillain–Barré syndrome (GBS) is an excellent model to show the causal pathogenesis of molecular mimicry, because the epidemiological association of GBS with several infections has been established. The present review describes recent findings regarding the causative role of molecular mimicry in GBS that arises after infection with several different bacteria and viruses, including Campylobacter jejuni, Mycoplasma pneumoniae, cytomegalovirus, Haemophilus influenzae, Epstein–Barr virus, hepatitis E virus and Zika virus. Although many issues must be resolved to fully understand GBS pathogenesis, molecular mimicry is highly likely to be involved in the development of C. jejuni‐associated GBS and probably of M. pneumoniae‐associated GBS. Candidate autoantibodies that are generated in cytomegalovirus‐ and H. influenzae‐associated GBS types can also provide clues to the causal role of molecular mimicry. For other diseases associated with antecedent infections, clarification of pathogeneses is premature and warrants further research on molecular mimicry, as well as other autoimmune‐triggering mechanisms.

Zika Virus and Guillain-Barré Syndrome

Recent studies revealed an association between Zika virus infection and a variety of neurological disorders, including microcephaly, meningoencephalitis, myelitis, and Guillain-Barré syndrome (GBS). Following the first report of a patient diagnosed with GBS after Zika virus infection in December 2013, the number of GBS patients significantly increased in endemic countries, such as French-Polynesia and Latin American countries. Electrophysiological studies suggested that patients suffering from GBS associated with Zika virus infection manifest acute inflammatory demyelinating polyneuropathy (AIDP), rather than acute motor axonal neuropathy (AMAN). Causative autoantibodies, such as the anti-ganglioside antibodies in AMAN associated with Campylobacter jejuni infection, have not been identified in GBS associated with Zika virus infection. However, a recent study revealed a high level of peptide sharing between Zika virus polyprotein and human proteins related to myelin, demyelination, and axonal neuropathies. Additionally, another study reported significant peptide overlap between Zika virus and Cytomegalovirus, which is also related to microcephaly and AIDP. Further reserch is needed to elucidate the pathogenesis of GBS associated with Zika virus infection.

The clinical significance of neutrophil-to-lymphocyte ratio and monocyte-to-lymphocyte ratio in Guillain–Barré syndrome

ABSTRACTPurpose/Aim of the study: Guillain Barré syndrome (GBS) is a severe peripheral nervous disease that leads to muscle weakness and areflexia. We now commonly accept a synthesis that inflammation and immunity play key role in GBS pathogenesis. Many studies pointed out that neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR) are novel promising markers of inflammation or immunity. Our study aimed to evaluate whether the NLR and the MLR were associated to GBS or not.Materials and Methods: We measured blood cell count in 334 individuals including 117 GBS and 217 healthy controls.Results: Our findings demonstrated that the GBS patients had higher levels of NLR and MLR than the healthy controls. The severe group also had higher levels of NLR and MLR compared to the mild group. We took the method of receiver-operating characteristic curve to find out the cut-off value of NLR for GBS occurrence and severity; it was 2.295 and 3.05, respectively. The cut-off values of MLR for GBS incidence and severity were the same, it was 0.235.Conclusion: In the setting of GBS, the NLR and MLR were significantly increased and they may be pathophysiologically and clinically relevant in GBS. The NLR and MLR would be new biomarkers of medical application.

Approach for identifying of treatment option for pediatric patients in Guillain-Barre syndrome considering results of pharmacoeconomic analysis

A pharmacoeconomic analysis of direct costs on treatment with high dose intravenous immunoglobulins (IVIG) and plasmapheresis (PP) in children. Literature data on the pathogenesis of Guillain-Barre syndrome (GBS) were analyzed. The results of pharmacoeconomic analysis of direct costs on treatment of GBS using IVIG and PP are presented. Risks for complications during treatment with IVIG and PP are calculated. The pharmacoeconomic analysis demonstrates comparable costs of treatment with IVIG or PP in the Russian Federation. Nevertheless, a less number of complications, convenience in use and the good safety and tolerability profile make it more preferable to this group of patients. In a clinical case of a 7-year child described in the article, treatment with 10% IVIG - privigen in dose 2 g/kg during 5 days started in the 3rd week of disease showed a marked positive effect.

Beneficial or Harmful Role of Macrophages in Guillain-Barré Syndrome and Experimental Autoimmune Neuritis.

Guillain-Barré syndrome (GBS), an immune-mediated demyelinating peripheral neuropathy, is characterized by acute weakness of the extremities and areflexia or hyporeflexia. Experimental autoimmune neuritis (EAN) is a common animal model for GBS, which represents a CD4+ T cell-mediated inflammatory autoimmune demyelination of the peripheral nervous system (PNS), and is used to investigate the pathogenic mechanism of GBS. It has been found that macrophages play a critical role in the pathogenesis of both GBS and EAN. Macrophages have been primarily classified into two major phenotypes: proinflammatory macrophages (M1) and anti-inflammatory macrophages (M2). The two different macrophage subsets M1 and M2 may play a decisive role in initiation and development of GBS and EAN. However, recently, it has been indicated that the roles of macrophages in immune regulation and autoimmune diseases are more complex than those suggested by a simple M1-M2 dichotomy. Macrophages might exert either inflammatory or anti-inflammatory effect by secreting pro- or anti-inflammatory cytokines, and either inducing the activation of T cells to mediate immune response, resulting in inflammation and demyelination in the PNS, or promoting disease recovery. In this review, we summarize the dual roles of macrophages in GBS and EAN and explore the mechanism of macrophage polarization to provide a potential therapeutic approach for GBS in the future.

Intrathecal antibody responses to GalC in Guillain-Barré syndrome triggered by Mycoplasma pneumoniae

Mycoplasma pneumoniae (Mp) triggers Guillain-Barré syndrome (GBS) and elicits anti-galactocerebroside (GalC) antibodies. Specifically anti-GalC IgG is associated with Mp-GBS, possibly because of its better ability to cross the blood-nerve barrier (BNB). We here investigated CSF for the presence of anti-GalC in GBS. Intrathecal anti-GalC was found in 46% of Mp-GBS patients (n=6/13), in contrast to 16% of GBS controls (n=4/25) and 0% of non-GBS controls (n=0/7). The antibodies most likely originated from increased BNB permeability and/or intrathecal synthesis. Intrathecal anti-GalC IgG was specifically associated with Mp-GBS, further supporting that anti-GalC IgG contributes to the pathogenesis of GBS.

Clinical efficacy and mechanism of lymphoplasma exchange in the treatment of Guillain-Barre syndrome.

Guillain-Barre syndrome (GBS) is an autoimmune disease of the nervous system and is the most common acute polyneuropathy. Both cellular and humoral immunity are believed to be involved in the pathogenesis of GBS, and various types of activated CD4+ T cells are thought to orchestrate the onset and progression of GBS. Lymphoplasma exchange (LPE) filtering out activated lymphocytes while exchanging plasma has been used for GBS treatment for years. However the treatment is still not yet optimal. In order to assess the efficacy of this treatment, we evaluate the effect of LPE and determine the appropriate frequency of LPE treatments for GBS patients through comparing the neurological deficit scores and the changes in related immunology indicators of GBS patients before and after LPE treatment. Twenty-four patients with GBS who received LPE were evaluated for immunologic indicants before treatment, on the second day, and the fourth day after the treatment. The immunoglobulin complement and CD4+ T lymphocyte subsets were tested by flow cytometry. The patients' Medical Research Council sum scores were increased from 25.7±10.4 up to. 36.7±10.4 (P=0.019) and their Hughes scores decreased from 3.7±0.76 to 3.1±0.73 (P=0.027) at 7 days after LPE. In the peripheral blood from patients received LPE treatment, the levels of immunoglobulin, complement, monocytes and fibrinogen were significantly reduced. The percentages of Th1 and Th17 cells in the CD4+ T lymphocyte subsets were significantly decreased, whereas the Th2 and Treg cells were increased in patients after treatment. The changes in CD4+T lymphocyte subsets were correlated with patient MRC score changes. Our data indicate that LPE is effective in treating GBS patients by directly removing immunoglobulin, complement, monocytes, and fibrinogen as well as regulating lymphocyte subsets in the peripheral blood.

Tumor necrosis factor-alpha -863C/A polymorphism is associated with Guillain–Barré syndrome in Bangladesh

Guillain-Barré syndrome (GBS) is a post-infectious autoimmune polyneuropathy regulated by pro- and anti-inflammatory cytokines; TNFA polymorphisms may exert immune pathogenic roles in GBS. We assessed TNFA promoter region polymorphisms (-238G/A, -308G/A, -857C/T, -863C/A) in Bangladeshi patients with GBS (n=300) and healthy controls (n=300) by PCR-RFLP and ASO-PCR. TNFA -863CA was significantly associated with GBS disease susceptibility (P=0.0154) and disease severity (P=0.0492). TNFA -238A allele was more frequent among anti-ganglioside (GM1) antibody-positive patients (P=0.0092) and -863AA associated with AMAN subtype of GBS (P=0.0398). TNFA -863C/A may contribute to GBS severity and pathogenesis in Bangladeshi patients.

Mycoplasma pneumoniae triggering the Guillain-Barré syndrome: A case-control study.

Guillain-Barré syndrome (GBS) is an acute postinfectious immune-mediated polyneuropathy. Although preceding respiratory tract infections with Mycoplasma pneumoniae have been reported in some cases, the role of M. pneumoniae in the pathogenesis of GBS remains unclear. We here cultured, for the first time, M. pneumoniae from a GBS patient with antibodies against galactocerebroside (GalC), which cross-reacted with the isolate. This case prompted us to unravel the role of M. pneumoniae in GBS in a case-control study. We included 189 adults and 24 children with GBS and compared them to control cohorts for analysis of serum antibodies against M. pneumoniae (n = 479) and GalC (n = 198). Anti-M. pneumoniae immunoglobulin (Ig) M antibodies were detected in GBS patients and healthy controls in 3% and 0% of adults (p = 0.16) and 21% and 7% of children (p = 0.03), respectively. Anti-GalC antibodies (IgM and/or IgG) were found in 4% of adults and 25% of children with GBS (p = 0.001). Anti-GalC-positive patients showed more-frequent preceding respiratory symptoms, cranial nerve involvement, and a better outcome. Anti-GalC antibodies correlated with anti-M. pneumoniae antibodies (p < 0.001) and cross-reacted with different M. pneumoniae strains. Anti-GalC IgM antibodies were not only found in GBS patients with M. pneumoniae infection, but also in patients without neurological disease (8% vs 9%; p = 0.87), whereas anti-GalC IgG was exclusively found in patients with GBS (9% vs 0%; p = 0.006). M. pneumoniae infection is associated with GBS, more frequently in children than adults, and elicits anti-GalC antibodies, of which specifically anti-GalC IgG may contribute to the pathogenesis of GBS. Ann Neurol 2016;80:566-580.

Polymorphisms in exon 2 of CD1 genes are associated with susceptibility to Guillain–Barré syndrome

Guillain–Barré syndrome (GBS) is a post-infectious autoimmune peripheral neuropathy. Studies have shown that a T cell-mediated immune response to peripheral nerve is associated with the pathogenesis of GBS. CD1 molecules are MCH-like glycoproteins specialized to capture and present glycolipids to T cells. Polymorphisms of CD1 genes may affect susceptibility to GBS. We investigated the polymorphisms of CD1 genes in GBS patients in a Chinese Han population. In 126 patients and in 138 controls we genotyped exon 2 of the CD1A and CD1E genes. The results indicated that polymorphisms of CD1A genes are associated with GBS. Furthermore, subjects with CD1A*01/02 had a 2.9 times lower risk of developing GBS, and those with CD1A*02/02 had a 2.5 times higher risk to developing GBS than the controls, while there was no association between polymorphisms of CD1E genes and the susceptibilities to GBS.

Proximal nerve lesions in early Guillain-Barré syndrome: implications for pathogenesis and disease classification.

Guillain-Barré syndrome (GBS) is an acute-onset, immune-mediated disorder of the peripheral nervous system. In early GBS, arbitrarily established up to 10days of disease onset, patients could exhibit selective manifestations due to involvement of the proximal nerves, including nerve roots, spinal nerves and plexuses. Such manifestations are proximal weakness, inaugural nerve trunk pain, and atypical electrophysiological patterns, which may lead to delayed diagnosis. The aim of this paper was to analyze the nosology of early GBS reviewing electrophysiological, autopsy and imaging studies, both in acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor/motor-sensory axonal neuropathy (AMAN/AMSAN). Early electrophysiology showed either well-defined demyelinating or axonal patterns, or a non-diagnostic pattern with abnormal late responses; there may be attenuated M responses upon lumbar root stimulation as the only finding. Pathological changes predominated in proximal nerves, in some studies, most prominent at the sides where the spinal roots unite to form the spinal nerves; on very early GBS endoneurial inflammatory edema was the outstanding feature. In the far majority of cases, spinal magnetic resonance imaging showed contrast enhancement of cauda equina, selectively involving anterior roots in AMAN. Both in AIDP and AMAN/AMSAN, ultrasonography has demonstrated frequent enlargement of ventral rami of C5-C7 nerves with blurred boundaries, whereas sonograms of upper and lower extremity peripheral nerves exhibited variable and less frequent abnormalities. We provide new insights into the pathogenesis and classification of early GBS.

Guillain–Barré syndrome following hepatitis E

Guillain–Barre syndrome (GBS) is often triggered by a preceding bacterial or viral infection. A molecular mimicry mechanism is supposed to be involved in the pathogenesis of GBS triggered by infectious agents, although the nature of the shared epitopes has not been characterized in most instances, including that in the case of hepatotropic viruses. We report a case of GBS following acute hepatitis E.

Risperidone - A Probable Cause of Guillain-Barre Syndrome: A Case Report

Background: Guillain-Barre syndrome (GBS) is an acute immune-mediated demyelinating polyneuropathy, and it has been suggested that immune-mediated mechanism underlying the pathogenesis of GBS was triggered by infectious agents, vaccination, head trauma, operation, and malignancy. Risperidone, one of the secondgeneration antipsychotic drugs, tends to alter cytokine levels that could partly be attributed to GBS occurrence. Findings: We herein present a 7 year-old-girl who developed GBS under risperidone treatment. The possibility of occurrence of GBS triggered by risperidone was analyzed using causality assessment scales of Naranjo and World Health Organization Collaborating Centre for International Drug Monitoring, the Uppsala Monitoring Centre (WHO–UMC). The results indicated that risperidone was a probable cause of GBS. Conclusion: Patients with newly-emerging neurologic symptoms under risperidone should undergo detailed neurologic examination, and if necessary neurophysiologic assessment.