Pathology explains various mechanisms of auto-immune inflammatory peripheral neuropathies.

Autoimmune neuropathies are a heterogeneous group of rare and disabling diseases in which the immune system is thought to target antigens in the peripheral nervous system: they usually respond to immune therapies. Guillain-Barré syndrome is divided into several subtypes including "acute inflammatory demyelinating polyradiculoneuropathy," "acute motor axonal neuropathy," "acute motor sensory neuropathy," and other variants. Chronic forms such as chronic inflammatory demyelinating polyneuropathy (CIDP) and other subtypes and polyneuropathy associated with IgM monoclonal gammopathy; autoimmune nodopathies also belong to this group of auto-immune neuropathies. It has been shown that immunoglobulin G from the serum of about 30% of CIDP patients immunolabels nodes of Ranvier or paranodes of myelinated axons. Whatever the cause of myelin damage of the peripheral nervous system, the initial attack on myelin by a dysimmune process may begin either at the internodal area or in the paranodal and nodal regions. The term "nodoparanodopathy" was first applied to some "axonal Guillain-Barré syndrome" subtypes, then extended to cases classified as CIDP bearing IgG4 antibodies against paranodal axoglial proteins. In these cases, paranodal dissection develops in the absence of macrophage-induced demyelination. In contrast, the mechanisms of demyelination of other dysimmune neuropathies induced by macrophages are unexplained, as no antibodies have been identified in such cases. The main objective of this presentation is to show that the pathology illustrates, confirms, and may explain such mechanisms.

Macrophages are scavengers for injured myelin in a rabbit model of acute inflammatory demyelinating polyneuropathy.

In acute inflammatory demyelinating polyneuropathy (AIDP), myelin vesiculation mediated by complement activation contributes to nerve injury. Macrophage infiltration of the spinal roots has been demonstrated in AIDP, but its pathological significance remains uncertain. The present study aimed to investigate the role of macrophages in the pathogenic sequence of AIDP. A rabbit model of AIDP was induced by immunization with galactocerebroside. Immunostaining was performed to localize the macrophages and myelin injury. The rabbit developed tetraparesis with electrophysiological and pathological features of peripheral nerve demyelination. Immunostaining demonstrated colocalization of IgG antibodies, complement deposition and myelin injury apart from macrophages. Immunostaining and electron microscopy showed myelin injury preceded macrophage infiltration. There was significant disruption of voltage-gated sodium channel clusters at the nodes of Ranvier in the spinal roots. Macrophages acted may as scavengers to remove myelin debris following complement activation-mediated demyelination in the AIDP rabbit. Lesions at the node of Ranvier contribute to conduction failure and muscle weakness.

Mental and Lingual Nerve Paresthesia Following Infiltration Anesthesia for Dental Implant Placement in a Patient With Guillain-Barré Syndrome.

Guillain-Barré syndrome (GBS) is a rare rapid onset autoimmune peripheral polyneuropathy, most commonly characterized by inflammatory demyelination of peripheral nerves. Patients with GBS are considered higher risk for anesthetic-induced neurotoxicity caused by demyelination. In the present report, a case is described of a 56-year-old man with GBS who experienced mental and lingual nerve paresthesia following infiltration anesthesia for dental implant placement in the posterior mandible. The pareshesia lasted 5 months postoperatively and subsided spontaneously without any intervention. The patient was successfully restored with fixed partial dental prosthesis without any other complication. This is considered the first report of such complication in patient with GBS after local anesthesia in the oral and maxillofacial region. Possible pathogenic mechanism of the complication and clinical implications are discussed.

Peripherin is a biomarker of axonal damage in peripheral nervous system disease.

Valid, responsive blood biomarkers specific to peripheral nerve damage would improve management of peripheral nervous system (PNS) diseases. Neurofilament light chain (NfL) is sensitive for detecting axonal pathology but is not specific to PNS damage, as it is expressed throughout the PNS and CNS. Peripherin, another intermediate filament protein, is almost exclusively expressed in peripheral nerve axons. We postulated that peripherin would be a promising blood biomarker of PNS axonal damage. We demonstrated that peripherin is distributed in sciatic nerve, and to a lesser extent spinal cord tissue lysates, but not in brain or extra-neural tissues. In the spinal cord, anti-peripherin antibody bound only to the primary cells of the periphery (anterior horn cells, motor axons and primary afferent sensory axons). In vitro models of antibody-mediated axonal and demyelinating nerve injury showed marked elevation of peripherin levels only in axonal damage and only a minimal rise in demyelination. We developed an immunoassay using single molecule array technology for the detection of serum peripherin as a biomarker for PNS axonal damage. We examined longitudinal serum peripherin and NfL concentrations in individuals with Guillain-Barré syndrome (GBS, n = 45, 179 time points), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, n = 35, 70 time points), multiple sclerosis (n = 30), dementia (as non-inflammatory CNS controls, n = 30) and healthy individuals (n = 24). Peak peripherin levels were higher in GBS than all other groups (median 18.75 pg/ml versus < 6.98 pg/ml, P < 0.0001). Peak NfL was highest in GBS (median 220.8 pg/ml) and lowest in healthy controls (median 5.6 pg/ml), but NfL did not distinguish between CIDP (17.3 pg/ml), multiple sclerosis (21.5 pg/ml) and dementia (29.9 pg/ml). While peak NfL levels were higher with older age (rho = +0.39, P < 0.0001), peak peripherin levels did not vary with age. In GBS, local regression analysis of serial peripherin in the majority of individuals with three or more time points of data (16/25) displayed a rise-and-fall pattern with the highest value within the first week of initial assessment. Similar analysis of serial NfL concentrations showed a later peak at 16 days. Group analysis of serum peripherin and NfL levels in GBS and CIDP patients were not significantly associated with clinical data, but in some individuals with GBS, peripherin levels appeared to better reflect clinical outcome measure improvement. Serum peripherin is a promising new, dynamic and specific biomarker of acute PNS axonal damage.

CSF Findings in Relation to Clinical Characteristics, Subtype, and Disease Course in Patients With Guillain-Barré Syndrome.

BACKGROUND AND OBJECTIVES: To investigate CSF findings in relation to clinical and electrodiagnostic subtypes, severity, and outcome of Guillain-Barré syndrome (GBS) based on 1,500 patients in the International GBS Outcome Study. METHODS: Albuminocytologic dissociation (ACD) was defined as an increased protein level (>0.45 g/L) in the absence of elevated white cell count (<50 cells/µL). We excluded 124 (8%) patients because of other diagnoses, protocol violation, or insufficient data. The CSF was examined in 1,231 patients (89%). RESULTS: In 846 (70%) patients, CSF examination showed ACD, which increased with time from weakness onset: ≤4 days 57%, >4 days 84%. High CSF protein levels were associated with a demyelinating subtype, proximal or global muscle weakness, and a reduced likelihood of being able to run at week 2 (odds ratio [OR] 0.42, 95% CI 0.25-0.70; p = 0.001) and week 4 (OR 0.44, 95% CI 0.27-0.72; p = 0.001). Patients with the Miller Fisher syndrome, distal predominant weakness, and normal or equivocal nerve conduction studies were more likely to have lower CSF protein levels. CSF cell count was <5 cells/µL in 1,005 patients (83%), 5-49 cells/µL in 200 patients (16%), and ≥50 cells/µL in 13 patients (1%). DISCUSSION: ACD is a common finding in GBS, but normal protein levels do not exclude this diagnosis. High CSF protein level is associated with an early severe disease course and a demyelinating subtype. Elevated CSF cell count, rarely ≥50 cells/µL, is compatible with GBS after a thorough exclusion of alternative diagnoses. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that CSF ACD (defined by the Brighton Collaboration) is common in patients with GBS.

Relationship between Hypoxic and Immune Pathways Activation in the Progression of Neuroinflammation: Role of HIF-1α and Th17 Cells.

Neuroinflammation is a common event in degenerative diseases of the central and peripheral nervous system, triggered by alterations in the immune system or inflammatory cascade. The pathophysiology of these disorders is multifactorial, whereby the therapy available has low clinical efficacy. This review propounds the relationship between the deregulation of T helper cells and hypoxia, mainly Th17 and HIF-1α molecular pathways, events that are involved in the occurrence of the neuroinflammation. The clinical expression of neuroinflammation is included in prevalent pathologies such as multiple sclerosis, Guillain-Barré syndrome, and Alzheimer's disease, among others. In addition, therapeutic targets are analyzed in relation to the pathways that induced neuroinflammation.

Celastrol attenuates Guillain-Barré syndrome by inhibiting TLR4/NF-κB/STAT3 pathway-mediated Th1/Th17 cell differentiation.

Guillain-Barré syndrome (GBS) is an acute immune-mediated paralytic neuropathy with variable disease course and outcome. In this study, we aimed to investigate the therapeutic effects of celastrol on GBS and uncover its underlying mechanisms. Experimental autoimmune neuritis (EAN) is a typical animal model for GBS, and thus an EAN rat model was established with the injection of celastrol or/and LPS. We assessed the body weights and EAN clinical scores of rats. HE staining, flow cytometry, RT-qPCR, and Western blotting were respectively employed to measure pathological damage, proportions of cells (Th1, Th17, and Treg), Th1/Th17 cell differentiation-related mRNAs (IFN-γ, TBX21, IL-18, RORγT, IL-17, and IL-23) and TLR4/NF-κB/STAT3 pathway-related proteins (TLR4, NF-κB, p-NF-κB, STAT3, and p-STAT3). We found that celastrol attenuated clinical symptoms and pathological damage of GBS in EAN rats. Moreover, celastrol down-regulated Th1 and Th17 cell proportions, and the levels of IFN-γ, TBX21, IL-18, RORγT, IL-17, and IL-23 in EAN rats. Meanwhile, the levels of TLR4, p-NF-κB, and p-STAT3 were decreased by celastrol. Taken together, celastrol could restrain Th1/Th17 cell differentiation through inhibition of the TLR4/NF-κB/STAT3 pathway in EAN rats. Our findings suggest that celastrol may exert therapeutic effects on GBS by suppressing TLR4/NF-κB/STAT3 pathway-mediated Th1/Th17 cell differentiation.

Serum Inflammatory Markers in Patients with Guillain Barre Syndrome.

Background: Guillain Barre syndrome (GBS) is an immune-mediated peripheral neuropathy characterized by the demyelination and axonal damage of the peripheral neurons. The pathogenesis of GBS involves the breakdown of the blood-brain barrier after which pro inflammatory cytokines attack the neurons in the peripheral nervous system. Aims: This study aims to evaluate five markers, namely matrix metalloproteinase (MMP)-2 and MMP-9, vascular endothelial growth factor (VEGF)-A, basic fibroblast growth factor (bFGF), and SFLT-1, which could have a role in the inflammatory response in patients with GBS and healthy controls. Settings and Design: In this prospective study, patients diagnosed with GBS at the department of neurology, Kasturba Medical College, Manipal, Karnataka were enrolled. Methods and Material: The markers selected for this study were analyzed using the ELISA method and expressed as given in the kit provided by the company. Ethical clearance was obtained from the Institutional Ethical Committee. Statistical Analysis: Results were evaluated using SPSS version 17.0 and expressed as mean ± SD. Error bars for each were drawn. Results: The levels of all five parameters showed a significant increase in patients as compared to controls. Conclusions: Disruption of the basement membrane of endoneurium by MMP-2 and MMP-9, recruitment and migration of macrophages and other cytokines by VEGF-A, bFGF, and soluble fms-like tyrosine kinase-1 (SFLT-1) are plausible, which leads to inflammation process and thus neuronal damage leading to the development of GBS.

The underlying mechanism of Guillain-Barré syndrome in a young patient suffered from Japanese encephalitis virus infection: a case report.

BACKGROUND: The presentation of Guillain-Barré syndrome (GBS) caused by Japanese encephalitis virus (JEV) is uncommon, although clusters of GBS cases were observed in China in 2018. The underlying mechanism is unclear, particularly in individuals vaccinated against Japanese encephalitis in childhood. CASE PRESENTATION: We report a patient with acute flaccid paralysis involving four extremities and respiratory muscles, while magnetic resonance imaging of the brain and spine were standard. Electrophysiological examination displayed slowed motor nerve conduction speed and reduced evoked velocity amplitude. GBS was finally considered which was related to JEV infection verified by positive anti-JEV immunoglobulin M antibody and positive immunoglobulin G antibody in the serum. Unfortunately, the patient refused intravenous immunoglobulin and declined the use of mechanical ventilation again. He voluntarily withdrew from the hospital and died on the 36th day after the onset of illness. We also performed a review of previously reported related cases and discussed the underlying mechanism. CONCLUSION: JEV infection-associated GBS is unusual. We should pay attention to the atypical manifestations of JEV infection and explore possible pathogenesis in particular individuals.

Campylobacter jejuni induces autoimmune peripheral neuropathy via Sialoadhesin and Interleukin-4 axes.

Campylobacter jejuni is a leading cause of gastroenteritis that has been causally linked with development of the autoimmune peripheral neuropathy Guillain Barré Syndrome (GBS). Previously, we showed that C. jejuni isolates from human enteritis patients induced Type1/17-cytokine dependent colitis in interleukin-10 (IL-10)-/- mice, while isolates from GBS patients colonized these mice without colitis but instead induced autoantibodies that cross-reacted with the sialylated oligosaccharide motifs on the LOS of GBS-associated C. jejuni and the peripheral nerve gangliosides. We show here that infection of IL-10-/- mice with the GBS but not the colitis isolate led to sciatic nerve inflammation and abnormal gait and hind limb movements, with character and timing consistent with this syndrome in humans. Autoantibody responses and associated nerve histologic changes were dependent on IL-4 production by CD4 T cells. We further show that Siglec-1 served as a central antigen presenting cell receptor mediating the uptake of the GBS isolates via interaction with the sialylated oligosaccharide motifs found specifically on the LOS of GBS-associated C. jejuni, and the ensuing T cell differentiation and autoantibody elicitation. Sialylated oligosaccharide motifs on the LOS of GBS-associated C. jejuni therefore acted as both the Siglec-1-ligand for phagocytosis, as well as the epitope for autoimmunity. Overall, we present a mouse model of an autoimmune disease induced directly by a bacterium that is dependent upon Siglec-1 and IL-4. We also demonstrate the negative regulatory role of IL-10 in C. jejuni induced autoimmunity and provide IL-4 and Siglec-1 blockade as potential therapeutic interventions against GBS.

Guillain-Barre Syndrome After Two COVID-19 Vaccinations: Two Case Reports With Follow-up Electrodiagnostic Study.

Guillain-Barre syndrome (GBS) is an immune-mediated acute polyradiculoneuropathy and commonly occurs after a preceding infection or immunization sequalae. Following the severe acute respiratory syndrome-coronavirus-2 virus pandemic with co-introduction of massive vaccinations, several GBS cases associated with coronavirus disease 2019 (COVID-19) infection per se or after vaccination for COVID-19 were reported internationally. Herein, we report two cases of Korean GBS presenting with tetraplegia after two different COVID-19 vaccinations (42-year old man by AstraZeneca and 48-year woman by Pfizer vaccines) within four weeks after vaccination. The patients were diagnosed with clinical examination, serial electromyography, and compatible laboratory results and improved after comprehensive rehabilitative treatment and intravenous immunoglobulin therapy. Furthermore, we performed an electrodiagnostic follow-up study of each case to examine their unique characteristics.

NKT and NKT-like Cells in Autoimmune Neuroinflammatory Diseases-Multiple Sclerosis, Myasthenia Gravis and Guillain-Barre Syndrome.

NKT cells comprise three subsets-type I (invariant, iNKT), type II, and NKT-like cells, of which iNKT cells are the most studied subset. They are capable of rapid cytokine production after the initial stimulus, thus they may be important for polarisation of Th cells. Due to this, they may be an important cell subset in autoimmune diseases. In the current review, we are summarising results of NKT-oriented studies in major neurological autoimmune diseases-multiple sclerosis, myasthenia gravis, and Guillain-Barre syndrome and their corresponding animal models.

Guillain Barrè syndrome and myelitis associated with SARS-CoV-2 infection.

Despite a likely underestimation due to the many obstacles of the highly infectious, intensive care setting, increasing clinical reports about COVID-19 patients developing acute paralysis for polyradiculoneuritis or myelitis determine additional impact on the disease course and outcome. Different pathogenic mechanisms have been postulated basing on clinical, laboratory and neuroimaging features, and response to treatments. Here we provide an overview with insights built on the available reports. Besides direct viral pathogenicity, a crucial role seems to be represented by immune-mediated mechanisms, supporting and further characterizing the already hypothesized neurotropic potential of SARS-CoV-2 and implying specific treatments. Proper clinical and instrumental depiction of symptomatic cases, as well as screening for their early recognition is advocated.

SARS-CoV-2 Infection and Guillain-Barré Syndrome: A Review on Potential Pathogenic Mechanisms.

Since December 2019, the world has been facing an outbreak of a new disease called coronavirus disease 2019 (COVID-19). The COVID-19 pandemic is caused by a novel beta-coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 infection mainly affects the respiratory system. Recently, there have been some reports of extra-respiratory symptoms such as neurological manifestations in COVID-19. According to the increasing reports of Guillain-Barré syndrome following COVID-19, we mainly focused on SARS-CoV-2 infection and Guillain-Barré syndrome in this review. We tried to explain the possibility of a relationship between SARS-CoV-2 infection and Guillain-Barré syndrome and potential pathogenic mechanisms based on current and past knowledge.

Anti-glycan antibodies: roles in human disease.

Carbohydrate-binding antibodies play diverse and critical roles in human health. Endogenous carbohydrate-binding antibodies that recognize bacterial, fungal, and other microbial carbohydrates prevent systemic infections and help maintain microbiome homeostasis. Anti-glycan antibodies can have both beneficial and detrimental effects. For example, alloantibodies to ABO blood group carbohydrates can help reduce the spread of some infectious diseases, but they also impose limitations for blood transfusions. Antibodies that recognize self-glycans can contribute to autoimmune diseases, such as Guillain-Barre syndrome. In addition to endogenous antibodies that arise through natural processes, a variety of vaccines induce anti-glycan antibodies as a primary mechanism of protection. Some examples of approved carbohydrate-based vaccines that have had a major impact on human health are against pneumococcus, Haemophilus influeanza type b, and Neisseria meningitidis. Monoclonal antibodies specifically targeting pathogen associated or tumor associated carbohydrate antigens (TACAs) are used clinically for both diagnostic and therapeutic purposes. This review aims to highlight some of the well-studied and critically important applications of anti-carbohydrate antibodies.

Porphyric neuropathy.

Acute hepatic porphyrias are inherited metabolic disorders that may present with polyneuropathy, which if not diagnosed early can lead to quadriparesis, respiratory weakness, and death. Porphyric neuropathy is an acute to subacute motor predominant axonal neuropathy with a predilection for the upper extremities and usually preceded by a predominantly parasympathetic autonomic neuropathy. The rapid progression and associated dysautonomia mimic Guillain-Barré syndrome but are distinguished by the absence of cerebrospinal fluid albuminocytologic dissociation, progression beyond 4 wk, and associated abdominal pain. Spot urine test to assess the porphyrin precursors delta-aminolevulinic acid and porphobilinogen can provide a timely diagnosis during an acute attack. Timely treatment with intravenous heme, carbohydrate loading, and avoidance of porphyrinogenic medications can prevent further neurological morbidity and mortality.

Bioinformatic analyses hinted at augmented T helper 17 cell differentiation and cytokine response as the central mechanism of COVID-19-associated Guillain-Barré syndrome.

OBJECTIVES: Guillain-Barré syndrome (GBS) results from autoimmune attack on the peripheral nerves, causing sensory, motor and autonomic abnormalities. Emerging evidence suggests that there might be an association between COVID-19 and GBS. Nevertheless, the underlying pathophysiological mechanism remains unclear. MATERIALS AND METHODS: We performed bioinformatic analyses to delineate the potential genetic crosstalk between COVID-19 and GBS. RESULTS: COVID-19 and GBS were associated with a similar subset of immune/inflammation regulatory genes, including TNF, CSF2, IL2RA, IL1B, IL4, IL6 and IL10. Protein-protein interaction network analysis revealed that the combined gene set showed an increased connectivity as compared to COVID-19 or GBS alone, particularly the potentiated interactions with CD86, IL23A, IL27, ISG20, PTGS2, HLA-DRB1, HLA-DQB1 and ITGAM, and these genes are related to Th17 cell differentiation. Transcriptome analysis of peripheral blood mononuclear cells from patients with COVID-19 and GBS further demonstrated the activation of interleukin-17 signalling in both conditions. CONCLUSIONS: Augmented Th17 cell differentiation and cytokine response was identified in both COVID-19 and GBS. PBMC transcriptome analysis also suggested the pivotal involvement of Th17 signalling pathway. In conclusion, our data suggested aberrant Th17 cell differentiation as a possible mechanism by which COVID-19 can increase the risk of GBS.

Guillain-Barré syndrome.

Guillain-Barré syndrome is the most common cause of acute flaccid paralysis worldwide. Most patients present with an antecedent illness, most commonly upper respiratory tract infection, before the onset of progressive motor weakness. Several microorganisms have been associated with Guillain-Barré syndrome, most notably Campylobacter jejuni, Zika virus, and in 2020, the severe acute respiratory syndrome coronavirus 2. In C jejuni-related Guillain-Barré syndrome, there is good evidence to support an autoantibody-mediated immune process that is triggered by molecular mimicry between structural components of peripheral nerves and the microorganism. Making a diagnosis of so-called classical Guillain-Barré syndrome is straightforward; however, the existing diagnostic criteria have limitations and can result in some variants of the syndrome being missed. Most patients with Guillain-Barré syndrome do well with immunotherapy, but a substantial proportion are left with disability, and death can occur. Results from the International Guillain-Barré Syndrome Outcome Study suggest that geographical variations exist in Guillain-Barré syndrome, including insufficient access to immunotherapy in low-income countries. There is a need to provide improved access to treatment for all patients with Guillain-Barré syndrome, and to develop effective disease-modifying therapies that can limit the extent of nerve injury. Clinical trials are currently underway to investigate some of the potential therapeutic candidates, including complement inhibitors, which, together with emerging data from large international collaborative studies on the syndrome, will contribute substantially to understanding the many facets of this disease.

Over-Expression of Immune-Related lncRNAs in Inflammatory Demyelinating Polyradiculoneuropathies.

Long non-coding RNAs (lncRNAs) have crucial roles in the pathogenesis of immune-related disorders. However, their role in the pathobiology of inflammatory demyelinating polyradiculoneuropathies remains unclear. In the current study, we measured peripheral expression of four lncRNAs, namely TUG1, FAS-AS1, NEAT1, and GAS5, in patients with acute/chronic inflammatory demyelinating polyradiculoneuropathies (AIDP/CIDP) compared with healthy subjects. Notably, all lncRNAs were over-expressed in patients compared with controls (P < 0.0001 for all lncRNAs). When assessing their expressions in AIDP and CIDP groups separately, TUG1 and NEAT1 were up-regulated in both patient groups compared with controls, yet FAS-AS1 and GAS5 were only up-regulated in CIDP cases. There were remarkable pairwise correlations between expression levels of these lncRNAs in all study groups. Based on the above-mentioned data, we suggest participation of these for lncRNAs in the pathogenesis of inflammatory demyelinating polyradiculoneuropathies. Moreover, FAS-AS1 and GAS5 lncRNAs have type-specific roles in this regard. Future functional studies are needed to elaborate the molecular mechanisms of the contribution of these transcripts in AIDP/CIDP.