Anti-ganglioside Antibodies Research Articles

Analysis of anti-ganglioside antibodies by a line immunoassay in patients with chronic-inflammatory demyelinating polyneuropathies (CIDP).

Unlike for acute immune-mediated neuropathies (IN), anti-ganglioside autoantibody (aGAAb) testing has been recommended for only a minority of chronic IN yet. Thus, we used a multiplex semi-quantitative line immunoassay (LIA) to search for aGAAb in chronic-inflammatory demyelinating polyneuropathy (CIDP) and its clinical variants. Anti-GAAb to 11 gangliosides and sulfatide (SF) were investigated by LIA in 61 patients with IN (27 typical CIDP, 12 distal-acquired demyelinating polyneuropathy, 6 multifocal-acquired demyelinating sensory/motor polyneuropathy, 10 sensory CIDP, 1 focal CIDP and 5 multifocal-motoric neuropathy), 40 with other neuromuscular disorders (OND) (15 non-immune polyneuropathies, 25 myasthenia gravis), 29 with multiple sclerosis (MS) and 54 healthy controls (HC). In contrast to IgG, positive anti-GAAB IgM against at least one ganglioside/SF was found in 17/61 (27.9%) IN compared to 2/40 (5%) in OND, 2/29 MS (6.9%) and 4/54 (7.4%) in HC (p=0.001). There was a statistically higher prevalence of anti-sulfatide (aSF) IgM in IN compared to OND (p=0.008). Further, aGM1 IgM was more prevalent in IN compared to OND and HC (p=0.009) as well as GD1b in IN compared to HC (p<0.04). The prevalence of aGM1 IgM in CIDP was lower compared to in multifocal motor neuropathy (MMN) (12% vs. 60%, p=0.027). Patients showing aSF, aGM1 and aGM2 IgM were younger compared to aGAAb negatives (p<0.05). Patients with aSF IgM positivity presented more frequently typical CIDP and MMN phenotypes (p<0.05, respectively). The aGAAb LIA revealed an elevated frequency of at least one aGAAb IgM in CIDP/MMN patients. Anti-SF, aGM1 and aGM2 IgM were associated with younger age and anti-SF with IN phenotypes.

Antibodies to Zika virus, Campylobacter jejuni and gangliosides in Guillain-Barre syndrome: A prospective single-center study from southern India.

The objective of this article was to study the presence of antibodies against Zika virus (ZIKV), Campylobacter jejuni, and gangliosides in patients with Guillain-Barre syndrome (GBS). Ninety consecutive patients (age more than 12 years) with GBS admitted to a tertiary care center in southern India were included in this study. Data on clinical manifestations, nerve conduction studies, and response to therapy were collected. The following tests were done in stored serum samples - anti-ZIKV (IgM) antibodies, anti-C. jejuni (IgG) antibodies, and anti-ganglioside antibodies (IgG). Those samples which were positive to anti-Zika antibodies were tested for conventional polymerase chain reaction for ZIKV and IgM antibodies against dengue, and Japanese encephalitis virus. Of the 90 patients, 3 died and 8 had persistent weakness. Acute inflammatory demyelinating polyradiculoneuropathy was the most common type of GBS (56.7%). Anti-ganglioside antibodies were present in 62.2% patients with GT1b being the most common. Anti-C. jejuni antibodies were present in 46.6%. Anti-Zika antibodies (IgM) were present in 14 patients (15.5%). Four of these patients also had anti-dengue antibody (IgM) positivity. This is one of the largest studies on GBS from India and the first one to report on the presence of Zika virus antibodies from this geographical area. Our study had a high prevalence of anti-C. jejuni and anti-ganglioside antibodies. Evidence of recent ZIKV infection, as evidenced by anti-IgM antibodies, was present in 14 patients, with 4 of them being tested positive for anti-dengue IgM antibody. Whether this represents cross-reaction with dengue or prior/co-infection with dengue virus could not be addressed in this study.

Anti-ganglioside Antibodies in Peripheral Nerve Pathology.

Anti-ganglioside antibodies are principally associated with autoimmune peripheral neuropathies. In these disorders, immune attack is inadvertently directed at peripheral nerve by autoantibodies that target glycan structures borne by glycolipids, particularly gangliosides concentrated in nerve myelin and axons. The most thoroughly studied disorder is the acute paralytic disease, Guillain-Barré syndrome (GBS) in which IgG autoantibodies against gangliosides arise following acute infections, notably Campylobacter jejuni enteritis. Additionally, chronic autoimmune neuropathies are associated with IgM antibodies directed against many glycolipids including gangliosides. This introductory chapter briefly summarizes the immunological and pathological features of these disorders, focusing on the methodological development of antibody measurement and of animal models.

Clinical Heterogeneity of Anti-GM2-Ganglioside-Antibody Syndrome.

Background and PurposeAntiganglioside antibodies are known to play a pathogenic role in Guillain-Barré syndrome (GBS). Either an immunoglobulin (Ig)G- or IgM-type anti-GM2 antibody is detected in rare cases in GBS patients. However, the specific pathogenic role of these antibodies in GBS has not been reported previously. This study aimed to define and characterize the clinical spectrum of GBS with anti-GM2 positivity.MethodsWe reviewed the database of the Dong-A University Neuroimmunology Team, which has collected sera of GBS and its variants from more than 40 general and university-based hospitals in Korea. Detailed information about the involved patients was often obtained and then corrected by the charge doctor applying additional questionnaires.ResultsFour patients with acute monophasic peripheral neuropathy or cranial neuropathy with isolated IgM-type anti-GM2-antibody positivity were recruited. In addition, IgG-type anti-GM2 antibody was solely detected in the sera of another four patients. The IgM-positive group comprised heterogeneous syndromes: two cases of acute motor axonal neuropathy, one of acute inflammatory demyelinating polyneuropathy, and one of isolated facial diplegia. In contrast, all of the cases enrolled in the IgG-positive group manifested with dizziness with or without oculomotor palsy due to cranial neuropathy syndrome.ConclusionsThis study has identified that anti-GM2 antibody can be found in various subtypes of GBS and its variants in rare cases. Compared to the clinical heterogeneity of the IgM-positive group, the IgG-positive group can be characterized by cranial-dominant GBS variants presenting mainly with oculomotor and vestibular dysfunctions.

Gangliosides and Autoimmune Peripheral Nerve Diseases.

A wide range of neuroimmunological diseases, referred to as autoimmune neuropathies, affect the peripheral nervous systems (PNS). The PNS is structurally diverse with complex anatomical compartments enriched in many different myelin and neuronal glycolipids, notably gangliosides. Autoimmune neuropathies are a proportion of autoimmune neuropathies mediated by autoimmune attack due to antibodies reactive with these compartmentally localized gangliosides. Antiganglioside antibodies are principally associated with the acute paralytic disease, Guillain-Barré syndrome, and are also found in several chronic autoimmune neuropathy syndromes. These antibodies may arise spontaneously from the natural autoantibody repertoire, or be induced by infections that share structurally similar glycans to gangliosides, an immunological process often referred to as molecular mimicry. The principal infection exhibiting this structural similarity is Campylobacter jejuni, which displays mimics of GM1, GD1a, GT1a, and other gangliosides on its surface lipo-oligosaccharide. Autoantibodies thus induced bind glycan epitopes on peripheral nerve gangliosides where they activate complement and recruit macrophages, causing structural and functional disorganization of nerve conduction. Chronic autoimmune neuropathies are also associated with naturally arising IgM antibodies directed against ganglioside epitopes present on disialylated gangliosides, that induce a sensory neuropathy, and on GM1, that induce a motor neuropathy. In a third syndrome, the so-called "anti-MAG" neuropathy, the antibodies bind a sulfated glucuronic acid epitope present on myelin-associated glycoprotein and the glycolipid sulfated glucuronyl paragloboside. This review will describe the immunological, pathological, and clinical features of these disorders in the context of our broader knowledge of the ganglioside glycobiology of the peripheral nervous system.

Methods for the Preparation of Anti-ganglioside Monoclonal Antibodies.

The antibody preparation method to the glycolipid is basically same to the method to the protein. However, because the immunogenicity of the carbohydrate moieties of glycolipid is generally low in the mouse, the development of the anti-glycolipid antibody using purified glycolipid as an immunogen was not yet established. Here, we describe a method using a purified ganglioside adsorbed onto Salmonella minnesota for the efficient production of an anti-ganglioside mouse monoclonal antibody that recognizes the carbohydrate moieties of the ganglioside.

The Potential Misdiagnosis of Multifocal Motor Neuropathy as Amyotrophic Lateral Sclerosis—A Case Series

Multifocal motor neuropathy (MMN) is a rare neuropathy that is often treatable with immunomodulatory therapy if diagnosed early. However, accurate diagnosis is difficult due to a significant overlap of symptoms with other neurological conditions, such as amyotrophic lateral sclerosis (ALS). Evidence of immunoglobulin M (IgM) anti-ganglioside GM1 antibodies and electrodiagnostic findings of conduction block are useful diagnostic criteria for MMN but are not universal findings. This review explores the differential diagnosis of MMN and ALS and discusses three cases of MMN initially diagnosed as ALS, in which the correct diagnosis allowed effective treatment. These cases highlight the need for greater awareness of MMN among physicians.

Gangliosides in Axon Stability and Regeneration.

Gangliosides are a family of sialic acid-containing glycosphingolipids highly expressed in the nervous system of vertebrates. Over the last 25years, research has unmasked several of their neurobiological functions but the role of gangliosides in the nervous system remains not fully elucidated. Genetic disruption of genes for key enzymes involved in ganglioside biosynthesis led to the discovery of their diverse functions and highlighted the exquisite structural specificity required in this processes. In the nervous system, gangliosides regulate axonal caliber and organize ion channels at the nodes of Ranvier, a critical step to ensure fast conduction velocity of myelinated fibers. They also act as receptors for lectins located on apposing myelin membranes critical to maintain axon-glia interactions that result in cytoskeleton stabilization. After a lesion, gangliosides acting as receptors for glial-derived molecules present in the extracellular milieu can halt axon regeneration. Similarly, antiganglioside antibodies present in autoimmune neurological conditions can mimic this inhibitory effect on nerve repair. Studying the molecular details of the molecular interaction of gangliosides in trans with ligands present on apposing cell membranes and receptor/transducer molecules in cis interaction at the axolemma membrane, together with their downstream signaling pathways, represent a unique opportunity to expand our knowledge about the role of gangliosides in the nervous system.

An adult onset sporadic neuronal intranuclear inclusion disease case reminiscent with Fisher syndrome

A 63-year-old woman presented to our hospital with sudden symptoms of unsteadiness while walking. Based on the neurological findings, i.e., ataxia and absence of tendon reflex in the extremities accompanied by antecedent infection at the time, she was tentatively diagnosed with Fisher syndrome. Following intravenous immunoglobulin (IVIg) therapy for 5 days, her ataxic symptoms improved. Laboratory data were negative for antiganglioside antibody against GQ1b in the IgG subclass. Six months after her first admission, cognitive impairment gradually developed. She was re-admitted owing to new onset of unsteadiness while walking 1.5 years after her first admission. Diffusion-weighted brain MRI (DWI) revealed linear high-intensity signals in the region of the corticomedullary junction. Cutaneous skin biopsy revealed intranuclear inclusion bodies in sweat gland cells. Considering her family history along with the examination results, we diagnosed with adult-onset sporadic neuronal intranuclear inclusion disease (NIID). Retrospective investigation of the previous DWI obtained at the first admission had also shown slight linear high-intensity areas, suggesting that a series of events, including repeated sudden-onset transient ataxia, resulted due to NIID.

Chronic inflammatory demyelinating polyneuropathy and malignancy: A systematic review.

A systematic review of the literature was performed on the association of chronic inflammatory demyelinating polyneuropathy (CIDP) with malignancy. Hematological disorders are the most common association, particulalry non-Hodgkin lymphoma. CIDP frequently precedes the malignancy diagnosis, and there is a favorable CIDP response to treatment more than 70% of the time. Melanoma is the second most common association and may be accompanied by antiganglioside antibodies; CIDP shows a good response to immunotherapy. Other cancers are rare, with variable timings and presentations but good responses to immunomodulation and/or cancer therapy. Unusual neurological features such as ataxia, distal/upper limb predominance, or cranial/respiratory/autonomic involvement may suggest associated malignancy as may abdominal pain, diarrhea/constipation, poor appetite/weight loss, dermatological lesions, and lymphadenopathy. In the appropriate clinical and electrophysiological setting, CIDP associated with cancer should be considered. Immunomodulatory therapy, cancer treatment alone, or a combination may be effective. Muscle Nerve 57: 875-883, 2018.

Analysis of the clinical and electrophysiological characteristics of multifocal motor neuropathy

Ten patients diagnosed with multifocal motor neuropathy (MMN) were recruited in the Department of Neurology at Chinese PLA General Hospital from January 1, 2009 to August 31, 2015. The clinical and electrophysiological features were analyzed retrospectively. All patients complained of progressive asymmetric limb weakness, which was more severe in distal than in proximal. Five presented muscle atrophy. None had sensory disturbances. All suffered diminished or disappeared tendon reflex, whereas Babinski signs were negative. Multi-focal conduction block (CB) was confirmed by nerve conduction studies (NCS) in all patients and 7 showed spontaneous potentials in needle electrode electromyography. Abnormal sensory nerve conduction was seen in 3 patients. Laboratory test revealed anti-ganglioside GM1 antibody in cerebrospinal fluid (CSF) in 6 cases and elevated CSF protein in 7 cases. Limb weakness alleviated greatly in 9 cases after intravenous immunoglobulin (IVIg) treatment. But the other one reported poor response, who had long course of disease, serious limb weakness and obvious muscle atrophy. Motor nerve damage is the most important manifestation of MMN and sensory nerve damage may also appear. NCS is essential to the diagnosis of this disease, with CB as the characteristic electrophysiological feature. IVIg is an effective treatment.

Sialic acid and anti-ganglioside antibody levels in children with autism spectrum disorders

BackgroundAutism spectrum disorders (ASD) may result from a combination of genetic and environmental factors, and impact neurological functions and behaviors. Sialic acid (SA) is an indispensable nutrient for early brain development, and its polymer polySia (PSA) can modify neural cell adhesion molecules (NCAM), thereby indirectly mediating neuronal outgrowth, synaptic connectivity and memory formation. To investigate the association between SA and ASD, we conducted a case-control study. MethodsThe study sample included 82 autistic children and 60 healthy children. We measured the levels of plasma SA and serum anti-gangliosides M1 antibodies (anti-GM1 antibodies) in the ASD and control groups. We also examined the severity of autistic children. ResultsThe level of plasma SA in the control group was significantly higher than that in the ASD group (p < .01). Autistic children had higher positive rates of anti-GM1 antibodies (37.8%) than controls (21.67%, P = .04). However, there was no correlation between autistic severity and the levels of SA. SA may be as a biomarker for diagnosis of ASD with a positive predictive value of 84.42%, a negative predictive value of 73.85% and an area under the ROC curve value of 0.858. ConclusionsThese results indicate that SA and anti-GM1 antibodies are associated with ASD. Our data suggested that future studies to explore the function of SA in the etiology of ASD may be needed.

Antibodies against peripheral nerve antigens in chronic inflammatory demyelinating polyradiculoneuropathy

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a heterogeneous disease in which diverse autoantibodies have been described but systematic screening has never been performed. Detection of CIDP-specific antibodies may be clinically useful. We developed a screening protocol to uncover novel reactivities in CIDP. Sixty-five CIDP patients and 28 controls were included in our study. Three patients (4.6%) had antibodies against neurofascin 155, four (6.2%) against contactin-1 and one (1.5%) against the contactin-1/contactin-associated protein-1 complex. Eleven (18.6%) patients showed anti-ganglioside antibodies, and one (1.6%) antibodies against peripheral myelin protein 2. No antibodies against myelin protein zero, contactin-2/contactin-associated protein-2 complex, neuronal cell adhesion molecule, gliomedin or the voltage-gated sodium channel were detected. In IgG experiments, three patients (5.3%) showed a weak reactivity against motor neurons; 14 (24.6%) reacted against DRG neurons, four of them strongly (7.0%), and seven (12.3%) reacted against Schwann cells, three of them strongly (5.3%). In IgM experiments, six patients (10.7%) reacted against DRG neurons, while three (5.4%) reacted against Schwann cells. However, results were not statistically significant when compared to controls. Immunoprecipitation experiments identified CD9 and L1CAM as potential antigens, but reactivity could not be confirmed with cell-based assays. In summary, we describe a diverse autoantibody repertoire in CIDP patients, reinforcing the hypothesis of CIDP’s pathophysiological heterogeneity.

Clinical Features of Acute Flaccid Myelitis Temporally Associated With an Enterovirus D68 Outbreak: Results of a Nationwide Survey of Acute Flaccid Paralysis in Japan, August-December 2015.

Acute flaccid myelitis (AFM) is an acute flaccid paralysis syndrome with spinal motor neuron involvement of unknown etiology. We investigated the characteristics and prognostic factors of AFM clusters coincident with an enterovirus D68 (EV-D68) outbreak in Japan during autumn 2015. An AFM case series study was conducted following a nationwide survey from August to December 2015. Radiographic and neurophysiologic data were subjected to centralized review, and virology studies were conducted for available specimens. Fifty-nine AFM cases (58 definite, 1 probable) were identified, including 55 children and 4 adults (median age, 4.4 years). The AFM epidemic curve showed strong temporal correlation with EV-D68 detection from pathogen surveillance, but not with other pathogens. EV-D68 was detected in 9 patients: 5 in nasopharyngeal, 2 in stool, 1 in cerebrospinal fluid (adult case), and 1 in tracheal aspiration, nasopharyngeal, and serum samples (a pediatric case with preceding steroid usage). Cases exhibited heterogeneous paralysis patterns from 1- to 4-limb involvement, but all definite cases had longitudinal spinal gray matter lesions on magnetic resonance imaging (median, 20 spinal segments). Cerebrospinal fluid pleocytosis was observed in 50 of 59 cases (85%), and 8 of 29 (28%) were positive for antiganglioside antibodies, as frequently observed in Guillain-Barré syndrome. Fifty-two patients showed variable residual weakness at follow-up. Good prognostic factors included a pretreatment manual muscle strength test unit score >3, normal F-wave persistence, and EV-D68-negative status. EV-D68 may be one of the causative agents for AFM, while host susceptibility factors such as immune response could contribute to AFM development.

Evaluations of serum anti-ganglioside antibody, initial symptoms and effectiveness of immunoglobulin therapy in patients with Guillain-Barre syndrome

Background: Anti-ganglioside antibodies (AGA) are often detected in Guillain-Barre syndrome (GBS) patients and Intravenous immunoglobulin (IVIg) therapy is performed in acute phase.

Correlations between cytomegalovirus, epstein-barr virus, anti-ganglioside antibodies, electrodiagnostic findings and functional status in guillain-barre syndrome

Background: The underlying autoimmune background of Guillain-Barré syndrome (GBS) and the possible role of infectious agents cytomegalovirus (CMV) and Epstein-Barr virus (EBV) have been investigated. Also the association of anti-ganglioside antibodies with GBS is considerable.

Anti-ganglioside complex antibodies in chronic immune-mediated neuropathies

Background: Recently, IgG anti-ganglioside complex (GSCs) antibodies have been reported in patients with Guillain-Barré and Miller Fisher syndrome. Some researchers in Europe reported IgM anti-GSCs antibodies in multifocal motor neuropathy (MMN) and other chronic immune-mediated neuropathies.

Ca(2 +)-dependent anti-ganglioside antibodies in seronegative AMAN, AIDP, and SAN

Ca(2 +)-dependent anti-ganglioside antibodies in seronegative AMAN, AIDP, and SAN

Diagnostics of dysimmune peripheral neuropathies.

This document presents the guidelines for anti-ganglioside antibody testing that have been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Main clinical information on dysimmune peripheral neuropathies, indications and limits of anti-ganglioside antibody testing, instructions for result interpretation, and an agreed laboratory protocol (Appendix) are reported for the communicative community of neurologists and clinical pathologists.

S87 Issues in the electrodiagnosis of Guillain-Barré syndrome subtypes

Electrophysiology plays a determinant role in Guillain–Barre syndrome (GBS) diagnosis, classification of the subtypes and in establishing prognosis. Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) has been electrophysiologically characterized by conduction slowing, conduction block, and temporal dispersion. Acute motor axonal neuropathy (AMAN) was initially thought to be characterized by simple axonal degeneration and the electrophysiological correlate limited to reduced amplitude of compound muscle action potentials. However AMAN and acute motor and sensory axonal neuropathy (AMSAN) patients show transient conduction block/slowing due to nodal dysfunction mimicking demyelination but without the development of abnormal temporal dispersion. This has been referred to as reversible conduction failure (RCF) and it is thought to be due to the attack of antiganglioside antibodies at the Ranvier node inducing a transitory dysfunction not progressing to axonal degeneration both in motor and sensory fibers. RCF it can be recognized only by serial studies and it is not included in the current electrodiagnostic criteria of GBS. The lack of distinction between RCF and demyelinating conduction block led to erroneous classification in up to 38% of patients. There is a need for an innovative approach to reach an earlier and more accurate electrodiagnosis based on a single study. In this talk the pitfalls in GBS electrodiagnosis will be highlighted and the inadequacy of current criteria discussed. A new criteria set for AIDP, AMAN and AMSAN, defining also the cut-offs for RCF in motor and sensory fibers, will be illustrated and the electrodiagnostic accuracy of a statistical method of supervised classification (sparse linear discriminant analysis) reported.