anti-GM1 IgM Research Articles

Polyclonal IgM and IgA block in vitro complement deposition mediated by anti-ganglioside antibodies in autoimmune neuropathies

Intravenous immunoglobulin (IVIG), consisting of IgG, is the first-line treatment for Guillain–Barré syndrome and multifocal motor neuropathy. IgG, but neither IgM nor IgA, has been demonstrated in vitro to inhibit complement deposition mediated by anti-ganglioside autoantibodies in sera from patients with both conditions. The objective of this study is to investigate the in vitro effectiveness of IgM and IgA in inhibiting complement deposition to ganglioside/anti-ganglioside antibody complexes. Serum samples were obtained from patients with multifocal motor neuropathy associated with anti-GM1 IgM antibodies, Guillain–Barré syndrome associated with anti-GM1 IgG antibodies and Miller Fisher syndrome associated with anti-GQ1b IgG antibodies. Inhibition of complement deposition using different immunoglobulin preparations was measured by enzyme-linked immunosorbent assay. IgM/A-enriched IVIG and immunoglobulin isotypes (polyclonal IgM and IgA) showed higher potential in inhibiting complement deposition than standard IVIG. Although the safety concerns about the use of IgM and IgA for an immunotherapy still remain, IgM and IgA may serve as an alternative immunotherapy in those anti-ganglioside antibody-mediated neuropathies.

Human immune globulin infusion in the management of multifocal motor neuropathy.

Multifocal motor neuropathy (MMN) is a debilitating and rare disease causing profound weakness with minimal to no sensory symptoms. Conduction block is frequently seen on electrodiagnostic testing. An immune-mediated pathology is suspected though the exact underlying pathophysiology has yet to be elucidated. The presence of anti-GM1 ganglioside IgM antibodies coupled with favorable response to intravenous and subcutaneous immunoglobulins supports a complement-mediated mechanism which leads to destruction of nerve tissue with probable predilection to the nodes of Ranvier. High-dose immunoglobulin currently is the only treatment with proven efficacy for MMN patients. Unfortunately, many patients experience decreased responsiveness to immunoglobulins over time, requiring higher and more frequent dosing. In this review, we will focus on the pharmacology, efficacy, safety, and tolerability of intravenous and subcutaneous immune globulin infusion for treatment of MMN.

Complement activity is associated with disease severity in multifocal motor neuropathy

Objective:To investigate whether high innate activity of the classical and lectin pathways of complement is associated with multifocal motor neuropathy (MMN) and whether levels of innate complement activity or the potential of anti-GM1 antibodies to activate the complement system correlate with disease severity.Methods:We performed a case-control study including 79 patients with MMN and 79 matched healthy controls. Muscle weakness was documented with Medical Research Council scale sum score and axonal loss with nerve conduction studies. Activity of the classical and lectin pathways of complement was assessed by ELISA. We also determined serum mannose-binding lectin (MBL) concentrations and polymorphisms in the MBL gene (MBL2) and quantified complement-activating properties of anti-GM1 IgM antibodies by ELISA.Results:Activity of the classical and lectin pathways, MBL2 genotypes, and serum MBL concentrations did not differ between patients and controls. Complement activation by anti-GM1 IgM antibodies was exclusively mediated through the classical pathway and correlated with antibody titers (p < 0.001). Logistic regression analysis showed that both high innate activity of the classical pathway of complement and high complement-activating capacity of anti-GM1 IgM antibodies were significantly associated with more severe muscle weakness and axonal loss.Conclusion:High innate activity of the classical pathway of complement and efficient complement-activating properties of anti-GM1 IgM antibodies are determinants of disease severity in patients with MMN. These findings underline the importance of anti-GM1 antibody–mediated complement activation in the pathogenesis and clinical course of MMN.

The Diagnostic Utility of Determining Anti-GM1: GalC Complex Antibodies in Multifocal Motor Neuropathy: A Validation Study.

Background: Multifocal motor neuropathy (MMN) is associated with IgM antibodies to GM1 ganglioside. The importance of the lipid milieu that might facilitate or inhibit antibody binding to GM1 in immunoassays is well recognised. Existing studies, using a range of different approaches, generally concur that anti-GM1 IgM antibody detection rates are improved by the addition of galactocerebroside (GalC) to the GM1 assay.Objective: The current study sought to formally evaluate the clinical utility of the GM1:GalC complex assay in the diagnosis of MMN.Methods: Anti-GM1 and -GM1:GalC antibodies were examined using ELISA and glycoarray (dot blot) in a fully blinded study design, consisting of 100 MMN patients, 100 ALS cases and 100 healthy controls.Results: The detection of anti-GM1 Abs using glycoarray was 67% sensitive and 85% specific. The addition of GalC to GM1, (1:1 weight to weight ratio), increased the sensitivity to 81% , whilst dropping specificity to 80% . Increasing the GalC content to a 1:5 ratio (or higher) further decreased specificity, and in doing so limited the usefulness of the GM1:GalC assay to the level of GM1 alone. The addition of GalC to the ELISA method also significantly increased sensitivity compared with GM1 alone, albeit with a significant decrease in specificity.Conclusions: This study indicates that the GM1:GalC assay is an advantageous assay adaptation for detecting anti-GM1 antibodies in MMN, using either glycoarray or ELISA, and warrants introduction into clinical diagnostic practice.

14. Autoimmune lower motor neurone disorder – Case report

Motor neurone diseases (MND) traditionally include a broad spectrum of neuromuscular disorders. First, we have to mention sporadic forms of ALS (amyotrophic lateral sclerosis) with mixed clinical presentation (syndromes with upper and lower motor neurone signs), then the isolated central type (primary lateral sclerosis, PLS) and at last the isolated peripheral type (primary muscular atrophy, PMA). The existence of familiar hereditary and genetic MND forms is well known, e.g. superoxide dismutase (SOD-1) and dynactin gene mutations are known to cause PMA variants also called LMND (lower motor neurone disease). Selected LMND cases are associated to specific autoantibodies. For example an asymmetric lower motor neurone syndrome with predominant distal involvement is associated to IgM anti-GM1 or to IgM anti-GalNAc-GD1a. Another LMND variant is an asymmetric lower motor neurone syndrome with particular damage of proximal upper extremities muscles (also known as Vulpian–Bernhard syndrome, brachial amyotrophic diplegia or flail arm syndrome) can be associated in 10–20% cases to anti-asialo GM1 autoantibodies. We present a patient’s case report with suspected Vulpian–Bernhard syndrome with bilateral non-symmetric cervico-brachial amyotrophy without sensory impairment. The autoimmune aetiology was clearly proven by clinical responsiveness to immunosuppression/immunomodulation therapy mainly to repetitive intravenous human polyclonal immunoglobulin application (IVIG).

High Levels of Anti-Ganglioside Antibodies in Patients with Parkinson?s Disease Associated with Cognitive Decline

Background: Increasing evidence suggests that gangliosides act as important mediators in both demyelination and remyelination. Objective: The purpose of the present study was to investigate the presence of IgM antibodies against GM1, GD1b and GQ1b gangliosides in the sera of in patients who suffered from Parkinson’s disease in correlation with the clinical parameters. Method: The present research is based on the investigation of 44 patients (63.7-73.3 years) for anti-ganglioside antibodies and 44 healthy age- matched individuals, as normal controls, using Enzyme-Linked Immuno-Sorbent Assays. Results: The patients revealed increased levels of the tested antibodies, compared to normal controls (p=0.0005). A correlation between IgM anti-GM1 and the level of cognitive impairment (Minimental State Examination, p=0.003; Unified Parkinson’s Disease Rating Scale I, p=0.013) was also noticed. Conclusion: A peripheral neuroimmune response may occur in patients who suffer from Parkinson’s disease especially those with cognitive impairment. Further investigation is needed to establish a direct connection between that immune response and disease pathophysiology.

ステロイド治療が有効であったサイトメガロウィルス感染後の急性運動・感覚・自律神経ニューロパチーの1例

We report a rare case of autonomic neuropathy associated with cytomegalovirus (CMV) infection. The patient, a 53-year-old male, was admitted to our hospital because of prolonged fever, headache and neck stiffness followed by urinary retention. Cerebrospinal fluid examination revealed pleocytosis (219/mm(3), predominantly lymphocytes) with a markedly increased protein level (217 mg/dl) and serum IgM anti-CMV antibody was detected. While his meningitic symptoms gradually improved after intravenous administration of ganciclovir, he complained of numbness in the extremities and difficulty in walking. Neurologically, marked orthostatic hypotension, glove and stocking type of paresthesia, severe muscle weakness in extremities, and neurogenic atonic bladder were noted. Nerve conduction studies showed normal except for F-waves, which were absent in the left tibial nerve. A sural nerve specimen appeared normal in both myelinated and unmyelinated fibers. He was given immunological therapies such as corticosteroid and intravenous high dose immunoglobulin therapies. After corticosteroid therapies, not only sensory and motor symptoms but also autonomic symptoms remarkably improved. Of the anti-ganglioside antibodies, IgM anti-GM1 antibody and IgM anti-GM2 antibody were detected. Although some cases with Guillain-Barré syndrome preceded by CMV infection have been reported, few cases with autonomic neuropathy have been described in association with successful corticosteroid therapies.

Association of IgM monoclonal gammopathy with progressive muscular atrophy and multifocal motor neuropathy: a case-control study.

Monoclonal gammopathy in patients with amyotrophic lateral sclerosis (ALS) and related disorders has been reported in small studies but the validity of the reported associations remains uncertain. Presence of monoclonal gammopathy may indicate specific pathogenic pathways and may facilitate the development of novel treatment strategies. The objective of this large case-control study was to determine the prevalence of monoclonal gammopathy in motor neuron diseases (MND) and multifocal motor neuropathy (MMN). Monoclonal gammopathy was determined by immunoelectrophoresis and immunofixation in serum from 445 patients with ALS, 158 patients with progressive muscular atrophy (PMA), 60 patients with primary lateral sclerosis (PLS), 88 patients with MMN and in 430 matched healthy controls. Anti-ganglioside antibody titers were determined in sera from patients with MMN and PMA, and in ALS and PLS patients with monoclonal gammopathy. Logistic regression analysis was used to investigate associations of monoclonal gammopathy with motor neuron diseases and clinical characteristics. Neither ALS nor PLS was associated with monoclonal gammopathy. IgM monoclonal gammopathy was more frequent in patients with PMA (8 %) (OR = 4.2; p = 0.001) and MMN (7 %) (OR = 5.8; p = 0.002) than in controls (2 %). High titers of anti-GM1 IgM antibodies were present in 43 % of MMN patients and 7 % of PMA patients. Patients with PMA and IgM monoclonal gammopathy or anti-GM1 antibodies had a higher age at onset, more often weakness of upper legs and more severe outcome than patients with MMN. PMA and MMN, but not ALS and PLS, are significantly associated with IgM monoclonal gammopathy and anti-GM1 antibodies. These results may indicate that a subset of patients presenting with PMA share pathogenic mechanisms with MMN.

Autoantibodies to GM1 and GQ1bα are not biological markers of Alzheimer's disease.

A few studies have reported the association of autoantibodies to GM1 or GQ1bα with Alzheimer's disease (AD) or vascular dementia. Here we investigated whether patients with AD or vascular dementia had high titers of the anti-ganglioside antibodies. Sera were obtained from patients with AD (n = 22), vascular dementia (n = 14), Guillain-Barré syndrome, and multifocal motor neuropathy as well as normal controls. Enzyme-linked immunosorbent assay showed titers of IgG and IgM anti-GM1, anti-GQ1bα, and anti-GT1aα antibodies did not differ among AD, vascular dementia, and normal controls, and being remarkably lower than those in Guillain-Barré syndrome and multifocal motor neuropathy. The anti-ganglioside antibodies are not biological markers of AD.

The probable auto-antigenic role of lipids (anti-ganglioside antibodies) in the pathogenesis of Alzheimer's disease.

We examined the sera of 103 demented patients of a mean age of 75 years and 60 age-matched healthy individuals, using ELISA, to investigate the levels of IgM antibodies against GM1, GD1b, and GQ1b gangliosides and their possible correlation with clinical parameters (age, severity, and type of dementia). All the individuals that demonstrated positive titers of anti-ganglioside antibodies were demented patients whereas normal controls showed borderline or negative values. Significant correlation was revealed between IgM anti-GM1 and both the age of the patients and the severity of dementia. Most of the patients with increased IgM anti-GD1b titers suffered from AD.

Clonality of anti-GM1 IgM antibodies in multifocal motor neuropathy and the Guillain-Barré syndrome

ObjectiveMultifocal motor neuropathy (MMN) and the Guillain-Barré syndrome (GBS) are immune-mediated motor neuropathies with antibodies against the ganglioside GM1. In GBS, these antibodies are induced by molecular mimicry, but in...

P214: Study of sympathetic skin response in diabetic patients with soft tissue rheumatism of the hand

P214: Study of sympathetic skin response in diabetic patients with soft tissue rheumatism of the hand

Antibodies against gangliosides in patients with dementia.

Increasing evidence suggests that gangliosides act as important mediators in both de- and remyelination. The scope of the present research was to investigate the presence of immunoglobulin (Ig) M antibodies against GM1, GD1b, and GQ1b gangliosides in the sera of patients with dementia and the possible connection with clinical parameters of the disease. This research topic demonstrates the investigation of 103 patients with dementia and 60 healthy individuals using enzyme-linked immunosorbent assay for the presence of 3 antiganglioside antibodies in their sera. The authors report a positive connection between IgM anti-GM1 and the age (P = .005) and the severity of dementia (P = .005). Most of the patients who revealed increased IgM anti-GD1b levels had Alzheimer's disease (AD; P = .002). This study indicates that elevated IgM anti-GM1 may be connected with the neurodegeneration in older patients with severe dementia and that AD may also be associated with increased IgM anti-GD1b levels.

Chronic Bickerstaff's encephalitis with cognitive impairment, a reality?

BackgroundBickerstaff’s encephalitis (BE) is an acute post-infectious demyelinating disease with albuminocytological dissociation. A chronic form has rarely been described previously.Case presentationA 44-year-old man was hospitalized for drowsiness, cognitive complaint limb weakness, ataxia and sensory disturbance after diarrhea. Neuropsychological evaluation showed slowing, memory and executive function impairment, while analysis of the CSF showed albuminocytological dissociation. Immunologic tests showed positive anti-ganglioside antibodies (anti-GM1 IgM, anti-GD1a IgG and anti-GD1b IgM). Brain MRI was normal but SPECT showed bilateral temporal and frontal hypoperfusion. Outcome under immunoglobulin treatment (IVIG) was favorable with an initial improvement but was marked by worsening after a few weeks. Consequently, the patient was treated with IVIG every 2 months due to the recurrence of symptoms after 6 weeks.ConclusionThis case raises the question of the existence of a chronic form of BE with cognitive impairment, in the same way as chronic inflammatory demyelinating polyneuropathy is considered to be a chronic form of Guillain–Barré syndrome.

Treatment of Multifocal Motor Neuropathy

Multifocal motor neuropathy (MMN) is a treatable immune disorder of the peripheral nerves that is characterized clinically by slowly progressive or stepwise asymmetric distal > proximal, upper > lower limb weakness in multiple motor nerve distributions; electrophysiologically by multifocal motor demyelination, specifically partial motor conduction block; laboratory evidence of high serum anti-GM1 IgM antibodies; and remarkable treatment response to intravenous immunoglobulin (IVIG). IVIG has become the treatment of choice, and the U.S. Food and Drug Administration (FDA) has approved Gammagard Liquid 10% [immune globulin infusion (human)] as a treatment for multifocal motor neuropathy (MMN). Response to IVIG in MMN is dose- and frequency-dependent, most patients needing high (2g/kg) and frequent (every 4-8weeks) doses for several years. Over time, response to IVIG may decrease despite higher and more frequent dosing of IVIG treatment. Subcutaneous immunoglobulin (dose equivalent to IVIG) given in weekly fashion has recently been used with equal efficacy and fewer side effects. There are some case reports and non-randomized trials suggesting variable results from therapeutic or adjunctive use of other immunosuppressive or immunomodulatory agents such as cyclophosphamide, cyclosporine, methotrexate, azathioprine, interferon beta-1a, and rituximab. Of these, cyclophosphamide and rituximab are the only immune treatments that have shown some benefits in case reports. One randomized controlled trial of mycophenolate mofetil used as adjunctive agent did not prove efficacious in altering the disease course. Although MMN, like chronic inflammatory demyelinating polyneuropathy (CIDP), is a chronic immune-mediated demyelinating neuropathy, the use of corticosteroids and plasma exchange - two other therapies used in CIDP - is not beneficial for MMN. Further investigations are warranted to evaluate the immunopathogenesis of MMN and to explore options for dose, frequency, and duration of IVIG treatment as well as the use of alternative immunomodulatory agents either as primary therapeutic or adjunctive agents.

Sensitivity and predictive value of anti-GM1/galactocerebroside IgM antibodies in multifocal motor neuropathy

BackgroundIncreased titres of serum IgM antibodies to GM1 ganglioside are often associated with multifocal motor neuropathy (MMN). Testing for IgM antibodies to other antigens including GM2, the mixture of GM1...

Antibodies Against Gangliosides in the Serum of Patients Suffering from Multiple Sclerosis Compared with Healthy Individuals

We examined the sera of 56 patients with definite multiple sclerosis (MS) and 44 healthy individuals using ELISA, for investigating the probable correlation between IgM antibodies against GM1, GD1b and GQ1b gangliosides and clinical parameters of MS. Patients revealed pathological concentrations of the examined antibodies, while healthy controls demonstrated normal levels (p=0.0005). A probable correlation between anti-GD1b and anti-GM1 IgM levels with the progression of MS and a positive comparison between the duration and the disability have also been indicated. Further investigation should be established in order to provide insights on the potential autoantigenic role of gangliosides in MS.

Antibodies to heteromeric glycolipid complexes in multifocal motor neuropathy

Measurement of anti-GM1 IgM antibodies in multifocal motor neuropathy (MMN) sera is confounded by relatively low sensitivity that limits clinical usefulness. Combinatorial assay methods, in which antibodies react to heteromeric complexes of two or more glycolipids, are being increasingly applied to this area of diagnostic testing. A newly developed combinatorial glycoarray able to identify antibodies to 45 different heteromeric glycolipid complexes and their 10 individual glycolipid components was applied to a randomly selected population of 33 MMN cases and 57 normal or disease controls. Comparison with an enzyme-linked immunosorbent assay (ELISA) was conducted for selected single glycolipids and their complexes. By ELISA, 22/33 MMN cases had detectable anti-GM1 IgM antibodies, whereas 19/33 MMN samples were positive for anti-GM1 antibodies by glycoarray. Analysis of variance (anova) revealed that of the 55 possible single glycolipids and their 1:1 complexes, antibodies to the GM1:galactocerebroside (GM1:GalC) complex were most significantly associated with MMN, returning 33/33 MMN samples as positive by glycoarray and 29/33 positive by ELISA. Regression analysis revealed a high correlation in absolute values between ELISA and glycoarray. Receiver operator characteristic analysis revealed insignificantly different diagnostic performance between the two methods. However, the glycoarray appeared to offer slightly improved sensitivity by identifying antibodies in four ELISA-negative samples. The use of combinatorial glycoarray or ELISA increased the diagnostic sensitivity of anti-glycolipid antibody testing in this cohort of MMN cases, without significantly affecting specificity, and may be a useful assay modification for routine clinical screening.

Associated autoimmune diseases in patients with multifocal motor neuropathy and their family members

Multifocal motor neuropathy (MMN) is a rare immune-mediated disorder and is characterized by male predominance, the presence of serum anti-GM1 IgM antibodies in up to half of all patients, responsiveness to intravenous immunoglobulins (IVIg) and an increased frequency of HLA type HLA-DRB1*15. The aim of this study was to assess whether the frequency of autoimmune diseases (AID) is increased in patients with MMN and their first-degree family members, since this would indicate that MMN shares pathogenic mechanisms with other AID. We conducted a case–control study using questionnaires to evaluate the prevalence of AID in MMN and controls, and their first-degree relatives. Questionnaires from 81 MMN patients (417 first-degree relatives) and 438 controls (2,377 first-degree relatives) were analyzed. Overall prevalence of AID was higher in MMN patients (11%) than in controls (5%) (OR 2.4, 95% CI 1.1–5.5, p = 0.037). Type 1 diabetes, Hashimoto’s thyroid disease, and celiac disease were significantly more prevalent in family members of patients than controls. The presence of an additional AID was not associated with age at MMN onset, disease duration, titer of serum anti-GM1 IgM antibodies or HLA type HLA-DRB1*15. The higher frequency of AID in patients with MMN indicates a common autoimmune diathesis.

Selective Depletion of Neuropathy-Related Antibodies from Human Serum by Monolithic Affinity Columns Containing Ganglioside Mimics

Monolithic columns containing ganglioside GM2 and GM3 mimics were prepared for selective removal of serum anti-ganglioside antibodies from patients with acute and chronic immune-mediated neuropathies. ELISA results demonstrated that anti-GM2 IgM antibodies in human sera and a mouse monoclonal anti-GM2 antibody were specifically and selectively adsorbed by monolithic GM2 mimic columns and not by blank monolithic columns or monolithic GM3 mimic columns. In control studies, serum antibodies against the ganglioside GQ1b from another neuropathy patient were not depleted by monolithic GM2 mimic columns. Fluorescence microscopy with FITC-conjugated anti-human immunoglobulin antibodies showed that the immobilized ganglioside mimics were evenly distributed along the column. The columns were able to capture ∼95% of the anti-GM2 antibodies of patients after only 2 min of incubation. A monolithic column of 4.4 μL can deplete 28.2 μL of undiluted serum. These columns are potential diagnostic and therapeutic tools for neuropathies related to anti-ganglioside antibodies.