Anti-ganglioside Antibodies Research Articles

Anti-ganglioside antibodies in Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy in Chinese patients.

In this study we investigated the relationships between anti-ganglioside antibodies and Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP). Samples from 48 Chinese patients diagnosed with GBS and 18 patients diagnosed with CIDP were retrospectively reviewed. In the GBS patients, 62.5% were classified as having acute inflammatory demyelinating polyneuropathy (AIDP), 27.1% were found to have acute motor axonal neuropathy (AMAN), and 10.4% were unclassified. Serum IgG anti-ganglioside antibodies were detected in 46.2% of the AMAN patients and in 6.7% of the AIDP patients (P < 0.05); 5.6% of the 18 CIDP patients were IgG antibody positive, and 27.8% were IgM antibody positive. Facial palsy and sensory impairment were significantly associated with IgM antibodies. These results suggest that IgG anti-GM1 antibodies are associated with AMAN, but not with AIDP, and that IgM antibodies against GM1, GM2, and GM3 are associated with facial nerve palsy. Muscle Nerve 55: 470-475, 2017.

Guillain Barré Syndrome is induced in Non-Obese Diabetic (NOD) mice following Campylobacter jejuni infection and is exacerbated by antibiotics

Campylobacter jejuni is a leading cause of bacterial gastroenteritis linked to several serious autoimmune sequelae such as the peripheral neuropathies Guillain Barré syndrome (GBS) and Miller Fisher syndrome (MFS). We hypothesized that GBS and MFS can result in NOD wild type (WT) mice or their congenic interleukin (IL)-10 or B7-2 knockouts secondary to C. jejuni infection. Mice were gavaged orally with C. jejuni strains HB93-13 and 260.94 from patients with GBS or CF93-6 from a patient with MFS and assessed for clinical neurological signs and phenotypes, anti-ganglioside antibodies, and cellular infiltrates and lesions in gut and peripheral nerve tissues. Significant increases in autoantibodies against single gangliosides (GM1, GQ1b, GD1a) occurred in infected NOD mice of all genotypes, although the isotypes varied (NOD WT had IgG1, IgG3; NOD B7-2−/− had IgG3; NOD IL-10−/− had IgG1, IgG3, IgG2a). Infected NOD WT and NOD IL-10−/− mice also produced anti-ganglioside antibodies of the IgG1 isotype directed against a mixture of GM1/GQ1b gangliosides. Phenotypic tests showed significant differences between treatment groups of all mouse genotypes. Peripheral nerve lesions with macrophage infiltrates were significantly increased in infected mice of NOD WT and IL-10−/− genotypes compared to sham-inoculated controls, while lesions with T cell infiltrates were significantly increased in infected mice of the NOD B7-2−/− genotype compared to sham-inoculated controls. In both infected and sham inoculated NOD IL-10−/− mice, antibiotic treatment exacerbated neurological signs, lesions and the amount and number of different isotypes of antiganglioside autoantibodies produced. Thus, inducible mouse models of post-C. jejuni GBS are feasible and can be characterized based on evaluation of three factors—onset of GBS clinical signs/phenotypes, anti-ganglioside autoantibodies and nerve lesions. Based on these factors we characterized 1) NOD B-7−/− mice as an acute inflammatory demyelinating polyneuropathy (AIDP)-like model, 2) NOD IL-10−/− mice as an acute motor axonal neuropathy (AMAN)-like model best employed over a limited time frame, and 3) NOD WT mice as an AMAN model with mild clinical signs and lesions. Taken together these data demonstrate that C. jejuni strain genotype, host genotype and antibiotic treatment affect GBS disease outcomes in mice and that many disease phenotypes are possible.

Top-100 cited articles on Guillain-Barré syndrome: a bibliometric analysis.

Since the first description of Guillain-Barré syndrome (GBS) 100 years ago, the concept of this syndrome has changed remarkably. The purpose of our study was to identify and characterize the most-cited articles that have contributed to advancing the understanding of GBS. Based on the database of Journal Citation Reports, we selected 554 journals that were considered as potential sources of reports on studies related to clinical neurology and general medicine. The Web of Science search tools were used to identify the most-cited articles relevant to GBS or other variants in the selected journals. Of the selected articles, 18 were review articles and the remainder were original articles or included only a few case series. Among the original articles, 13 described basic research associated with immunological pathogenesis involving anti-ganglioside antibodies. Most of the original studies (42/64, 66%) published after 1990 evaluated anti-ganglioside antibodies that mediated axonal GBS or Miller Fisher syndrome, with only a small number of the papers involving electrodiagnostic medicine (n = 4). Our bibliometric analysis has yielded a detailed list of the top-100 cited articles in the field of GBS.

Anti-sulfatide reactivity in patients with celiac disease

Objective: To explore a possible significance of the presence of anti-ganglioside and anti-sulfatide antibodies in sera of adult patients with celiac disease (CD) in different clinical scenario.Methods: We selected 22 adult patients with newly diagnosed CD and 20 age–sex matched non-CD controls. Patients’ serum was tested – before and after at least 6 months on a gluten-free diet (GFD) – for anti-GM1, GM2, GM3, GD1a, GD1b, GD3, GT1a, GT1b, GQ1b and sulfatide IgM, IgG and IgA auto-antibodies, by means of a dot blot technique and enzyme-linked immunosorbent assay (ELISA).Results: We found the presence of auto-antibodies in untreated patients. In particular, anti-sulfatide IgG antibodies were present in 8 (36%) patients independently of the presence of neurological symptoms. Anti-sulfatide IgA antibodies were present in 3 (19%) patients. During GFD, anti-sulfatide IgG disappeared in all the patients, whereas IgA were observed in 2 patients. Anti-sulfatide, anti-GM1 and anti-GM2 IgM antibodies were also observed in 2 patients on a GFD. All the other auto-antibodies were absent and no demographic or clinical parameters were associated. Non-CD controls did not present any auto-antibody.Conclusions: We found anti-sulfatide IgG antibodies in CD patients on a gluten-containing diet. Anti-sulfatide IgA antibodies persisted during GFD together with the occurrence of other IgM auto-antibodies. These data suggest a possible link between gluten and IgG auto-antibodies.

Guillain-Barré syndrome: a century of progress.

In 1916, Guillain, Barré and Strohl reported on two cases of acute flaccid paralysis with high cerebrospinal fluid protein levels and normal cell counts - novel findings that identified the disease we now know as Guillain-Barré syndrome (GBS). 100 years on, we have made great progress with the clinical and pathological characterization of GBS. Early clinicopathological and animal studies indicated that GBS was an immune-mediated demyelinating disorder, and that severe GBS could result in secondary axonal injury; the current treatments of plasma exchange and intravenous immunoglobulin, which were developed in the 1980s, are based on this premise. Subsequent work has, however, shown that primary axonal injury can be the underlying disease. The association of Campylobacter jejuni strains has led to confirmation that anti-ganglioside antibodies are pathogenic and that axonal GBS involves an antibody and complement-mediated disruption of nodes of Ranvier, neuromuscular junctions and other neuronal and glial membranes. Now, ongoing clinical trials of the complement inhibitor eculizumab are the first targeted immunotherapy in GBS.

43. The quest for optimal electrodiagnosis of Guillain–Barre’ syndrome subtypes: criteria sets versus a linear discriminant analysis model

Up to 38% of Guillain-Barré syndrome (GBS) patients change electrophysiological classification after serial recordings. Aim of this study is to compare at the first electrodiagnostic test the predictivity of final diagnosis of three diagnostic criteria sets versus a regularized form of linear discriminant analysis (LDA) model. In 98 GBS patients with serial conduction studies in three motor and sensory nerves 24 electrophysiological variables were analyzed. Final diagnosis, established by serial studies and result of anti-ganglioside antibodies testing, revealed 54 demyelinating and 44 axonal GBS. We applied a sparse LDA method which is a technique for partitioning a vector of parameters (predictors) into one of the two classes (demyelinating or axonal) based on a linear projection learned from the 98 labeled patients. The evaluation of the discriminant power of sparse LDA is based on the leave one out cross validation procedure. We also employed the electrodiagnostic criteria sets developed by Hadden et al. (1998), by Rajabally et al. (2015) and by us. The overall misclassification error rate of sparse LDA at first test is 14% with a sensitivity for demyelinating GBS of 87% and a specificity of 84%. Distal motor latency, duration of distal motor potentials, proximal/distal motor amplitude ratio and sensory nerve action potential amplitude play a prominent role for the appropriate classification of patients. The overall misclassification error rates with the electrodiagnostic criteria are: 45% for Hadden’s, 43% for Rajabally’s and 26% for ours. Conclusions: (1) the model based on sparse LDA performs much better than the “a priori” established criteria sets; (2) the criteria set we developed, including the analysis of duration of distal motor potentials and of sensory nerve action potential amplitude, performs better than the other two; (3) only serial studies were able to demonstrate reversible conduction failure in motor and sensory fibers.

Preparation of CD4+ T Cells for Analysis of GD3 and GD2 Ganglioside Membrane Expression by Microscopy.

The methods described herein for activation of naïve CD4+ T cells in suspension and their adherence in coverslips for confocal microscopy analysis allow the spatial localization and visualization of gangliosides involved in CD4+ T cell activation, that complement expression profiling experiments such as flow cytometry, western blotting or real-time PCR. The quantification of ganglioside expression through flow cytometry and their cellular localization through microscopy can be obtained by the use of anti-ganglioside antibodies with high affinity and specificity. Nonetheless, an adequate handling of cells in suspension involves the treatment of culture plates to promote the necessary adherence required for fluorescence or confocal microscopy acquisition. In this work, we describe a protocol for determining GD3 and GD2 ganglioside expression and colocalization with the TCR during naïve CD4+ T cell activation. Also, real-time PCR experiments using <40,000 cells are described for the determination of the GD3 and GM2/GD2 synthase genes, demonstrating that gene analysis experiments can be performed with a low number of cells and without the need of additional low input RNA kits.

Antiganglioside, antiganglioside-complex, and antiglycolipid-complex antibodies in immune-mediated neuropathies.

There has been a recent renewed interest in the prevalence of antiglycolipid antibodies and their associations with specific clinical phenotypes in Guillain-Barré syndrome. Recent reports have sought to confirm and expand the antibody-phenotype associations of antiganglioside antibodies, antiganglioside-complex antibodies, and antiglycolipid-complex antibodies in the various acute immune-mediated neuropathies. This is a rapidly developing field with technical advances in assay methodology, which have resulted in numerous new putative antibody-phenotype associations. Antibodies against single ganglioside species remain the most established serological marker of Guillain-Barré syndrome and its myriad clinical variants. Antibodies against combinations of gangliosides, ganglioside-complex antibodies, detected by the ELISA method have emerged as putative markers of certain clinical features or pathological subtypes, specifically acute motor axonal neuropathy, but do not seem to greatly increase the diagnostic sensitivity of antibody testing as most also react with single ganglioside species. The novel assay method of the combinatorial glycoarray allows high-throughput detection of antibodies recognizing combinations of gangliosides and other glycolipids and early studies suggest it identifies antibody-phenotype associations in addition to significantly increasing the sensitivity of serological testing, including for the acute inflammatory demyelinating polyneuropathy variant. Antibodies against single ganglioside species remain diagnostically useful in routine clinical practice. Antibodies against ganglioside complexes, or gangliosides and other glycolipid complexes, are emerging as useful markers of various clinic features and pathological subtypes; however, the precise associations remain to be fully delineated and confirmed. The antibody-complex detection methods are rapidly evolving but in most centres are not yet available in routine clinical practice.

Zika Virus and Guillain-Barre Syndrome: Is There Sufficient Evidence for Causality?

Worldwide concern over Zika virus causing Guillain–Barre syndrome (GBS) soared after recent reports that Zika-related weakness was due to GBS. A global strategic response plan was initiated with recommendations for at-risk countries to prepare for GBS. This plan has major economic implications, as nations with limited resources struggle to implement costly immunotherapy. Since confirmation of causality is prerequisite to providing specific management recommendations, it is prudent to review data endorsing a GBS diagnosis. We searched PubMed for manuscripts reporting original clinical, laboratory, and electrodiagnostic data on Zika virus and GBS. Five papers met criteria; four case reports and one large case–control study (French Polynesia) that attributed 42 paralysis cases to a motor variant of GBS. Brighton criteria were reportedly used to diagnose GBS, but no differential diagnosis was presented, which violates criteria. GBS was characterized by early onset (median 6 days post-viral syndrome), rapid progression (median 6 days from onset to nadir), and atypical clinical features (52% lacked areflexia, 48% of facial palsies were unilateral). Electrodiagnostic evaluations fell short of guidelines endorsed by American Academy of Neurology. Typical anti-ganglioside antibodies in GBS motor variants were rarely present. We conclude that there is no causal relationship between Zika virus and GBS because data failed to confirm GBS and exclude other causes of paralysis. Focus should be redirected at differential diagnosis, proper use of diagnostic criteria, and electrodiagnosis that follows recommended guidelines. We also call for a moratorium on recommendations for at-risk countries to prepare costly immunotherapies directed at GBS.

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.

Ca2+-dependent anti-GQ1b antibody in GQ1b-seronegative Fisher syndrome and related disorders

Although serum IgG anti-ganglioside GQ1b antibody is the most specific biomarker for Fisher syndrome and its related disorders (FS-RD), 10%–30% of the patients are still negative in conventional assays (“GQ1b-seronegative”) and the relationship between GQ1b-seropositive and -seronegative patients has been unclear. Some molecules require Ca2+ cations to interact with their ligands (Ca2+-dependency). Here we have investigated whether Ca2+-dependency is also present in anti-GQ1b antibodies in FS-RD, especially in the GQ1b-seronegative patients and show that IgG antibodies against GQ1b-related antigens (isolated GQ1b and GQ1b-containing complexes) are detected Ca2+-dependently in the majority of GQ1b-seronegative patients with FS-RD. The Ca2+-dependent antibodies might react specifically with GQ1b-Ca2+ conformation. This is the first demonstration of disease-related Ca2+-dependent antibodies in neurological field. GQ1b-related pathology would be involved in FS-RD more extensively than previously revealed.

Transient Isolated Lower Bulbar Palsy With Elevated Serum Anti-GM1 and Anti-GD1b Antibodies During Aripiprazole Treatment

BackgroundTransient bulbar palsy without involvement of the facial or extraocular muscles is a rare presentation. It is considered a form of cranial polyneuropathy, a variant of Guillain–Barré syndrome that is related to the autoimmune mechanisms induced by preceding infections or vaccinations. However, drug-induced cranial polyneuropathy has not previously been reported. We describe a boy with isolated bulbar palsy and positive serum antiganglioside antibodies during aripiprazole treatment. Patient DescriptionThis 12-year-old boy was admitted with a seven-day history of dysarthria, tongue discomfort, and tinnitus. Three weeks before symptom onset, aripiprazole was added to the patient's medications for attention-deficit hyperactivity disorder. On examination, he showed curtaining of the pharyngeal wall, tongue fasciculation and deviation, and a weak gag reflex. Cranial magnetic resonance imaging suggested lower cranial nerve involvement. Serum anti-GM1 IgG and anti-GD1b IgG antibodies were positive. After stopping aripiprazole, his bulbar symptoms improved. However, on readministration of aripiprazole seven weeks later, dysarthria recurred and again resolved after stopping the drug. ConclusionWe describe the first patient with anti-GM1 IgG and anti-GD1b IgG antibodies–associated transient cranial polyneuropathy presenting as isolated bulbar palsy. These findings could be an adverse effect of aripiprazole treatment.

Primary Sjögren's syndrome is associated with significant cognitive dysfunction.

Cognitive dysfunction is a neurologic manifestation in primary Sjögren syndrome (PSS). On the other hand, several antibodies are related to cognitive dysfunction. The aim of this study is to assess the cognitive dysfunction of PSS patients via detailed neurologic tests. Moreover, its associations with antibodies were also evaluated. Twenty-eight female patients with PSS and 17 healthy controls comprised the study groups. Short-term memory, long-term memory, verbal learning, visual memory, visual spatial perception, attention, verbal frequency function, executive functions and information processing speed were evaluated with neurologic tests in both of the study groups. Furthermore, anti-N-methyl-D-aspartate (NMDA) type anti-glutamate-receptor antibody, anti-ribosomal-p and antiganglioside antibodies were assessed in the study groups. The attention, data processing speed, verbal learning, short-term verbal memory and visuo-spatial perception performances were lower in the patients with PSS when compared to the healthy controls. The difference reached statistical significance in Paced Auditory Serial Addition Test (P < 0.01), Serial Digit Learning Test (P < 0.01), clock drawing (P = 0.03), Auditory Verbal Learning Test immediate verbal memory (P = 0.01) and Benton Judgement of Line Orientation Test (P = 0.03). Even if antiganglioside antibodies were more likely to be present in the PSS group when compared to the healthy controls, no relationship was found between its positivity and cognitive dysfunction. Results of this study suggest that cognitive dysfunction is quite prevalent in PSS patients without being associated with studied antibodies.

Ophthalmoplegic Guillain-Barré syndrome: An independent entity or a transitional spectrum?

Ophthalmoplegia can occur in both Miller Fisher syndrome (MFS) and Guillain-Barré syndrome (GBS) with typical limb involvement. However, ophthalmoplegic GBS (OGBS) has been poorly defined. We aimed to characterize OGBS and clarify the pathophysiological implications across the overall GBS spectrum. Twenty GBS and seven MFS patients from three university based teaching hospitals in Korea were enrolled and analyzed. Six GBS patients who were classified as OGBS commonly also had facial diplegia (50%) and bulbar palsy (50%), while only a small portion of non-ophthalmoplegic GBS (NOGBS) patients had facial diplegia (21%). None of the patients had bulbar palsy in the NOGBS or MFS groups. The most frequent anti-ganglioside antibody in OGBS was the IgG anti-GT1a antibody (50%). The IgG anti-GM1 antibody was found mainly in NOGBS (57%) with high concordance with the pure motor type classification on electrophysiology. IgG anti-GQ1b antibody was positive uniquely in MFS (100%), although some patients were also positive for anti-GT1a antibody (71%). OGBS had distinct clinical features, including bulbar palsy, as well as ophthalmoplegia and limb weakness for both GBS and MFS. Relevant immunological factors were anti-GT1a antibody. Whether OGBS is an independent entity or a transitional spectrum remains to be established and further study will be needed.

Clinical usefulness of Anti-ganglioside antibody in children with neurologic disease: single center study

Clinical usefulness of Anti-ganglioside antibody in children with neurologic disease: single center study

Neuronal endocytosis of anti-ganglioside antibodies: implications for Guillain-Barré syndrome.

This scientific commentary refers to ‘Anti-ganglioside antibodies are removed from circulation in mice by neuronal endocytosis’, by Cunningham et al. (doi:10.1093/brain/aww056). Guillain-Barre syndrome (GBS) is an acute disorder primarily of the peripheral nervous system that yearly affects ∼100 000 people worldwide. GBS is characterized by a rapidly progressive but variable degree of muscle weakness with or without sensory disturbances (van den Berg et al. , 2014). Patients may develop respiratory failure for which they require artificial ventilation. After a period of variable duration and supported by treatment with intravenous immunoglobulin (IVIg) or plasma exchange, patients start to recover, but recovery is often incomplete. GBS represents a spectrum of different subtypes, including regional variants and in rare cases even involvement of the CNS. The acute onset and monophasic disease course can be explained by the preceding infection that triggers a transient immune response to peripheral nerves. Various types of infections are associated with GBS, including Campylobacter jejuni , cytomegalovirus, Epstein-Barr virus, Mycoplasma pneumoniae , and hepatitis E virus. More recently Zika virus has been suggested to be related to GBS, but this possible association requires further investigation (Cao-Lormeau et al. , 2016). In the acute phase, serum antibodies against various gangliosides present in human nerves can be found in about half of all patients with GBS. Molecular mimicry is one mechanism by which preceding infections may trigger the production of cross-reactive antibodies to gangliosides, as has been demonstrated convincingly for C. jejuni -related GBS. Important questions remaining are why antibodies to gangliosides are not found in all patients with GBS and why some patients may even show signs of CNS involvement. In this issue of Brain , Cunningham and co-workers provide compelling evidence that anti-ganglioside antibodies are endocytosed at the nerve terminals, removed from the systemic circulation and transported …

Sialylated intravenous immunoglobulin suppress anti-ganglioside antibody mediated nerve injury

The precise mechanisms underlying the efficacy of intravenous immunoglobulin (IVIg) in autoimmune neurological disorders including Guillain-Barré syndrome (GBS) are not known. Anti-ganglioside antibodies have been reported to be pathogenic in some variants of GBS, and we have developed passive transfer animal models to study anti-ganglioside antibody mediated-endoneurial inflammation and associated neuropathological effects and to evaluate the efficacy of new therapeutic approaches. Some studies indicate that IVIg's anti-inflammatory activity resides in a minor sialylated IVIg (sIVIg) fractions and is dependent on an innate Th2 response via binding to a specific ICAM3-grabbing nonintegrin related 1 receptor (SIGN-R1). Therefore the efficacy of IVIg, IVIg fractions with various IgG Fc sialylation status, and the involvement of Th2 pathway were examined in one of our animal model of antibody-mediated inhibition of axonal regeneration. We demonstrate that both IVIg and sIVIg ameliorated anti-glycan antibody mediated-pathological effect, whereas, the unsialylated fractions of IVIg were not beneficial in our model. Tenfold lower doses of sIVIg compared to whole IVIg provided equivalent efficacy in our studies. Moreover, we found that whole IVIg and sIVIg significantly upregulates the gene expression of IL-33, which itself can provide protection from antibody-mediated nerve injury in our model. Our results support that the SIGN-R1-Th2 pathway is involved in the anti-inflammatory effects of IVIg on endoneurium in our model and elements of this pathway including IL-33 can provide novel therapeutics in inflammatory neuropathies.

Posterior Reversible Encephalopathy Syndrome: An Uncommon Presentation of Celiac Disease

Celiac disease is an autoimmune induced inflammatory disease of small intestine in genetically susceptible individuals by ingestion of gluten. Clinical manifestation of celiac disease is mostly gastrointestinal or atypical non-gastrointestinal symptoms or silent with no symptoms, despite the presence of a characteristic intestinal lesion. Wider spectrum of atypical symptoms include neurological syndrome like migraine, encephalopathy, mylopathy, neuropathy with positive antiganglioside antibodies and symptoms of osteomalacia. Autoimmune disorders occur ten times more frequently in adult patients with celiac disease than in the general population such as thyroid disease, type1 diabetes and Addison’s disease etc. If celiac disease remains unrecognized, it can increase the risk of life-threatening complications that are difficult to manage. Herein we are presenting a case of posterior reversible encephalopathy, presenting in department of medicine with seizures. Patient was a diagnosed case of celiac disease.

Cluster of Guillain-Barré Syndrome Associated with HLA DQB1*05:01 and the Occurrence of Anti-Ganglioside and Sulfatide Antibodies (P3.143)

Cluster of Guillain-Barré Syndrome Associated with HLA DQB1*05:01 and the Occurrence of Anti-Ganglioside and Sulfatide Antibodies (P3.143)

Anti-ganglioside antibodies are removed from circulation in mice by neuronal endocytosis.

SEE VAN DOORN AND JACOBS DOI101093/BRAIN/AWW078 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE : In axonal forms of Guillain-Barré syndrome, anti-ganglioside antibodies bind gangliosides on nerve surfaces, thereby causing injury through complement activation and immune cell recruitment. Why some nerve regions are more vulnerable than others is unknown. One reason may be that neuronal membranes with high endocytic activity, including nerve terminals involved in neurotransmitter recycling, are able to endocytose anti-ganglioside antibodies from the cell surface so rapidly that antibody-mediated injury is attenuated. Herein we investigated whether endocytic clearance of anti-ganglioside antibodies by nerve terminals might also be of sufficient magnitude to deplete circulating antibody levels. Remarkably, systemically delivered anti-ganglioside antibody in mice was so avidly cleared from the circulation by endocytosis at ganglioside-expressing plasma membranes that it was rapidly rendered undetectable in serum. A major component of the clearance occurred at motor nerve terminals of neuromuscular junctions, from where anti-ganglioside antibody was retrogradely transported to the motor neuron cell body in the spinal cord, recycled to the plasma membrane, and secreted into the surrounding spinal cord. Uptake at the neuromuscular junction represents a major unexpected pathway by which pathogenic anti-ganglioside antibodies, and potentially other ganglioside binding proteins, are cleared from the systemic circulation and also covertly delivered to the central nervous system.