Anti-ganglioside Autoantibodies Research Articles

Anti-ganglioside M1 autoantibodies in Egyptian children with autism: a cross-sectional comparative study

BackgroundAutism may be one of the pediatric autoimmune neuropsychiatric disorders, and several studies investigated the frequency of serum anti-ganglioside M1 autoantibodies in children with autism, as possible indicators of autoimmunity to the brain. The current study aimed to compare the level of anti-ganglioside M1 autoantibodies between autistic and normally developed children and to study the correlation between the level of anti-ganglioside M1 autoatibodies and the severity of autism. Forty children with autism and 40 age- and gender-matched healthy controls were enrolled. The Childhood Autism Rating Scale was used to assess the severity of autism in the patient group at the time of the study. The clinical and demographic data were recorded and plasma anti-ganglioside M1 autoantibodies level was measured in both groups.ResultsThe mean anti-ganglioside M1 autoantibodies level was significantly higher in autistic patients compared to the control group. The anti-ganglioside M1 autoantibodies level in patients with mild to moderate severity was insignificantly lower than its level in patients with severe autism.ConclusionsPlasma anti-ganglioside MI autoantibodies levels are higher in autistic patients than in healthy controls which may imply that some cases of autism may be autoimmune in nature.

Zoonotic Transmission of Campylobacter jejuni to Caretakers From Sick Pen Calves Carrying a Mixed Population of Strains With and Without Guillain Barré Syndrome-Associated Lipooligosaccharide Loci.

Campylobacter jejuni causes foodborne gastroenteritis and may trigger acute autoimmune sequelae including Guillain Barré Syndrome. Onset of neuromuscular paralysis is associated with exposure to C. jejuni lipooligosaccharide (LOS) classes A, B, C, D, and E that mimic and evoke antibodies against gangliosides on myelin and axons of peripheral nerves. Family members managing a Michigan dairy operation reported recurring C. jejuni gastroenteritis. Because dairy cattle are known to shed C. jejuni, we hypothesized that calves in the sick pen were the source of human infections. Fecal samples obtained from twenty-five calves, one dog, and one asymptomatic family member were cultured for Campylobacter. C. jejuni isolates were obtained from thirteen calves and the family member: C. coli from two calves, and C. hyointestinalis from two calves. Some calves had diarrhea; most were clinically normal. Typing of lipooligosaccharide biosynthetic loci showed that eight calf C. jejuni isolates fell into classes A, B, and C. Two calf isolates and the human isolate possessed LOS class E, associated mainly with enteric disease and rarely with Guillain Barré Syndrome. Multi-locus sequence typing, porA and flaA typing, and whole genome comparisons of the thirteen C. jejuni isolates indicated that the three LOS class E strains that included the human isolate were closely related, indicating zoonotic transmission. Whole-genome comparisons revealed that isolates differed in virulence gene content, particularly in loci encoding biosynthesis of surface structures. Family members experienced diarrheal illness repeatedly over 2 years, yet none experienced GBS despite exposure to calves carrying invasive C. jejuni with LOS known to elicit antiganglioside autoantibodies.

Induction of broadly reactive influenza antibodies increases susceptibility to autoimmunity.

Infection and vaccination repeatedly expose individuals to antigens that are conserved between influenza virus subtypes. Nevertheless, antibodies recognizing variable influenza epitopes greatly outnumber antibodies reactive against conserved epitopes. Elucidating factors contributing to the paucity of broadly reactive influenza antibodies remains a major obstacle for developing a universal influenza vaccine. Here, we report that inducing broadly reactive influenza antibodies increases autoreactive antibodies in humans and mice and exacerbates disease in four distinct models of autoimmune disease. Importantly, transferring broadly reactive influenza antibodies augments disease in the presence of inflammation or autoimmune susceptibility. Further, broadly reactive influenza antibodies spontaneously arise in mice with defects in B cell tolerance. Together, these data suggest that self-tolerance mechanisms limit the prevalence of broadly reactive influenza antibodies, which can exacerbate disease in the context of additional risk factors.

The clinical spectrum and immunopathological mechanisms underlying ZIKV-induced neurological manifestations.

Since the 2015 to 2016 outbreak in America, Zika virus (ZIKV) infected almost 900,000 patients. This international public health emergency was mainly associated with a significant increase in the number of newborns with congenital microcephaly and abnormal neurologic development, known as congenital Zika syndrome (CZS). Furthermore, Guillain–Barré syndrome (GBS), a neuroimmune disorder of adults, has also been associated with ZIKV infection. Currently, the number of ZIKV-infected patients has decreased, and most of the cases recently reported present as a mild and self-limiting febrile illness. However, based on its natural history of a typical example of reemerging pathogen and the lack of specific therapeutic options against ZIKV infection, new outbreaks can occur worldwide, demanding the attention of researchers and government authorities. Here, we discuss the clinical spectrum and immunopathological mechanisms underlying ZIKV-induced neurological manifestations. Several studies have confirmed the tropism of ZIKV for neural progenitor stem cells by demonstrating the presence of ZIKV in the central nervous system (CNS) during fetal development, eliciting a deleterious inflammatory response that compromises neurogenesis and brain formation. Of note, while the neuropathology of CZS can be due to a direct viral neuropathic effect, adults may develop neuroimmune manifestations such as GBS due to poorly understood mechanisms. Antiganglioside autoantibodies have been detected in multiple patients with ZIKV infection–associated GBS, suggesting a molecular mimicry. However, further additional immunopathological mechanisms remain to be uncovered, paving the way for new therapeutic strategies.

The role of antibodies to peripheral nerve antigens in pathogenesis and laboratory evaluation of immune-mediated neuropathies

Detection of antiganglioside autoantibodies and their association with clinically defined subtypes implicate an autoimmune mechanism of peripheraland cranial nerve damage in peripheral neuropathies. Increased titer of antibodies that react with human peripheral nerve antigens have been reported in patients with motor neuropathy including Guillain-Barré syndrome,chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy and sensory motor neuropathy. This study represents review of the data related to increased titers of anti-glucoconjugate antibodies in different autoimmune neuropathies and their correlation with existence of structural homology between bacterial and glycoconjugated structures, as a basis for understanding the immune pathological response to glycoproteins and glycolipids present in the human peripheral nerve as target antigens in autoimmune neuropathies. Evaluation of presence and increased level of autoantibodies against peripheral nerve antigens could be an important parameter in laboratory evaluation, diagnosis and prognosis of autoimmune neuropathies and contribute in more efficient therapeutic approaches in treatment of these pathological conditions. Keywords: anti-glycoconjugate antibodies, anti-ganglioside antibodies, peripheral nerves, autoimmune neuropathies

Anti-GD1b and anti-GM1 positive, acute inflammatory demyelinating polyneuropathy associated with advanced ovarian carcinoma: A case report

Introduction: Paraneoplastic neurological syndromes (PNSs) are mostly associated with non-epithelial ovarian cancers. We report the case of an advanced high-grade serous ovarian adenocarcinoma, diagnosed during the etiological investigation of a subacute motor-sensory axonal neuropathy variant (AMSAN) of Guillain-Barre syndrome (GBS). According to our literature review, only a single case-control study described a positive association between GBS and cancer. Case Report: A 73-year-old woman was admitted to the emergency department for a progressive symmetrical distal tetraparesis, associated with hypoesthesia and abdominal pain. There was no sign of viral or bacterial infection. Over a period of 10 days, she presented a rapid neurological deterioration with nearly complete paralysis of all extremity, facial, and respiratory muscles. The laboratory testing ruled out active infection but the computed tomography (CT) scanner described diffuse peritoneal carcinomatosis, associated with bilateral ovarian tumors. Laparoscopic biopsies confirmed a high-grade serous ovarian cancer. Cerebrospinal fluid analysis confirmed the presence of elevated protein with a normal white blood cell count and anti-ganglioside autoantibodies anti-GD1b and anti-GM1. The patient received systemic chemotherapy together with plasmapheresis and intravenous immunoglobulins, and she experienced a rapid neurological recovery and long-term tumor remission. Conclusion: Neurological paraneoplastic syndromes are rarely associated with epithelial ovarian cancer. Cerebellar ataxia is most frequently associated with this cancer type. Guillain-Barre syndrome can rarely be associated with high-grade serous ovarian cancer. It can delay the tumor diagnosis and treatment. In the case of our patient, early supportive and etiological treatment was of paramount importance for the complete recovery of our patient.

Zika virus-induced neuro-ocular pathology in immunocompetent mice correlates with anti-ganglioside autoantibodies

ABSTRACT A severe consequence of adult Zika virus (ZIKV) infection is Guillain-Barré Syndrome (GBS), where autoreactive antibodies attack peripheral and central nervous systems (CNS) resulting in neuro-ocular pathology and fatal complications. During virally induced GBS, autoimmune brain demyelination and macular degeneration correlate with low virus neutralization and elevated antibody-mediated infection among Fcγ-R bearing cells. The use of interferon-deficient mice for ZIKV studies limits elucidation of antibody-dependent enhancement (ADE) and long-term pathology (≥120 days), due to high lethality post-infection. Here we used immunocompetent BALB/c mice, which generate robust humoral immune responses, to investigate long-term impacts of ZIKV infection. A high infectious dose (1x106 FFU per mouse) of ZIKV was administered intravenously. Control animals received a single dose of anti-IFNAR blocking monoclonal antibody and succumbed to lethal neurological pathology within 13 days. Immunocompetent mice exhibited motor impairment such as arthralgia, as well as ocular inflammation resulting in retinal vascular damage, and corneal edema. This pathology persisted 100 days after infection with evidence of chronic inflammation in immune-privileged tissues, demyelination in the hippocampus and motor cortex regions of the brain, and retinal/corneal hyperplasia. Anti-inflammatory transcriptional responses were tissue-specific, likely contributing to differential pathology in these organs. Pathology in immunocompetent animals coincided with weakly neutralizing antibodies and increased ADE among ZIKV strains (PRVABC59, FLR, and MR766) and all Dengue virus (DENV) serotypes. These antibodies were autoreactive to GBS-associated gangliosides. This study highlights the importance of longevity studies in ZIKV infection and confirms the role of anti-ganglioside antibodies in ZIKV-induced neuro-ocular disease.

Changes of Serum IgG Dimer Levels after Treatment with IVIg in Guillain-Barré Syndrome.

Intravenous immunoglobulins (IVIg) are standard treatment for Guillain-Barré syndrome (GBS). Their exact mechanisms of action are versatile and not fully understood. One possible mechanism is neutralization of circulating autoantibodies via binding to anti- idiotypic antibodies forming idiotype-anti-idiotype dimeric IgG immune complexes. To examine the role of immune complex formation as mechanism of action for IVIg in GBS, 34 C57Bl/6 mice were either treated with anti-ganglioside antibodies and IVIg or IVIg and PBS alone, whereas eight additional mice were treated either with anti-ganglioside autoantibodies and IVIg or anti-ganglioside autoantibodies alone. Subsequently IgG dimer formation was assessed by high performance liquid chromatography (HPLC) and enzyme- linked immunosorbent assay (ELISA). In addition, IgG dimer formation was measured in sera of eight GBS patients who were treated with IVIg. In mice, a significant increase of dimeric IgG after administration of anti-ganglioside antibodies and IVIg could be observed. Re-monomerized IgG dimers showed immunoreactivity against gangliosides and serum immunoreactivity was significantly reduced after IVIg infusion. Likewise also in GBS patients, IgG dimer formation could be detected after IVIg treatment. Our data indicate that dimeric IgG immune complexes contain anti-idiotypic antibodies and provide proof of concept that IVIg treatment in GBS results in measurable amounts of IgG dimers. Larger patient cohorts are needed to evaluate serum IgG dimer increase as a possible marker for treatment response in GBS. Graphical Abstract Mechanism of action: Intravenous immunoglobulins (IVIg) and anti-ganglioside antibodies form dimeric IgG immune complexes, preventing axonal damage in Guillain-Barré Syndrome.

Distal limb weakness phenotype of Guillain-Barré syndrome

ObjectiveSeveral regional variants of Guillain-Barré syndrome (GBS) have been proposed in western countries, but other variants remain unclear, especially among mildly disabled cases. The aim of this study was to identify unvalidated GBS phenotypes among Japanese patients with mild GBS. MethodsRetrospective study of a cohort of patients at a University Hospital in Japan. ResultsAmong 107 GBS patients, 25 (23%) were classified as having mild GBS (GBS disability scale ≤ 2 at nadir). A review of mild cases identified 8 patients (7.5% of all GBS and 32% of mild GBS) with an unusual phenotype, namely a distal limb weakness form of GBS (DL-GBS), which showed limited distribution of limb weakness within hands and feet with preserved strength in proximal limb muscles. The patients with DL-GBS were characterized by mild-to-moderate weakness in distal parts of limbs especially fingers, lacking or mild sensory disturbance at distal limbs, sometimes hyperreflexia at legs, and having prior Campylobacter jejuni enteritis. Among the patients with GBS after C. jejuni enteritis, DL-GBS patients were characterized by frequent detection of anti-GM1 antibodies without anti-GD1a antibodies, whereas the others were often positive for the two antibodies. ConclusionsDL-GBS is a distinct regional phenotype of GBS, which should be differentiated from cervical myelopathy. It can be generally categorized as a mild type of GBS after C. jejuni enteritis, which has characteristic pattern of anti-ganglioside autoantibodies.

Transplanted human fecal microbiota enhanced Guillain Barr\xe9 syndrome autoantibody responses after Campylobacter jejuni infection in C57BL/6 mice

BackgroundCampylobacter jejuni is the leading antecedent infection to the autoimmune neuropathy Guillain-Barré syndrome (GBS), which is accompanied by an autoimmune anti-ganglioside antibody attack on peripheral nerves. Previously, we showed that contrasting immune responses mediate C. jejuni induced colitis and autoimmunity in interleukin-10 (IL-10)-deficient mice, dependent upon the infecting strain. Strains from colitis patients elicited T helper 1 (TH1)-dependent inflammatory responses while strains from GBS patients elicited TH2-dependent autoantibody production. Both syndromes were exacerbated by antibiotic depletion of the microbiota, but other factors controlling susceptibility to GBS are unknown.MethodsUsing 16S rRNA gene high-throughput sequencing, we examined whether structure of the gut microbial community alters host (1) gastrointestinal inflammation or (2) anti-ganglioside antibody responses after infection with C. jejuni strains from colitis or GBS patients. We compared these responses in C57BL/6 mice with either (1) stable human gut microbiota (Humicrobiota) transplants or (2) conventional mouse microbiota (Convmicrobiota).ResultsInoculating germ-free C57BL/6 wild-type (WT) mice with a mixed human fecal slurry provided a murine model that stably passed its microbiota over >20 generations. Mice were housed in specific pathogen-free (SPF) facilities, while extra precautions of having caretakers wear sterile garb along with limited access ensured that no mouse pathogens were acquired. Humicrobiota conferred many changes upon the WT model in contrast to previous results, which showed only colonization with no disease after C. jejuni challenge. When compared to Convmicrobiota mice for susceptibility to C. jejuni enteric or GBS patient strains, infected Humicrobiota mice had (1) 10-100 fold increases in C. jejuni colonization of both strains, (2) pathologic change in draining lymph nodes but only mild changes in colon or cecal lamina propria, (3) significantly lower Th1/Th17-dependent anti-C. jejuni responses, (4) significantly higher IL-4 responses at 5 but not 7 weeks post infection (PI), (5) significantly higher Th2-dependent anti-C. jejuni responses, and (6) significantly elevated anti-ganglioside autoantibodies after C. jejuni infection. These responses in Humicrobiota mice were correlated with a dominant Bacteroidetes and Firmicutes microbiota.ConclusionsThese data demonstrate that Humicrobiota altered host-pathogen interactions in infected mice, increasing colonization and Th-2 and autoimmune responses in a C. jejuni strain-dependent manner. Thus, microbiota composition is another factor controlling susceptibility to GBS.

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.

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.

Eosinophil cationic protein (ECP) as a marker of eosinophil activation in autistic children: relation to autoimmunity

Background: Eosinophil cationic protein (ECP), a cytotoxic protein contained in eosinophils granules, can contribute to various inflammatory and immune responses. Autism may be one of the pediatric autoimmune neuropsychiatric disorders. The exact possible role of eosinophils in autism has not yet been elucidated. The aim of this study was to evaluate serum expression of ECP and its relation to anti-ganglioside M1 brain specific auto-antibodies in autistic children. Methods: Serum ECP and anti-ganglioside M1 auto-antibodies were measured by ELISA test in 45 autistic children aged between 3-11 years and 45 healthy-matched controls. Results: Serum levels of ECP were significantly higher in autistic children (median (IQR) = 30.8 (14.1) ug/L) than healthy control children (median (IQR) = 13.6 (11.9) ug/L), P < 0.001. There was a significant positive correlation between serum levels of ECP and results of CARS (r=0.98, P < 0.001). Autistic children had significantly higher percent positivity of serum anti-ganglioside M1 auto-antibodies (62.2%) than healthy controls (4.4%), P < 0.001. Autistic patients with positive serum anti- ganglioside M1 auto-antibodies had significantly higher serum levels of ECP (median (IQR) = 33.8 (25) ug/L) than children with negative serum anti-ganglioside M1 auto-antibodies (median (IQR) = 21.8 (5.5) ug/L), P < 0.001. Conclusions: Serum ECP levels were elevated in some autistic children and they were significantly associated with the increased levels of serum anti-ganglioside M1 auto-antibodies. Further research is recommend to determine the pathogenic role of ECP in autism and its relation to brain specific auto-antibodies that have been found in some autistic children.

Cerebrospinal fluid profile and seroprevalence of antiganglioside reactivity in patients with neuralgic amyotrophy

Neuralgic amyotrophy (NA), also known as acute brachial plexitis, is postulated as an autoimmune pathogenesis. In a well-defined cohort of patients with NA, we analyzed the cerebrospinal fluid (CSF) profile and the prevalence of antiganglioside antibodies. Patients with Varicella zoster-associated radiculitis and healthy blood donors served as controls. An abnormal routine laboratory CSF profile was found in 29% of those with NA, mostly showing a disruption of the blood-brain barrier. Antibodies predominantly from the immunoglobulin M (IgM) isotype against at least one human ganglioside were detected in 36% of sera from patients with NA but in only 2% of controls. An NA-specific reactivity pattern was not detected, and there was no significant association with clinical or CSF parameters. This suggests that the seroprevalence of antiganglioside autoantibodies in patients with NA is nonspecific.

Antecedent Infections in Guillain-Barré Syndrome: Knowledge in Clinical Practice

Guillain-Barré syndrome (GBS) is a post-infectious disease in which a diversity of pathogenetic factors and clinical features is surely determined by the type of preceding infections. It is necessary in clinical practice and research to identify the antecedent infectious agent in each case. Several lines of evidence indicate that the ganglioside-like epitopes on the infectious agents induce the production of anti-ganglioside autoantibodies and thereby cause GBS. This makes it possible to evaluate the causal significance of the pathogen by examining the cross-reactivity of the detected autoantibodies with outer antigens of the pathogens, although such an investigation is practical only when the pathogen is successfully isolated from the patients. The term "antecedent infection" should be strictly used in the situation in which the infection is thought to be closely related to the development of GBS but not for the situation without findings that suggest such a relationship. Simple but non-validated criteria for the judgment of antecedent infection in each GBS case are proposed in this review in order to prevent numerous and unreliable suspicions of "new" and "unknown" prior infectious agents of GBS, which are only built on the precedence in the disease.

Ambiguous value of anti-ganglioside IgM autoantibodies in Guillain-Barré syndrome and its variants.

Anti-ganglioside autoantibodies of the IgG type are detected in a half of patients with Guillain-Barré syndrome (GBS), and their detection strongly supports the diagnosis of GBS. In contrast, anti-ganglioside IgM antibodies are also often detected in GBS patients, but it remains unclear whether IgM antibodies indicate a diagnosis of GBS. We identified four GBS patients (3.3%) who tested positive for IgM antibodies but negative for IgG antibodies among 122 patients with GBS and its variants. These four patients were all adolescents or young adults (age 13-22 years), experienced preceding gastrointestinal symptoms, and had serological and/or bacterial evidence of recent Campylobacter jejuni enteritis. Serum IgG reacted strongly with the lipo-oligosaccharide (LOS) of the C. jejuni isolates from these patients' stool specimens. Thin-layer chromatography with immunostaining showed that their serum IgG reacted with resorcinol-positive portion of LOS, suggesting that these patients had IgG autoantibodies against sialic acid-containing epitopes, probably unrecognized ganglioside-like structures on the bacterial LOS. We also examined anti-ganglioside autoantibodies in 22 patients with C. jejuni enteritis without subsequent neurological disorders and detected IgM antibodies in seven (32%) patients. Our data indicate that anti-ganglioside IgM antibodies can be detected in C. jejuni enteritis without complication of GBS, and that the detection of anti-ganglioside IgM antibodies does not always support a diagnosis of GBS. IgG autoantibodies against unrecognized gangliosides might play a role in the development of disease in patients with GBS in whom only anti-ganglioside IgM antibodies are detected by routine clinical testing.

Autoimmune peripheral neuropathies

Peripheral nervous system axons and myelin have unique potential protein, proteolipid, and ganglioside antigenic determinants. Despite the existence of a blood–nerve barrier, both humoral and cellular immunity can be directed against peripheral axons and myelin. Molecular mimicry may be triggered at the systemic level, as was best demonstrated in the case of bacterial oligosaccharides.The classification of immune neuropathy has been expanded to take into account specific syndromes that share unique clinical, electrophysiological, prognostic and serological features.Guillain-Barré syndrome encompasses a classical syndrome of acute demyelinating polyradiculoneuropathy and many variants: axonal motor and sensory, axonal motor, Miller-Fisher, autonomic, and sensory. Similarly, chronic immune neuropathy is composed of classic chronic inflammatory demyelinating polyradiculoneuropathy and variants characterized as multifocal (motor or sensorimotor), sensory, distal symmetric, and syndromes associated with monoclonal gammopathy.Among putative biomarkers, myelin associated glycoprotein and several anti-ganglioside autoantibodies have shown statistically significant associations with specific neuropathic syndromes. Currently, the strongest biomarker associations are those linking Miller-Fisher syndrome with anti-GQ1b, multifocal motor neuropathy with anti-GM1, and distal acquired symmetric neuropathy with anti-MAG antibodies. Many other autoantibody associations have been proposed, but presently lack sufficient specificity and sensitivity to qualify as biomarkers. This field of research has contributed to the antigenic characterization of motor and sensory functional systems, as well as helping to define immune neuropathic syndromes with widely different clinical presentation, prognosis and response to therapy. Serologic biomarkers are likely to become even more relevant with the advent of new targeted forms of immunotherapy, such as monoclonal antibodies.

Lack of association between autism and anti-GM1 ganglioside antibody

Forty of 54 children with autism were reported to have an elevated antibody response to GM1 ganglioside that correlated with disease severity.1 Anti-ganglioside autoantibodies, especially those directed at GM1, are known to be associated with and play a pathogenic role in some immune-mediated peripheral neuropathies.2,3 The presumed link between autism and anti-GM1 antibodies, therefore, implies that testing may identify a sizable subset of patients who would benefit from immunomodulatory therapy. To evaluate the proposed association between autism and anti-GM1 antibodies, we performed serologic testing on children diagnosed with autism by strict clinical criteria and those without autism, using a standard and validated immunoassay protocol.

Comparison of Commercial Tests for Detecting Multiple Anti-Ganglioside Autoantibodies in Patients with Well-Characterized Immune-Mediated Peripheral Neuropathies

To assess the performance of commercial anti-ganglioside antibody assays, we determined anti-ganglioside antibody IgG and IgM isotype profiles of patients with acute and chronic well-characterized immune-mediated peripheral neuropathies by one immunodot assays (Zentec/Ingen: Dotzen Ganglio Profile Ab, Euroimmun/BioAdvance: Euroline ganglioprofile), two line-immuno assay (GA Generic Assays/Labodia: Anti-Gangli osid Dot, Euroimmun/BioAdvance: Euroline ganglioprofile), and one enzyme-linked immunosorbent assay (ELISA) (Bühlmann: GanglioCombi). Specific antibody profiles were compared with those obtained by our validated standard in-house immunodot assay (IDA). We selected 33 sera with high levels of IgG and IgM anti-ganglioside antibodies from 15 patients with Guillain-Barre syndrome (GBS) subtypes and variants, 12 patients with CANOMAD syndrome (chronic ataxic neuropathy with ophthalmoplegia, M-paraprotein, cold agglutinins, disialosyl antibodies), 5 patients with chronic motor peripheral neuropathies, and 1 patient with sensory neuropathy and a control group composed of 10 patients with non-autoimmune neuropathy. The 3 commercial IDAs employing hydrophobic membranes and the ELISA demonstrated different carbohydrate epitopes on 6 to 12 glycolipid antigens used for anti-ganglioside antibody detection. Comparison with the validated in-house IDA showed large variations in sensitivity between tests and a more diverse reactivity to gangliosides than expected. The test with the largest panel of glycolipids detecting 11 anti-ganglioside antibody reactivities (GM1, GM2, GM3, GM4, GD1a, GD1b, GD2, GD3, GT1a, GT1b, GQ1b, and sulfatide) revealed the best concordance with our in-house assay. However, even with this test, differences were observed in the immunoreactivity against some gangliosides and weakly stained bands were not easy to interpret. Our data suggest an urgent need for standardization of commercial anti-ganglioside assays and the introduction of international anti-ganglioside antibody reference standards.

A Descending Cranial Nerve Palsy During the Christmas Holidays

A previous healthy 11-year-old child with a 24-hour history of asthenia, diplopia, dysarthria, dysphonia, swallowing difficulty, and vomiting was admitted to our institution on Christmas eve. The child complained of perioral paresthesias and blurry vision 2 days prior to admission and an unusual tiredness after skiing on the day of admission. He presented with a temperature of 36.8°C, blood pressure 100/70 mm Hg, pulse 80 beats/min, respiratory rate 20/min, and oxygen saturation 99% on room air. He was awake, well oriented and his physical examination was within normal limits. Neurological examination showed bilateral ophthalmoplegia with unreactive pupils, dysphonia, dysphagia with minimal limb weakness with associated hyporeflexia. Sensation was maintained, but he presented with urinary retention described as a poor urinary stream with intermittent flow, straining, and a sense of incomplete voiding and hesitancy. A complete blood count, electrolytes, arterial blood gas, C-reactive protein and herpes virus 1 and 2 (HSV-1 and HSV-2), Epstein-Barr virus (EBV) antibodies were within the normal range. Cerebrospinal fluid (CSF) examination was unremarkable (glucose 81 mg/dL, normal values 40-70), protein 20 mg/dL (normal values 15-45), lactate 11.7 mg/dL (normal values 10.8-19.8), and no erythrocytes or leucocytes. Polymerase chain reaction (PCR) for neurotropic viruses (human herpes virus 6, human herpes virus 7, human herpes virus 8, adenovirus, Parvovirus, EBarrV, herpes simplex virus 1 and 2, and varicella-zoster virus), cultures for meningococcus and fungi, and serology for Borrelia, Chlamydia Pneumoniae, enterovirus, influenza A and B, metapneumovirus, morbillivirus, and Mycoplasma Pneumoniae were all negative. The electroencephalography (EEG) was also normal. Intoxication or snakebite were excluded by medical history, a detailed neurological examination, and laboratory tests (urine and plasma toxicology screen for amphetamines, cannabinoids, cocaine, opiates, phencyclidine,alcohol, benzodiazepines and tricyclic antidepressants). There was no history of ingestion of homemade or rotten food that could contain botulinum spore or toxins. Twenty-four hours after admission, the patient developed respiratory failure and areflexia of the upper limbs requiring mechanical ventilation and admission to the pediatric intensive care unit (PICU). Repeat CSF examination showed normal glucose, protein and lactic acid, negative bacterial cultures, and PCR for viruses. No albuminocytologic dissociation was observed. Under the working diagnosis of a Miller-Fisher syndrome (MFS), the child was treated with intravenous immunoglobulin G (IgG) infusion (400 mg/kg) for 5 days with no clinical response, followed by 5 cycles of plasmapheresis. The child gradually recovered and it was possible to perform electromyography and nerve conduction studies (EMG/NCSs) which showed a normal conduction pattern. The edrophonium test, antibodies to voltage-gated calcium channels, to acetylcholine receptors (AChRs), and anti-ganglioside autoantibodies (IgG and IgM for GM1, GM2, GD1a, GD1b, and GQ1B) were also negative. A diagnostic result was received.