g(m1)-ganglioside and Chronic-Disease

Multifocal motor neuropathy (MMN) is a recently identified peripheral nerve disorder characterized by progressive, predominantly distal, asymmetric limb weakness mostly affecting upper limbs, minimal or no sensory impairment, and by the presence on nerve conduction studies of multifocal persistent partial conduction blocks on motor but not sensory nerves. The etiopathogenesis of MMN is not known, but there is some evidence, based mostly on the clinical improvement after immunological therapies, that the disease has an immunological basis. Antibodies, mostly IgM, to the gangliosides GM1, and though less frequently, GM2 and GD1a, are frequently detected in patients' sera, helping in the diagnosis of this disease. Even if there is some experimental evidence that these antibodies may be pathogenic in vitro, their role in the neuropathy remains to be established. Patients with MMN do not usually respond to steroids or plasma exchange, which may occasionally worsen the symptoms, while the efficacy of cyclophosphamide is limited by its relevant side effects. More than 80% of MMN patients rapidly improve with high dose intravenous immunoglobulin therapy (IVIg). The effect of this therapy is, however, transient and improvement has to be maintained with periodic infusions. A positive response to interferon-beta has been recently reported in a minority of patients, some of whom were resistant to IVIg. Even if many progresses have been made on the diagnosis and therapy of MMN, there are still several issues on the nosological position, etiopathogenesis and long-term treatment of this neuropathy that need to be clarified.

Topics: Autoantibodies; Chronic Disease; Cyclophosphamide; Diagnosis, Differential; Electrodiagnosis; Female; G(M1) Ganglioside; Humans; Immunoglobulins, Intravenous; Interferon-beta; Male; Motor Neuron Disease; Neural Conduction; Peripheral Nervous System Diseases; Polyradiculoneuropathy

Topics: Antibody Specificity; Autoantibodies; Autoantigens; Autoimmune Diseases; Brain; Carbohydrate Sequence; CD57 Antigens; Chronic Disease; G(M1) Ganglioside; Gangliosides; Globosides; Glycolipids; Guillain-Barre Syndrome; Humans; Immunoglobulin M; Molecular Sequence Data; Motor Neuron Disease; Myelin Sheath; Paraproteinemias; Peripheral Nervous System; Polyradiculoneuropathy; Sulfoglycosphingolipids

Pure motor neuropathy syndromes resemble amyotrophic lateral sclerosis variants with no upper motor neuron signs. Their identification is important, as, in contrast to amyotrophic lateral sclerosis, they are often immune mediated and treatable. Typically the immune-mediated motor neuropathy syndromes are distal and asymmetrical and progress slowly. The clinical features may help alert the clinician to the diagnosis, but other ancillary evidence such as abnormalities on electrophysiological testing and the presence of serum autoantibodies to neural antigens are helpful in making the diagnosis more secure. Electrophysiological abnormalities include not only motor conduction block but also other evidence of a demyelinative process such as prolonged distal latencies or F-wave abnormalities. High-titer anti-GM1 antibodies occur frequently but more specific patterns of reactivity may be especially helpful. Treatment of these motor neuropathy syndromes includes cyclophosphamide, which we use in combination with plasma exchange, and in some patients, human immune globulin. Clinical responses to therapy may occur within the first 2 to 4 months in patients with motor neuropathy syndromes with demyelinative features, but only become obvious 6 months or later after starting treatment in patients with predominantly axonal disorders.

Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Antibody Specificity; Antigens; Autoantibodies; Autoimmune Diseases; Chronic Disease; Cyclophosphamide; Diagnosis, Differential; Female; G(M1) Ganglioside; Humans; Immunosuppressive Agents; Male; Middle Aged; Neural Conduction; Neuromuscular Diseases

Chagas disease involves a cardiac impairment, being the first alterations of autonomic disorders which affect heart rate and blood pressure control. At this stage, diminished heart rate responses to atropine and propranolol are observed. Prior studies have shown that short term ganglioside treatment improves the responses to these agents, but there is no information about the long term effect of gangliosides and the evolution of antiGM1 titers. The effects of long term treatment with gangliosides on autonomic tests in patients with chagasic cardiodisautonomy and the evolution of antiGM1 titers were studied in 90 patients (57 men, 33 women, aged 25-60 years) with positive serology for Chagas disease and electrocardiogram showing sinusal bradycardia and incomplete right branch block, without cardiomegaly, with autonomic alterations by postural and Valsalva's tests. All patients were submitted to a test that consisted of intravenous injection of atropine 0.04 mg/kg followed 3 min later by intravenous injection of propranolol 0.2 mg/kg. During these tests heart rate and blood pressure were recorded continuously. Subsequently, 30 patients were treated with 100 mg/day of a mixture of gangliosides by intramuscular injection during 15 days in a row, followed by 40 mg/day during another 75 days. Another 30 patients received continuous treatment for 12 months. The remaining 30 patients were controls. The antiGM1 antibody circulating titers were determined before the treatment, at the third and 12th month. Seventy-four patients completed the study. Before treatment, the heart rate increased, though slightly, after the injection of atropine. After 3 months of ganglioside treatment a statistically significant increase in the response to atropine was recorded. In the controls at 12 months, the response to atropine remained increased without differences between the patients treated for 3 and 12 months. The control patients did not show any modification of the heart rate response during 12 months. Both ganglioside-treated groups showed an increase in the response to propranolol. The antiGM1 titer distribution was similar in both healthy subjects and chagasic patients. None of the patients had positive antiGM1 titers in basal conditions nor significant modifications after the ganglioside treatment. Chagasic cardioneuropathy was not associated in this study with high antiGM1 antibody titers. Chagasic patients showed a diminished heart rate response to atropine as well as t

Topics: Adult; Atropine; Autoantibodies; Autonomic Nervous System Diseases; Chagas Cardiomyopathy; Chronic Disease; Female; G(M1) Ganglioside; Gangliosides; Heart Rate; Humans; Injections, Intramuscular; Male; Middle Aged; Propranolol; Time Factors

Eosinophilia myalgia syndrome (EMS) has been related to intake of "contaminated" L-tryptophan, and an alteration in tryptophan 5-hydroxytryptamine (5-HT, serotonin) metabolism has been reported in EMS patients. Recently we found that a defined autoantibody pattern consisting of antibodies to nucleoli, gangliosides, and phospholipids is closely related to the fibromyalgia syndrome (FS) which clinically resembles the EMS. We were therefore interested to see whether these antibodies can also be detected in patients with EMS. Studied were 27 patients with acute EMS (13 of whom were also examined 2 years after acute onset), 100 patients with FS, and 40 patients with progressive systemic sclerosis (PSS). As controls, sera from 100 blood donors were analyzed. Antibodies to nucleoli were demonstrated by immunofluorescence test on cell cultures in 52% of patients with acute EMS, 62% of patients with chronic EMS, and 37% of FS patients. Western blotting with a nuclear extract from HeLa cells revealed in both diseases the same epitopes at 63, 57, and 53 kDa. Antibodies to 5-HT, gangliosides (Gm1), and phospholipids were determined by enzyme-linked immunosorbent assay. Among patients with FS 73% had antibodies to 5-HT, in contrast to only 19% of patients with acute EMS. However, 77% of the 13 EMS patients analyzed 2 years later had become anti-5-HT antibody positive during that time. Also the incidence of antibodies to Gm1 increased from 37% at acute onset to 69% in patients with chronic EMS (30%). The various antibodies were detected in only 18% of healthy controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Adult; Aged; Antibodies, Antiphospholipid; Autoantibodies; Blotting, Western; Cell Nucleolus; Chronic Disease; Eosinophilia-Myalgia Syndrome; Female; Fibromyalgia; Follow-Up Studies; G(M1) Ganglioside; Humans; Male; Middle Aged; Serotonin; Tryptophan

In a randomized double-blind cross-over study, humans with chronic spinal cord injury received ganglioside GM-1 or placebo for 2 months. GM-1, administered intravenously at a dose of 100 mg, 6 days a week, resulted in a statistically significant improvement of motor scores (P < 0.05), whether administered before or after 2 months of placebo. There was no placebo effect on motor scores. Subjects who received GM-1 before placebo maintained their improvement during the placebo phase. Subjects who received GM-1 ambulated with a reciprocal gait, using orthotics, for longer distances and at a faster rate whether the drug was administered before or after placebo. These results constitute the first finding that any chemical substance improves locomotion in human chronic spinal cord injury.

Topics: Adult; Chronic Disease; Combined Modality Therapy; Double-Blind Method; Female; G(M1) Ganglioside; Humans; Male; Muscles; Physical Therapy Modalities; Spinal Cord Injuries; Walking

Cancer progression involves carcinogenesis, an increase in tumour size, and metastasis. Here, we investigated the effect of overexpressed CXC chemokine ligand 14 (CXCL14) on these processes by using CXCL14/BRAK (CXCL14) transgenic (Tg) mice. The rate of AOM/DSS-induced colorectal carcinogenesis in these mice was significantly lower compared with that for isogenic wild type C57BL/6 (Wt) mice. When tumour cells were injected into these mice, the size of the tumours that developed and the number of metastatic nodules in the lungs of the animals were always significantly lower in the Tg mice than in the Wt ones. Injection of anti-asialo-GM1 antibodies to the mice before and after injection of tumour cells attenuated the suppressing effects of CXCL14 on the tumor growth and metastasis, suggesting that NK cell activity played an important role during CXCL14-mediated suppression of tumour growth and metastasis. The importance of NK cells on the metastasis was also supported when CXCL14 was expressed in B16 melanoma cells. Further, the survival rates after tumour cell injection were significantly increased for the Tg mice. As these Tg mice showed no obvious abnormality, we propose that CXCL14 to be a promising molecular target for cancer suppression/prevention.

Topics: Animals; Antigens, Ly; Autoantibodies; Cell Transformation, Neoplastic; Chemokines, CXC; Chronic Disease; Colitis; Disease Models, Animal; Female; G(M1) Ganglioside; Galactosylceramides; Killer Cells, Natural; Lung Neoplasms; Lymphocyte Depletion; Melanoma, Experimental; Mice; Mice, Transgenic; Neoplasms; NK Cell Lectin-Like Receptor Subfamily B; Tumor Burden

Low-dose naloxone-precipitated withdrawal hyperalgesia is a reliable indicator of physical dependence after chronic morphine treatment. A remarkably similar long-lasting (>3-4 h) hyperalgesia is evoked by injection of a low dose of naloxone (10 microg/kg, s.c.) in naïve mice after acute pretreatment with the glycolipid, GM1 ganglioside (1 mg/kg) (measured by warm-water-immersion tail-flick assays). GM1 treatment markedly increases the efficacy of excitatory Gs-coupled opioid receptor signaling in nociceptive neurons. Co-treatment with an ultra-low-dose (0.1 ng/kg, s.c.) of the broad-spectrum opioid receptor antagonist, naltrexone or the selective kappa opioid receptor antagonist, nor-binaltorphimine, blocks naloxone-evoked hyperalgesia in GM1-pretreated naïve mice and unmasks prominent, long-lasting (>4 h) inhibitory opioid receptor-mediated analgesia. This unmasked analgesia can be rapidly blocked by injection after 1-2 h of a high dose of naltrexone (10 mg/kg) or nor-binaltorphimine (0.1 mg/kg). Because no exogenous opioid is administered to GM1-treated mice, we suggest that naloxone may evoke hyperalgesia by inducing release of endogenous bimodally acting opioid agonists from neurons in nociceptive networks by antagonizing putative presynaptic inhibitory opioid autoreceptors that "gate" the release of endogenous opioids. In the absence of exogenous opioids, the specific pharmacological manipulations utilized in our tail-flick assays on GM1-treated mice provide a novel bioassay to detect the release of endogenous bimodally acting (excitatory/inhibitory) opioid agonists. Because mu excitatory opioid receptor signaling is blocked by ultra-low doses of naloxone, the higher doses of naloxone that evoke hyperalgesia in GM1-treated mice cannot be mediated by activation of mu opioid receptors. Co-treatment with ultra-low-dose naltrexone or nor-binaltorphimine may selectively block signaling by endogenous GM1-sensitized excitatory kappa opioid receptors, unmasking inhibitory kappa opioid receptor signaling, and converting endogenous opioid receptor-mediated hyperalgesia to analgesia. Co-treatment with kelatorphan stabilizes putative endogenous opioid peptide agonists released by naloxone in GM1-treated mice, so that analgesia is evoked rather than hyperalgesia. Acute treatment of chronic morphine-dependent mice with ultra-low-dose naltrexone (0.1 ng/kg) results in remarkably similar rapid blocking of naloxone (10 microg/kg)-precipitated withdrawal hyperalgesia

Topics: Analgesics, Opioid; Animals; Chronic Disease; Dipeptides; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Synergism; G(M1) Ganglioside; Hyperalgesia; Male; Mice; Morphine; Morphine Dependence; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptors; Opioid Peptides; Receptors, Opioid, kappa; Substance Withdrawal Syndrome

This study characterized the proinflammatory cytokines, interleukin-2 (IL-2) and tumor necrosis factor alpha (TNFalpha), the antiinflammatory cytokines, IL-4 and IL-10, autoantibodies specific for GM1 ganglioside (anti-GM1), IgG and IgM, and myelin-associated glycoprotein (anti-MAG), in the sera of infection-free, chronic (>12 months), traumatically injured SCI patients (n = 24). Healthy able-bodied subjects (n = 26) served as controls. The proinflammatory cytokines and anti-GM1 antibodies were of particular interest as they have been implicated in an autoimmune "channelopathy" component to central and peripheral conduction deficits in various chronic neuroinflammatory diseases. Antibody and cytokine titers were established using enzyme-linked immunosorbent assays (ELISA). The mean anti-GM(1) (IgM) titer value for the SCI group was significantly higher (p < 0.05) than controls. The SCI group also demonstrated significantly higher titers (p < 0.05) of IL-2 and TNF alpha than controls. No differences were found between the SCI group and control group mean levels of IL-4 or IL-10. Overall, the serum of 57% of SCI patients contained increased levels of autoantibodies or proinflammatory cytokines relative to control values. These results provide preliminary support for the hypothesis that chronic immunological activation in the periphery occurs in a subpopulation of chronic SCI patients. It remains to be established whether elevated serum titers of proinflammatory cytokines and autoantibodies against GM1 are beneficial to the patients or whether they are surrogate markers of a channelopathy that compounds the neurological impairment associated with traumatic axonopathy or myelinopathy.

Topics: Adult; Autoantibodies; B-Lymphocytes; Chronic Disease; Female; G(M1) Ganglioside; Humans; Interleukin-10; Interleukin-2; Interleukin-4; Male; Middle Aged; Myelin-Associated Glycoprotein; Spinal Cord Injuries; Tumor Necrosis Factor-alpha

Topics: Antibodies, Anti-Idiotypic; Chronic Disease; Demyelinating Diseases; G(M1) Ganglioside; Guillain-Barre Syndrome; Humans; Odds Ratio; Polyneuropathies; Predictive Value of Tests; Sensitivity and Specificity

We describe a patient with a pure motor chronic demyelinating polyneuropathy with an IgM monoclonal component showing anti-GM2, GalNAc-GD1a and GalNAc-GM1b reactivity whose common epitope appears to be -[GalNAcbeta1-4Gal(3-2alphaNeuAc)beta1]. We used intracellular recording to study how IgM from this patient affected neurotransmitter release in the mouse diaphragm in vitro. Adding serum (and specifically, the purified monoclonal IgM component) blocked the nerve-evoked response in both quantal content and evoked endplate potential (EPP) amplitude in a complement-independent and reversible manner. The IgM increased the frequency of spontaneous miniature endplate potentials (MEPPs) in a complement-dependent and reversible manner but had no effect on MEPP amplitude.

Topics: Adult; Animals; Antibodies, Monoclonal; Antibody Specificity; Blood Physiological Phenomena; Chronic Disease; Demyelinating Diseases; Diaphragm; Electrophysiology; G(M1) Ganglioside; G(M2) Ganglioside; Gangliosides; Humans; Immunoglobulin M; Male; Mice; Motor Endplate; Neuromuscular Junction; Neurotransmitter Agents; Peripheral Nervous System Diseases; Reference Values

Toxoplasmosis is a potentially fatal opportunistic infection of immunocompromised hosts. Improved animal models of toxoplasmosis are needed to more nearly approximate conditions that occur in immunocompromised humans. The development of models of toxoplasmosis using human peripheral blood lymphocytes (hu-PBL) transplanted into severe combined immunodeficiency (SCID) mice is described here. Transplantation of hu-PBL into SCID mice without prior conditioning of the mice resulted in detectable differences in quantitative histological scores of brain inflammation due to Toxoplasma gondii infection, but did not alter mortality when compared to SCID mouse controls. The lack of detectable differences in survival were due to inadequate engraftment of hu-PBL, as assessed by flow cytometry. Unconditioned hu-PBL SCID mice had low titre T. gondii-specific antibody detectable after infection. When pretransplantation conditioning with irradiation and antiasialo GM 1 (n-glucolyl neuraminic acid) antibody was used, prolonged hu-PBL engraftment was observed in SCID mice, which was associated with worsened histopathology and usually impaired survival when compared with SCID mouse controls. When pretransplantation conditioning with irradiation, antiasialo GM antibody and polyethylene glycol-conjugated IL-2 was used, prolonged hu-PBL engraftment was also documented, but this did not affect survival from T. gondii infection when compared with similarly conditioned SCID mouse controls. The latter conditioning protocol resulted in hu-PBL SCID mice producing high titre T. gondii-specific antibody after infection. Conditioned hu-PBL SCID mice had evidence of increased T. gondii-induced inflammatory scores when compared with conditioned SCID mice. These models show promise for the study of the pathogenesis of toxoplasmosis and conditioned hu-PBL SCID mice may have applications for the evaluation of novel therapies for toxoplasmosis in immunocompromised humans.

Topics: Acute Disease; Animals; Antibodies; Antibodies, Protozoan; Chronic Disease; Cytotoxicity Tests, Immunologic; Disease Models, Animal; Flow Cytometry; G(M1) Ganglioside; Humans; Killer Cells, Natural; Liver; Lymphocyte Count; Lymphocyte Transfusion; Mice; Mice, SCID; Spleen; Survival Rate; Toxoplasma; Toxoplasmosis, Animal; Transplantation Conditioning; Whole-Body Irradiation

The pathogenetic role of anti-GM1 in chronic acquired demyelinating polyneuropathy (CADP) is uncertain. An association between antibodies and disease activity has not yet been established. In 8 patients with CADP followed longitudinally, anti-GM1 antibodies were monitored with a standardized enzyme-linked immunosorbent assay technique and muscle performance with isokinetic dynamometry. During a mean observation period of 24 months, strength improved in 6 of 8 patients by a median value of 54.5%, and anti-GM1 fell in all 6 patients; the reduction being 43%. In 2 patients, muscle performance deteriorated by 30 and 8%, whereas anti-GM1 titers increased by 10 and 9%, respectively. The relative change in anti-GM1 was inversely related to muscle performance. Clinical scoring of muscle performance according to the Medical Research Council scale failed to show an association with anti-GM1. It is concluded that anti-GM1 antibodies are closely related to disease activity, and that the close association indicates a role of anti-GM1 in the pathogenesis of CADP.

Topics: Adult; Antibodies; Chronic Disease; Demyelinating Diseases; Female; G(M1) Ganglioside; Humans; Immunoglobulin M; Male; Middle Aged; Muscles; Peripheral Nervous System Diseases

Antibodies reactive with the core glycan of asialoganglioside (GA1), monosialoganglioside (GM1), and disialoganglioside (GD1a) were studied in human sera. In healthy individuals, GA1-, GM1-, and GD1a-reactive antibodies were mainly of the IgM class, but also of the IgA and IgG classes, and were present at low titers in the serum of 68%, 79%, and 91% of the individuals studied, respectively. Levels of anti-GA1 and anti-GM1 antibodies, mainly of the IgA and IgG classes, were significantly elevated (P < 0.001) in 62% and 72% of subjects, respectively, chronically infected with Trypanosoma cruzi, with no association found with the degree of myocardial damage. No significant increase in anti-GA1 and anti-GM1 antibodies was found in dilated cardiomyopathy patients. The level of anti-GD1a antibody was not significantly different between healthy controls and chronic chagasic or dilatatory cardiomyopathy patients. Since the peripheral nervous system is very rich in gangliosides, it is possible that the increases in GA1- and GM1-specific antibodies that develop during chronic T. cruzi infection are involved in the pathology of peripheral neuropathy in Chagas' disease.

Topics: Animals; Antibodies, Protozoan; Autoantibodies; Cattle; Chagas Disease; Chronic Disease; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; Gangliosides; Glycosphingolipids; Humans; Immunoglobulins; Peripheral Nervous System Diseases

Polyclonal immunoglobulin M antibodies to the monosialoganglioside GM2, sulfoglucuronyl glycolipids, and sulfatide were detected by thin-layer chromatography and enzyme-linked immunosorbent assay in the serum of a patient with melanoma and chronic inflammatory demyelinating polyneuropathy. Both the patient's serum and polyclonal antibodies against GM2 reacted strongly with a biopsy of melanomatous tissue from the patient, suggesting a process of molecular mimicry.

Topics: Aged; Antibody Specificity; Chronic Disease; Demyelinating Diseases; Enzyme-Linked Immunosorbent Assay; Female; G(M1) Ganglioside; Humans; Immunoglobulin G; Immunoglobulin M; Melanoma; Molecular Mimicry; Myelin-Associated Glycoprotein; Polyneuropathies

In January 1993, a 43-year-old man was admitted to our hospital for left wrist-drop. Neurological examinations revealed asymmetrical distal weakness in the upper limbs. Deep tendon reflexes were normal in all 4 limbs. Sensory and autonomic nervous functions were intact. CSF examinations were within normal limits. Thin-layer chromatography with immunostaining revealed serum antibodies that reacted with GM1 and GalNAc-GD1a. Motor nerve conduction studies revealed abnormal temporal dispersion, and a low amplitude of compound muscle action potential in the left radial nerve. Neurological symptoms gradually improved with prednisolone over one and a half years. He was hospitalized again in January 1995, because of right wrist-drop and slight sensory loss of the limbs. Those findings were improved by methylprednisolone (1,000 mg/day) for 3 days. The interval until maximal disability in this patient was more than one month for each admission. This case must belong to inflammatory demyelinating neuropathy.

Topics: Acetylgalactosamine; Anti-Inflammatory Agents; Autoantibodies; Chronic Disease; Demyelinating Diseases; G(M1) Ganglioside; Humans; Male; Methylprednisolone; Middle Aged; Prednisolone; Recurrence

Unlike CNS myelin, human peripheral nerve myelin has the acidic glycosphingolipids sialosyl paragloboside (SPG), sialosyl lactosaminyl paragloboside (SLPG), and sulfated glucuronyl paragloboside (SGPG). To elucidate the pathogenesis of Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating neuropathy (CIDP), we investigated the autoantibodies to peripheral nerve molecules in patients with these diseases and compared the frequency of the autoantibodies with that of autoantibody to GM1 which is present in both the CNS and PNS. The report of Sheikh et al. (Ann. Neurol. 1995; 38: 350) that Campylobacter jejuni bears the SGPG epitope led us to study whether sera from patients with GBS subsequent to C. jejuni enteritis have anti-SGPG antibody; but, high anti-SGPG antibody titers were not found in the GBS patients from whom C. jejuni was isolated. Although the frequency of the anti-SPG, anti-SLPG and anti-SGPG antibodies were lower than that of the anti-GM1 antibody in GBS, 5 patients with demyelinating GBS had high IgG anti-SPG antibody titers. IgG anti-SPG antibody may function in the development of demyelinating GBS. We found that 6 CIDP patients had elevated IgM anti-SGPG antibody titers. Immunoelectrophoresis failed to detect IgM M-protein in 3 of the patients. IgM anti-SGPG antibody could be a diagnostic marker for a subgroup of CIDP with or without paraprotein.

Topics: Aged; Antibody Specificity; Antigens, Bacterial; Autoantibodies; Autoantigens; Autoimmune Diseases; Biomarkers; Campylobacter jejuni; Carbohydrate Sequence; Chronic Disease; Cross Reactions; Demyelinating Diseases; Epitopes; Female; G(M1) Ganglioside; Globosides; Humans; Immunoelectrophoresis; Immunoglobulin G; Immunoglobulin M; Inflammation; Lipopolysaccharides; Male; Middle Aged; Molecular Mimicry; Molecular Sequence Data; Peripheral Nerves; Polyradiculoneuropathy

In a study on 67 chronic neuropathies, we have shown that anti-GM1 antibodies are particularly frequent in multifocal motor neuropathies (MMN) with conduction blocks (17/24 cases). The detection of these antibodies by ELISA necessitates a confirmation by immunodetection on thin-layer chromatography, so as to distinguish the anti-GM1 antibodies present in MMN from natural antibodies which are polyreactive and of low affinity. There is no direct correlation between the anti-GM1 antibody titer, the immunosuppressive treatment and the clinical evolution. Nevertheless, the detection of high titer of anti-GM1 antibodies is an additional argument in favor of treatment by IVIg.

Topics: Autoantibodies; Chromatography, Thin Layer; Chronic Disease; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; Humans; Immunoglobulins, Intravenous; Motor Neuron Disease; Peripheral Nervous System Diseases; Time Factors

Topics: Chronic Disease; G(M1) Ganglioside; Humans; Spinal Cord Injuries

Patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and with a chronic polyneuropathy (non-CIDP) were studied for the presence of anti-GM1 antibodies. In pretreatment sera of CIDP patients, we found IgG anti-GM1 antibodies in 23%, IgM in 7%, and IgA in 14%. Predominantly motor involvement was associated with IgG and IgM anti-GM1 antibodies in CIDP patients (P = 0.002). Improvement after intravenous immunoglobulin (IVIg) therapy was not associated with anti-GM1 antibody titer before or after treatment. Anti-GM1 antibody titers before onset of treatment was not related to poor clinical outcome, although large clinical improvements after IVIg therapy were observed less often (P = 0.057) in patients with high titer anti-GM1 antibodies before treatment.

Topics: Action Potentials; Antibodies; Chronic Disease; Demyelinating Diseases; G(M1) Ganglioside; Humans; Immunoglobulins, Intravenous; Movement; Polyneuropathies; Sensation

We report a 19-year-old female with chronic inflammatory demyelinating polyneuropathy (CIDP) with recurrent ophthalmoplegia. The patient had chronic, recurrent, asymmetrical, predominantly, distal limb weakness, and numbness of extremities with recurrent external ophthalmoplegia. Ophthalmoplegia developed in each attack of distal limb weakness, and also rapidly subsided with recovery of limb weakness. Motor nerve conduction studies revealed conduction block in more than one nerve and conduction velocities were generally normal in those segments of the nerve where conduction block was not detected. Serum anti-gangliosides GM1 IgM antibody investigated by ELISA was elevated. Thin-layer chromatography immunostaining also confirmed this result. Sural nerve biopsy showed normal findings. In spite of improvement of her signs and symptoms after prednisolone therapy, multifocal conduction block was persistent. Muscle power improved in association with decreased in anti-GM1 antibody activity. There were many reports of CIDP with cranial nerve involvements, but recurrent ophthalmoplegia in CIDP is rare. It is widely accepted that serum anti-GQ1b IgG antibody is associated with ophthalmoplegia in Miller Fisher syndrome and Guillain-Barré syndrome. However, serum anti-GQ1b IgG antibody was not detected in this case. It is unclear whether anti-GM1 antibody may play a role to pathogenesis of ophthalmoplegia or not in this case.

Topics: Adult; Autoantibodies; Chronic Disease; Demyelinating Diseases; Female; G(M1) Ganglioside; Humans; Neural Conduction; Ophthalmoplegia; Peripheral Nervous System Diseases; Polyneuropathies; Recurrence

Topics: Adult; Autoantibodies; Chronic Disease; Female; G(M1) Ganglioside; Gangliosides; Humans; Neuromuscular Diseases

The clinical and electrophysiological features were prospectively studied of 75 patients (46 men and 29 women) with chronic polyneuropathy presenting in middle or old age in whom a diagnosis could not be made even after extensive evaluation and a follow up of six months. The mean age at the onset of symptoms was 56.5 years. The clinical features of chronic idiopathic polyneuropathy are heterogeneous. On clinical grounds 44 patients had a sensorimotor, 29 patients a sensory, and two patients a motor polyneuropathy. The overall clinical course in chronic idiopathic polyneuropathy was slowly progressive. None of the patients became severely disabled. Electrophysiological and nerve biopsy studies were compatible with an axonal polyneuropathy. Antibodies against myelin associated glycoprotein, gangliosides, and sulphatides were assessed in 70 patients and found to be negative.

Topics: Age of Onset; Autoantibodies; Chronic Disease; Electromyography; Female; G(M1) Ganglioside; Humans; Male; Middle Aged; Myelin Proteins; Myelin-Associated Glycoprotein; Neural Conduction; Peripheral Nerves; Peripheral Nervous System Diseases; Prospective Studies; Sulfoglycosphingolipids

Clinical and experimental findings suggest that humoral factors, such as anti-peripheral nerve antibodies and cytokines, may be implicated in the immunopathogenesis of Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Interleukin-6 (IL-6) is a multifunctional cytokine that promotes immunoglobulin synthesis by B lymphocytes. Increased IL-6 release is associated with autoantibody production in a number of immune-mediated and neoplastic disorders. To investigate the possible involvement of abnormal IL-6 release in inflammatory polyneuropathies, we assayed IL-6 levels in the cerebrospinal fluid (CSF) and serum of 23 patients with acute GBS and seven with CIDP. We also studied 69 patients with other non-inflammatory neurological diseases (NIND), 25 with other inflammatory neurological diseases (IND), four with brain tumors (BT), and 15 normal donors (serum alone) as controls. We found detectable levels of IL-6 in the CSF of 57% of GBS, 43% of CIDP, 60% of IND, 75% of BT, and 4% of NIND. In GBS patients, no correlation was found between CSF IL-6 values and other laboratory or clinical parameters, such as CSF total protein, CSF albumin, CSF IgG, CSF/serum albumin ratio, functional disability score, and time elapsed from disease onset. Serum IL-6 levels were increased in six of 23 (26%) GBS, in one of 39 (3%) NIND, and in one of seven (14%) IND, but in none of the CIDP or BT patients. There was no correlation between serum and CSF IL-6 values, but cytokine levels in GBS sera correlated with time elapsed from clinical onset.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Autoantibodies; Chronic Disease; Demyelinating Diseases; Enzyme-Linked Immunosorbent Assay; Female; G(M1) Ganglioside; Humans; Immunoglobulin G; Immunoglobulin M; Interleukin-6; Male; Middle Aged; Nervous System Diseases; Polyradiculoneuropathy

High titers of antibodies directed against gangliosides, especially GM1, are found in the serum of patients with a variety of polyneuropathies, including those of the inflammatory type. We assayed anti-GM1 IgG and IgM levels in the serum and cerebrospinal fluid (CSF) of 23 patients with Guillain-Barré syndrome (GBS) and 10 with chronic inflammatory demyelinating polyneuropathy (CIDP) to investigate whether this immune response may also be localized within the intrathecal compartment and correlate with clinical parameters such as time interval since disease onset, disability score, preceding infectious episodes, and GM1 therapy. When compared to the control group, anti-GM1 IgG was increased in the serum of 39% of GBS and 10% of CIDP patients, whereas anti-GM1 IgM was elevated in 17% of GBS and none of the CIDP patients. In both patient groups, however, anti-GM1 antibody levels were more frequently elevated in CSF than paired sera: they belonged to the IgG class in 48% of GBS and 50% of CIDP patients, and to the IgM class in 48% of GBS and 55% of CIDP patients. In the GBS group, anti-GM1 IgM serum levels inversely correlated with time elapsed between sample collection and onset of disease (P < 0.05), whereas serum anti-GM1 IgG levels positively correlated with the loss of functional ability (P < 0.005). Increased anti-GM1 antibodies in GBS serum were not associated with clinical or serological evidence of infectious antecedents nor with previous GM1 treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Antibodies; Chromatography, Thin Layer; Chronic Disease; Demyelinating Diseases; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; Humans; Immunoglobulin G; Immunoglobulin M; Polyneuropathies; Polyradiculoneuropathy

Serum IgG in a patient with chronic polyneuropathy after Mycoplasma pneumoniae infection reacted with ganglioside GM1, GD1b and asialo-GM1 on thin-layer chromatograms using an immunostaining technique as well as an enzyme-linked immunosorbent assay, suggesting that the galactosyl (beta 1-3)N-acetylgalactosaminyl moiety could be a target antigen in this patient. Serum IgG reacting with these glycolipids may be involved in the pathogenesis of both motor and sensory neuropathies in this patient.

Topics: Adolescent; Adult; Aged; Autoantibodies; Autoimmune Diseases; Child; Chronic Disease; Enzyme-Linked Immunosorbent Assay; Female; G(M1) Ganglioside; Gangliosides; Humans; Immunoglobulin G; Male; Middle Aged; Neurologic Examination; Pneumonia, Mycoplasma; Polyradiculoneuropathy

Acute symmetric demyelinating polyneuropathy of the Guillain-Barré type is known in systemic lupus erythematosus (SLE). Chronic idiopathic demyelinating polyneuropathy (CIDP) has been reported rarely with SLE. A case is reported of CIDP accompanying SLE with autoantibodies against GM1- and GM3-gangliosides. There was no historical evidence to suggest SLE, and CIDP was the first manifestation of SLE. The 38-year-old patient had elevated CSF-protein, slow nerve conduction velocities, sural nerve biopsy revealed mixed axon loss with demyelination and CIDP white matter lesions were observed in magnetic resonance imaging, the GM1- and GM3-autoantibodies may play a role in the pathogenesis of CIDP in SLE.

Topics: Adult; Autoantibodies; Chronic Disease; Demyelinating Diseases; G(M1) Ganglioside; G(M2) Ganglioside; Humans; Lupus Erythematosus, Systemic; Male; Neurologic Examination; Polyradiculoneuropathy

Molecular analysis of the human beta-galactosidase gene revealed six different mutations in 10 of 11 Japanese GM1-gangliosidosis patients. They were the only abnormalities in each allele examined in this study. A 165-nucleotide duplication (positions 1103-1267) was found in two infantile patients, producing an abnormally large mRNA; one patient was probably a homozygote, and the other was a heterozygote of this mutation. The other two infantile patients had different mutations; a 123 Gly(GGG)----Arg(AGG) mutation in one patient and a 316 Tyr(TAT)----Cys(TGT) mutation in the other. A 201 Arg(CGC)----Cys(TGC) mutation, eliminating a BspMI site, was detected in a late-infantile/juvenile patient; the restriction-site analysis of amplified genomic DNA confirmed his heterozygosity for this mutation. A 51 Ile(ATC)----Thr(ACC) mutation was found in all five adult/chronic patients examined in this study. It created a SauI site, and restriction-site analysis confirmed that four patients were homozygous mutants. The other was a compound heterozygote for this mutation and another 457 Arg(CGA)----Gln(CAA) mutation. These mutant genes expressed markedly decreased or completely deficient enzyme activities in beta-galactosidase-deficient human fibroblasts transformed by adenovirus-SV40 recombinants. We conclude that gene mutations are heterogeneous in GM1-gangliosidosis but that the 51 Ile(ATC)----Thr(ACC) mutation is common among the Japanese adult/chronic cases. Genotype-phenotype correlations in GM1-gangliosidosis are briefly discussed.

Topics: Adolescent; Adult; Alleles; Base Sequence; beta-Galactosidase; Cells, Cultured; Child; Chronic Disease; Cloning, Molecular; G(M1) Ganglioside; Gangliosidoses; Genes; Humans; Infant; Japan; Molecular Sequence Data; Mutation; Oligonucleotide Probes; Polymerase Chain Reaction; RNA, Messenger

Clinical and biochemical studies are reported on a 32-year-old man with GM1 gangliosidosis who presented with a slowly progressive dystonia that began when he was aged 7 years and eventually became almost totally incapacitating at the age of 35. There was only mild intellectual deterioration, but myoclonus, seizures and macular cherry-red spots were never observed. Proton-density and T2-weighted MRI scans showed symmetrical hyperintense lesions of both putamina. No increase of GM1 ganglioside was found in plasma or cerebrospinal fluid, and the metabolism of GM1 ganglioside in cultured skin fibroblasts from the patient was also almost normal, although the residual activity of GM1 ganglioside beta-galactosidase activity was only 10% of normal. These findings suggest that impaired GM1 ganglioside metabolism is not present systemically as it is in the infantile and juvenile types of the disorder, but is mainly confined to the central nervous system in chronic GM1 gangliosidosis.

Topics: Adult; Chronic Disease; Dystonia; G(M1) Ganglioside; Gangliosidoses; Humans; Male

Topics: Acute Disease; Alopecia; Animals; Chronic Disease; Dermatitis; Female; G(M1) Ganglioside; Glycosphingolipids; Graft vs Host Disease; Mice; Mice, Inbred C57BL; Mice, Inbred DBA

The effect of recombinant human interleukin-2 (rIL-2) on the course of experimental chronic respiratory tract infection caused by Klebsiella pneumoniae in mice was examined. rIL-2 was administered subcutaneously once a day for 7 or 14 days, starting 2 weeks after the mice were infected. Administration of 2 or 20 micrograms of rIL-2 per mouse daily for 7 days reduced bacterial counts in the lungs dose dependently. At a dose of 0.2 microgram per day, proliferation of bacteria in the lungs was suppressed after 14 days of administration. Agglutinin titers in serum were not affected by rIL-2 treatment. Monocyte and lymphocyte counts in peripheral blood were increased by administration of 20 micrograms of rIL-2 daily for 14 days but not by treatment for 7 days. In addition, clearance of bacteria from the lungs after aerosol exposure was enhanced by treatment for 7 days before infection. Thus, rIL-2 acted therapeutically or prophylactically in the presence or absence, respectively, of a specific antigen. These effects were not abolished by anti-asialo GM1 antibody. This suggests that activation of natural killer cells does not play a critical role in the therapeutic and prophylactic effects of rIL-2.

Topics: Aerosols; Agglutination Tests; Animals; Antibodies; Chronic Disease; Female; G(M1) Ganglioside; Glycosphingolipids; Interleukin-2; Kinetics; Klebsiella Infections; Klebsiella pneumoniae; Leukocyte Count; Lung Diseases; Mice; Mice, Inbred CBA; Recombinant Proteins; Respiratory Tract Infections

The effect of the ganglioside GM1 on amplitude of the electroencephalogram, neurologic function, and histology has been studied in chronic middle cerebral artery occlusion in cats. Ischemia was produced by a 2-hour occlusion of the left middle cerebral artery and was followed by a 7-day observation period. GM1 was intravenously administered 30 minutes after occlusion and daily during the observation period. Using the reduction in the electroencephalogram amplitude to measure stroke severity, three cats with mild, three cats with moderate, and three cats with severe stroke were treated with 5 mg/kg GM1. Nine cats, three in each group, were treated with 30 mg/kg GM1, while nine cats, three in each group, received middle cerebral artery occlusion but no treatment. In all cats there was a precipitous fall in mean electroencephalogram amplitude during occlusion, followed by a secondary fall during the observation period. Treated cats showed better recovery of electroencephalogram amplitude during the first 4 hours of reperfusion and a smaller secondary fall than untreated cats. Treated cats, especially those treated with 5 mg/kg GM1, showed significant recovery of neurologic deficits compared with untreated cats. Histologic damage was less in treated cats than in untreated cats. Some cats treated with 30 mg/kg GM1 exhibited convulsions, whereas no untreated cat showed any seizure activity. Our findings suggest that gangliosides may improve the recovery of both neurologic deficits and morphologic damage in the central nervous system. These positive effects might be tentatively explained by stimulation of enzymatic activities such as Na+, K+-ATPase and adenyl cyclase.

Topics: Animals; Arterial Occlusive Diseases; Brain Ischemia; Cats; Cerebral Arterial Diseases; Chronic Disease; Electroencephalography; G(M1) Ganglioside; Nervous System

Cerebral lipids of patients with GM1-gangliosidoses, infantile, juvenile, and chronic type which are caused by deficiency of beta-galactosidase, were examined and compared to each other. The infantile type demonstrated abnormal accumulation of GM1 and asialo-GM1 in contrast with marked decrease in such major cerebral lipids as cholesterol, phospholipids, cerebroside, and sulfatide. It was also noted that significant amounts of such unusual lipids as free fatty acids, GlcCer, LacCer, GbOse3Cer, and GbOse-4Cer plus nLcOse4Cer were found in the brain. These findings pointed out that this infantile type might accompany a severe cerebral dysgenesis with poor myelination. The juvenile type also showed marked increase in GM1 and asialo-GM1, but the decrease in cholesterol, phospholipids, cerebroside, and sulfatide was not so much as the infantile type. These findings along with the occurrence of cholesterol ester suggested that the brain caused progressive demyelination after the immature myelin appeared. An autopsized brain tissue of a male patient who was eventually diagnosed as a case of GM1-gangliosidosis chronic type after his death, showed some accumulation of GM1 and asialo-GM1 particularly in the caudate nucleus and putamen, whereas it showed moderate amounts of GM1 in apparently normal gray and white matters. It seemed that there are no abnormal cerebral lipids except for gangliosides and some neutral glycosphingolipids in the chronic type.

Topics: Adult; Age Factors; Brain; Child, Preschool; Chronic Disease; Female; G(M1) Ganglioside; Gangliosidoses; Glycosphingolipids; Humans; Infant; Lipid Metabolism; Male; Phospholipids

Topics: Animals; Autoantibodies; Autoantigens; Chronic Disease; Complement Fixation Tests; Encephalomyelitis, Autoimmune, Experimental; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; Galactosylceramides; Guinea Pigs; Myelin Basic Protein; Myelin Sheath; Precipitin Tests; Rats

A patient with chronic GM1 gangliosidosis was studied enzymatically and biochemically. Leukocyte acid beta-galactosidase activity was severely deficient. In brain and liver, the 4-methylumbelliferyl beta-galactosidase with acidic pH optimum and lactosylceramidase II were deficient while other hydrolases were present in normal amounts, including sialidase determined with N-acetylneuramin-lactose and fetuin as substrates. Neutral beta-galactosidase in liver was increased up to fourfold over the control. Corresponding to the pathological findings, GM1 ganglioside sialic acid was increased in the basal ganglia to 57% of the total (normal, 12 to 16%), accounting for the rise in total ganglioside to 180% of normal in this origin. Only slight to moderate elevations in the proportion of GM1 ganglioside were noted in the cerebral cortex and white matter, without major increase in total ganglioside. Elevated asialo GM1 ganglioside was also confined to the basal ganglia. There was no increase in hepatic glycoproteins or in keratan sulfate-like materials. This is the only known patient with chronic GM1 gangliosidosis in whom abnormal accumulation of GM1 ganglioside has been demonstrated in affected tissue and sialidase deficiency has been excluded as the primary genetic defect.

Topics: Adult; beta-Galactosidase; Brain Chemistry; Chronic Disease; G(M1) Ganglioside; Gangliosides; Gangliosidoses; Humans; Lactose Intolerance; Leukocytes; Liver; Lysosomes; Male