RESUMEN
Herpes simplex encephalitis (HSE) is an acute form of encephalitis that can lead to poor neurological outcomes. Although the exact pathogenesis of HSE remains elusive, recent reports suggest a significant role for postinfectious immune-inflammatory processes in the central nervous system (CNS). This study aimed to clarify the association between CNS autoimmune responses and clinical presentation in patients with HSE, focusing on cerebrospinal fluid (CSF) characteristics, particularly the IgG index. We retrospectively analyzed 176 consecutive patients suspected of having aseptic meningitis /encephalitis for chronological changes in CSF findings and clinical presentations. These patients underwent PCR screening for herpesviruses (HV) in their CSF. We identified seven patients positive for herpes simplex virus type 1 (HSV-1), 20 patients positive for varicella-zoster virus, and 17 patients who met the criteria for aseptic meningitis but were PCR-negative for HV. Patients in the HSV-1-positive group exhibited a significant increase in the IgG index at the time of PCR-negative conversion compared with on admission (p = 0.0156), while such a change was not observed in the other two groups. Additionally, all patients in the HSV-1-positive group tested negative for anti-neural autoantibodies in CSF and serum samples collected approximately 3 weeks after onset. This study, therefore, highlights that CSF IgG index elevation occurs even after PCR-confirmed HSV-1 clearance, which might indicate immunopathogenesis that is independent of antibody-mediated mechanisms.
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Anticuerpos Antivirales , Encefalitis por Herpes Simple , Herpesvirus Humano 1 , Inmunoglobulina G , Humanos , Inmunoglobulina G/líquido cefalorraquídeo , Inmunoglobulina G/sangre , Femenino , Masculino , Encefalitis por Herpes Simple/líquido cefalorraquídeo , Encefalitis por Herpes Simple/inmunología , Herpesvirus Humano 1/inmunología , Estudios Retrospectivos , Persona de Mediana Edad , Adulto , Anciano , Anticuerpos Antivirales/líquido cefalorraquídeo , Anticuerpos Antivirales/sangre , Adulto Joven , Adolescente , Herpesvirus Humano 3/inmunología , Reacción en Cadena de la Polimerasa , Autoanticuerpos/líquido cefalorraquídeo , Autoanticuerpos/sangre , Anciano de 80 o más Años , Niño , Líquido Cefalorraquídeo/virología , Líquido Cefalorraquídeo/inmunologíaRESUMEN
BACKGROUND: Encephalomyeloradiculoneuropathy (EMRN) is characterized by progressive neurological symptoms in the central and peripheral nervous systems. The autoantibodies against neutral sphingolipids are disease-specific antibodies against EMRN. Although adults with EMRN typically present with symptoms of peripheral nervous system involvement, the symptoms in pediatric patients are not well understood. CASE: A 4-year-old boy was admitted to our hospital on the 10th day of fever due to poor oral intake and hyponatremia. The day after admission, he developed seizures and impaired consciousness and was transferred to our hospital. When he arrived at our hospital, he experienced disturbances in consciousness, neck rigidity, and opisthotonus. MRI of the head revealed scattered white matter lesions and pleocytosis in the cerebrospinal fluid (CSF). During treatment with intravenous methylprednisolone (IVMP), the patient developed diminished deep tendon reflexes in the lower extremities four days later, with no improvement in cervical stiffness or opisthotonos. Additional evaluations revealed enlarged cerebral white matter lesions on brain MRI, cauda equina enhancement on MRI of the spinal cord, axonal neuropathy in the bilateral tibial nerves, and positive anti-neutral glycosphingolipid (GSL) antibodies in both serum and CSF. Intensive immunomodulatory therapy, and neurorehabilitation, led to substantial neurological recovery within three months of onset. CONCLUSION: Pediatric antineutral GSL antibody-positive EMRN may initially present with extensive cerebral white matter lesions and delayed onset of peripheral radiculoneuropathy. Our case extends the disease spectrum of EMRN and may aid in the early diagnosis of EMRN in the pediatric population.
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Encéfalo , Enfermedades Desmielinizantes , Masculino , Adulto , Humanos , Niño , Preescolar , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Metilprednisolona , Autoanticuerpos , Imagen por Resonancia Magnética , GlicoesfingolípidosRESUMEN
BACKGROUND: Distinguishing between central nervous system lymphoma (CNSL) and CNS infectious and/or demyelinating diseases, although clinically important, is sometimes difficult even using imaging strategies and conventional cerebrospinal fluid (CSF) analyses. To determine whether detection of genetic mutations enables differentiation between these diseases and the early detection of CNSL, we performed mutational analysis using CSF liquid biopsy technique. METHODS: In this study, we extracted cell-free DNA from the CSF (CSF-cfDNA) of CNSL (N = 10), CNS infectious disease (N = 10), and demyelinating disease (N = 10) patients, and performed quantitative mutational analysis by droplet-digital PCR. Conventional analyses were also performed using peripheral blood and CSF to confirm the characteristics of each disease. RESULTS: Blood hemoglobin and albumin levels were significantly lower in CNSL than CNS infectious and demyelinating diseases, CSF cell counts were significantly higher in infectious diseases than CNSL and demyelinating diseases, and CSF-cfDNA concentrations were significantly higher in infectious diseases than CNSL and demyelinating diseases. Mutation analysis using CSF-cfDNA detected MYD88L265P and CD79Y196 mutations in 60% of CNSLs each, with either mutation detected in 80% of cases. Mutual existence of both mutations was identified in 40% of cases. These mutations were not detected in either infectious or demyelinating diseases, and the sensitivity and specificity of detecting either MYD88/CD79B mutations in CNSL were 80% and 100%, respectively. In the four cases biopsied, the median time from collecting CSF with the detected mutations to definitive diagnosis by conventional methods was 22.5 days (range, 18-93 days). CONCLUSIONS: These results suggest that mutation analysis using CSF-cfDNA might be useful for differentiating CNSL from CNS infectious/demyelinating diseases and for early detection of CNSL, even in cases where brain biopsy is difficult to perform.
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Ácidos Nucleicos Libres de Células , Neoplasias del Sistema Nervioso Central , Enfermedades Transmisibles , Enfermedades Desmielinizantes , Linfoma no Hodgkin , Humanos , Factor 88 de Diferenciación Mieloide , Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/líquido cefalorraquídeo , Biopsia LíquidaRESUMEN
OBJECTIVE: Recent studies have revealed an association between Parkinson's disease (PD) and Fabry disease, a lysosomal storage disorder; however, the underlying mechanisms remain to be elucidated. This study aimed to investigate the enzymatic properties of serum alpha-galactosidase A (GLA) and compared them with the clinical parameters of PD. METHODS: The study participants consisted of 66 sporadic PD patients and 52 controls. We measured serum GLA activity and calculated the apparent Michaelis constant (Km ) and maximal velocity (Vmax ) by Lineweaver-Burk plot analysis. Serum GLA protein concentration was measured by enzyme-linked immunosorbent assay. We examined the potential correlations between serum GLA activity and GLA protein concentration and clinical features and the plasma neurofilament light chain (NfL) level. RESULTS: Compared to controls, PD patients showed significantly lower serum GLA activity (P < 0.0001) and apparent Vmax (P = 0.0131), but no change in the apparent Km value. Serum GLA protein concentration was lower in the PD group (P = 0.0168) and was positively associated with GLA activity. Serum GLA activity and GLA protein concentration in the PD group showed a negative correlation with age. Additionally, serum GLA activity was negatively correlated with the motor severity score and the level of plasma NfL, and was positively correlated with the score of frontal assessment battery. INTERPRETATION: This study highlights that the lower serum GLA activity in PD is the result of a quantitative decrement of GLA protein in the serum and that it may serve as a biomarker of disease severity.
Asunto(s)
Enfermedad de Fabry , Enfermedad de Parkinson , Humanos , alfa-Galactosidasa/metabolismo , Biomarcadores , Gravedad del PacienteRESUMEN
Anti-Lactosylceramide (LacCer) antibodies are associated with neurological inflammation involving both the peripheral and central nervous system (PNS, CNS respectively), however, the documented number of cases is small. Uncertainty remains whether its positivity can identify a unique clinical entity. Here, we describe two anti-LacCer antibody positive cases, both with long histories (> 30 years) of teenage-diagnosed chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). CNS lesions including the medulla oblongata were observed for the first time in adulthood. We suggest that this secondary progression of CNS lesions in juvenile-onset CIDP can be one of the characteristic features of anti-LacCer antibody associated neurological disorder.
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Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Polirradiculoneuropatía , Adolescente , Humanos , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/diagnóstico , Inflamación , Sistema Nervioso CentralRESUMEN
Objective: In this study, we aimed to clarify the relationship between initial treatment response, prednisolone (PSL) dosage, clinical type, and recurrence in patients with hypertrophic pachymeningitis (HP). Methods: The study cohort comprised eight patients with HP who had been admitted to our hospital from April 2015 to June 2020. Diagnostic criteria for HP included neurological abnormalities and dural thickening on magnetic resonance gadolinium-enhanced T1-weighted images. Results: Relevant characteristics of the eight study patients are as follows. There were two men and six women. The average age at onset was 58.3 (range: 29-79) years. Three of them had myeloperoxidase-antineutrophil cytoplasmic antibody-related vasculitis, one immunoglobulin G4-related disease, and one ulcerative colitis. The remaining three patients had idiopathic HP. The average maximum dosage of PSL was 0.79 mg/kg/day, and the average daily maintenance dosage 0.18 mg/kg/day. Three patients needed additional immunosuppressive drugs. Both idiopathic and secondary HP initially responded well to PSL, with improvement in activities of daily living. Six patients had some sequelae related to cranial nerve involvement. No relapses occurred while the patients were taking moderate doses of PSL; however, all patients with idiopathic HP had recurrences when their PSL dosage was reduced. Conclusions: Patients with idiopathic HP and HP associated with immune disorders respond to steroids and immunosuppressive drugs and recover well. However, there is a high rate of relapse after reduction of PSL dosage, mainly in those with idiopathic HP.
RESUMEN
Accumulating evidence suggests that various sphingolipids and glycosphingolipids can act as mediators for inflammation or signaling molecules in the nervous system. In this article, we explore the molecular basis of a new neuroinflammatory disorder called encephalomyeloradiculoneuropathy (EMRN), which affects the brain, spinal cord, and peripheral nerves; in particular, we discuss whether glycolipid and sphingolipid dysmetabolism is present in patients with this disorder. This review will focus on the pathognomonic significance of sphingolipid and glycolipid dysmetabolism for the development of EMRN and the possible involvement of inflammation in the nervous system.
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Glucolípidos , Esfingolípidos , Humanos , Inflamación , Encéfalo , Médula EspinalRESUMEN
Idiopathic normal pressure hydrocephalus usually exhibits triad of symptoms including gait disturbance, urinary incontinence, and dementia with ventriculomegaly. Currently, its pathogenesis remains to be fully elucidated. To provide a better understanding of this order, we examined whether dysmetabolism of sphingolipids as major lipid components in the brain present in cerebrospinal fluid (CSF) of the patients. Here, we measured various sphingolipidsincluding ceramide and sphingomyelin and glycolipids by electrospray ionization-tandem mass spectrometry in the cerebrospinal fluid of 19 consecutive idiopathic normal pressure hydrocephalus patients, 49 Parkinson's disease patients, and 17 neurologically normal controls. The data showed that there was a significant and specific reduction of all galactosylceramide subspecies levels in idiopathic normal pressure hydrocephalus patients compared with other groups, whereas ceramide and sphingomyelin levels as well as other neutral glycolipids such as glucosylceramide and lactosylceramide were similar in both disease states. Multiple regression analysis of sex and age did not show any correlation with galactosylceramide levels. We also examined whether MMSE scores are correlated with sphingolipid levels in iNPH patients. A specific subspecies of sphingomyelin (d18:1/18:0) only exhibited a statistically significant negative correlation (p = 0.0473, R = -0.4604) with MMSE scores but no other sphingolipids in iNPH patients. These data strongly suggest that myelin-rich galactosylceramide metabolism is severely impaired in idiopathic normal pressure hydrocephalus patients and might serve as the basis of biomarker for this disorder.
Asunto(s)
Hidrocéfalo Normotenso , Humanos , Hidrocéfalo Normotenso/diagnóstico , Proyectos Piloto , Esfingolípidos , Esfingomielinas , GalactosilceramidasRESUMEN
Introduction: The anti-lactosylceramide (LacCer) antibody is an anti-neutral glycolipid antibody that is involved in the pathogenesis of encephalomyeloradiculoneuropathy (EMRN). It causes acute and subacute injuries to both the central and peripheral nerves. However, no pediatric cases of anti-LacCer antibody-positive EMRN have been reported so far. Case: A 12-year-old girl presented with signs of meningitis. She subsequently showed disturbance of consciousness and flaccid tetraplegia and was placed on mechanical ventilation due to respiratory failure. MRI showed lesions in the cerebral white matter, basal ganglia, medulla oblongata, as well as the anterior horn of the spinal cord at the C2 to Th1 and Th11 to L1 levels. Nerve-conduction studies showed axonal neuropathy of the motor nerves. After steroid pulse therapy, high-dose immunoglobulin therapy, and plasma exchange, the lesions gradually regressed, and the neurological symptoms improved steadily. The neurological sequelae were minimal at 6 months after disease onset. Although serum anti-aquaporin 4 and anti-myelin oligodendrocyte glycoprotein antibodies were negative, she showed positive anti-lactosylceramide antibody in both serum and cerebrospinal fluid, indicating that these antibodies may be involved in the pathogenesis of this disease. Conclusion: The first pediatric case of anti-LacCer antibody-positive EMRN showed similar features to the same disease in adults. Anti-neutral glycolipid antibodies should be measured in children presenting with a wide range of neurological symptoms involving both central and peripheral nerves.
RESUMEN
Glycolipids are now known to be rapidly converted to mediators for inflammatory reactions or to signaling molecules that control inflammatory events in the nervous system. The present study aimed to explore whether disturbed glycolipids metabolism in the nervous system is present in patients with a neuroinflammatory disorder, encephalo-myelo-radiculo-neuropathy (EMRN), because most EMRN patients have been reported to exhibit autoantibodies against neutral glycolipids. Although molecular pathogenesis of this disorder remains unknown, we tried to search the immunochemical abnormalities in this disorder. ELISA for activated peripheral C5 complement and mass spectrometry analysis of cerebrospinal fluid clearly disclosed a significant upregulation of active C5 complement, C5a levels in sera as well as a significant accumulation of species-specific ceramides but not sphingomyelin in cerebrospinal fluid from EMRN patients. Furthermore, we confirmed the occurrence of anti-neutral glycolipids antibodies in all EMRN patients. Thus, the present study might indicate the pathophysiology of this disorder is the dysregulation of glycolipids metabolism and abnormal production of autoantibodies against neutral glycolipids resulting in the abnormal complement activation, although molecular basis for these sphingolipids dysregulation and the occurrence of autoantibodies against glycolipids remains to be elucidated at present. The present study implicates a new therapeutic strategy employing anti-ceramide and/or anti-complement therapy for this disorder.
Asunto(s)
CeramidasRESUMEN
The full spectrum of human herpesviruses (HHV)-associated neuroinfectious diseases in immunocompetent adults remains unclear. Hence, we sought to elucidate the epidemiology and clinical features of these diseases. The study subjects were patients over 16 years old suspected of neuroinfectious diseases who underwent spinal tap performed by neurologists in our university hospital between April 2013 and March 2018. The presence of seven HHV DNAs in cerebrospinal fluid (CSF) was determined by real-time PCR. HHV DNAs were detected in 33 (10.2%) of the 322 patients. The most frequently detected herpesvirus was varicella zoster virus (VZV) (19 patients), followed by HHV-6 (four patients), herpes simplex virus (HSV)-1 (three patients), HSV-2 (three patients), and Epstein-Barr virus (two patients). HHV DNAs were detected in CSF collected from patients with various neuroinfectious diseases, including myelitis, peripheral neuritis, encephalitis, and meningitis. All patients with HSV-1 DNA had encephalitis, whereas all patients with HSV-2 DNA had meningitis. Eleven of the 19 patients with VZV DNA had meningitis. Patients with VZV-associated encephalitis (median age, 80 years) were significantly older than non-encephalitis patients (median age, 60.5 years) (P = 0.046). Although post-herpetic neuralgia was observed in seven (54%) of the 13 patients with VZV and without encephalitis, no such neurological sequela was observed in the four encephalitis patients. In conclusion, HHVs were associated with approximately 10% of neuroinfectious diseases in this cohort. VZV was the most common pathogen, probably due to the large number of VZV meningitis patients. In addition, patients with VZV-associated meningitis were significantly younger than patients with VZV-associated encephalitis.
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Encefalitis , Infecciones por Virus de Epstein-Barr , Infecciones por Herpesviridae , Herpesvirus Humano 1 , Adolescente , Adulto , Anciano de 80 o más Años , ADN Viral/líquido cefalorraquídeo , Herpesvirus Humano 1/genética , Herpesvirus Humano 2/genética , Herpesvirus Humano 3/genética , Herpesvirus Humano 4 , Humanos , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Clioquinol has been implicated as a causative agent for subacute myelo-optico-neuropathy (SMON) in humans, although the mechanism remains to be elucidated. In this study, we utilized astrocyte-derived cell line, KT-5 cells to explore its potential cytotoxicity on glial cells. KT-5 cells were exposed in vitro to a maximum of 50 µM clioquinol for up to 24 h. 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenylte trazolium bromide (MTT) assay of the cells revealed that clioquinol induced significant cell damage and death. We also found that clioquinol caused accumulation of microtubule-associated protein light chain-3 (LC3)-II and sequestosome-1 (p62) in a dose- and time-dependent manner, suggesting the abnormality of autophagy-lysosome pathway. Consistent with these findings, an exposure of 20 µM clioquinol induced the accumulation of cellular autophagic vacuoles. Moreover, an exposure of 20 µM clioquinol provoked a statistically significant reduction of intracellular lysosomal acid hydrolases activities but no change in lysosomal pH. It also resulted in a significant decline of intracellular ATP levels, enhanced cellular levels of reactive oxygen species, and eventually cell death. This cell death at least did not appear to occur via apoptosis. 10 µM Chloroquine, lysosomal inhibitor, blocked the autophagic degradation and augmented clioquinol-cytotoxicity, whereas rapamycin, an inducer of autophagy, rescued clioquinol-induced cytotoxicity. Thus, our present results strongly suggest clioquinol acts as a potentially cytotoxic agent to glial cells. For future clinical application of clioquinol on the treatment of neurological and cancer disorders, we should take account of this type of cell death mechanism.
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Astrocitos/efectos de los fármacos , Autofagia/efectos de los fármacos , Clioquinol/toxicidad , Lisosomas/efectos de los fármacos , Proteínas Asociadas a Microtúbulos/metabolismo , Proteína Sequestosoma-1/metabolismo , Adenosina Trifosfato/metabolismo , Apoptosis , Astrocitos/metabolismo , Línea Celular , Cloroquina/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Neuroglía/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Factores de TiempoRESUMEN
Cerebrospinal fluid (CSF) contains glycosphingolipids, including lactosylceramide (LacCer, Galß(1,4)Glcß-ceramide). LacCer and its structural isomer, galabiosylceramide (Gb2, Galα(1,4)Galß-ceramide), are classified as ceramide dihexosides (CDH). Gb2 is degraded by α-galactosidase A (GLA) in lysosomes, and genetic GLA deficiency causes Fabry disease, an X-linked lysosomal storage disorder. In patients with Fabry disease, Gb2 accumulates in organs throughout the body. While Gb2 has been reported to be in the liver, kidney, and urine of healthy individuals, its presence in CSF has not been reported, either in patients with Fabry disease or healthy controls. Here, we isolated CDH fractions from CSF of patients with idiopathic normal pressure hydrocephalus. Purified CDH fractions showed positive reaction with Shiga toxin, which specifically binds to the Galα(1,4)Galß structure. The isolated CDH fractions were analyzed by hydrophilic interaction chromatography (HILIC)-electrospray ionization tandem mass spectrometry (ESI-MS/MS). HILIC-ESI-MS/MS separated LacCer and Gb2 and revealed the presence of Gb2 and LacCer in the fractions. We also found Gb2 in CSF from neurologically normal control subjects. This is the first report to show Gb2 exists in human CSF.
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Gangliósidos/líquido cefalorraquídeo , Vías Biosintéticas , Galactosiltransferasas/metabolismo , Gangliósidos/biosíntesis , Gangliósidos/química , Glicoesfingolípidos/aislamiento & purificación , Glicosiltransferasas/metabolismo , Células HeLa , Humanos , Hidrocefalia/líquido cefalorraquídeoRESUMEN
BACKGROUND: As mutations in glucocerebrosidase 1 (GBA1) are a major risk factor for Parkinson's disease (PD), decreased GBA1 activity might play an important role in the pathogenesis of the disease. However, there are currently no reports on glucosylceramide levels in the cerebrospinal fluid (CSF) in PD. OBJECTIVE: We investigated whether glucosylceramide accumulation and abnormal immune status in the brain are associated with PD. METHODS: We measured glucosylceramide by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) as well as levels of the active fragment of complement C5, C5a, in the CSF of 33 PD, 15 amyotrophic lateral sclerosis (ALS) and 22 neurologically normal control (NNC) subjects. Serum C5a levels in all PD and ALS cases and in a limited number of NNC subjects (nâ=â8) were also measured. RESULTS: C5a levels in CSF were significantly downregulated in PD compared with NNC. Moreover, CSF C5a/serum C5a ratio showed pronounced perturbations in PD and ALS patients. LC-ESI-MS/MS revealed a statistically significant accumulation of a specific subspecies of glucosylceramide (d18â:â1/C23â:â0 acyl chain fatty acid) in ALS, but not in PD. Interestingly, CSF glucosylceramide (d18â:â1/C23â:â0) exhibited a significant correlation with CSF C5a levels in PD, but not ALS. No correlation was observed between C5a levels or glucosylceramide subspecies content and disease duration, levodopa equivalent daily dose or Hoehn & Yahr staging in PD. CONCLUSION: Our findings demonstrate complement dysregulation without glucosylceramide accumulation in PD CSF. Furthermore, we found an association between a specific glucosylceramide subspecies and immune status in PD.
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Esclerosis Amiotrófica Lateral/líquido cefalorraquídeo , Complemento C5/líquido cefalorraquídeo , Glucosilceramidas/líquido cefalorraquídeo , Enfermedad de Parkinson/líquido cefalorraquídeo , Adulto , Anciano , Anciano de 80 o más Años , Esclerosis Amiotrófica Lateral/sangre , Esclerosis Amiotrófica Lateral/inmunología , Cromatografía Liquida , Regulación hacia Abajo , Femenino , Humanos , Inmunidad Innata/inmunología , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/inmunología , Espectrometría de Masa por Ionización de Electrospray , Espectrometría de Masas en TándemRESUMEN
OBJECTIVE: Approximately 15%-20% of patients with Guillain-Barré syndrome (GBS) are unable to walk independently at 6 months from the onset of neurological symptom. The modified Erasmus GBS outcome score (mEGOS) has been reported as a prognostic tool.Herein we investigated the association between a poor outcome, inability to walk independently at 6 months and presence of antiganglioside antibodies. METHODS: The clinical and serological data of 177 patients with GBS were retrospectively collected in Japan to assess the associations between a poor outcome and serum IgG antibodies against each ganglioside (GM1, GD1a, GalNAc-GD1a, GQ1b and GT1a). In addition, we investigated whether the combination of mEGOS and serum IgG antibodies against gangliosides is useful in predicting a poor outcome. RESULTS: The patients with IgG anti-GD1a antibodies more frequently showed poor outcomes than those without these antibodies (9 (36%) of 25 vs 8 (6%) of 127 patients, p<0.001). Particularly, 80% showed a poor outcome when they had both serum IgG anti-GD1a antibody and a high mEGOS of ≥10 on day 7 of admission. CONCLUSIONS: The combination of serum IgG anti-GD1a antibodies and a high mEGOS could help in making a more accurate prognosis of patients than mEGOS alone, especially for predicting poor outcomes.
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Gangliósidos/inmunología , Síndrome de Guillain-Barré/inmunología , Inmunoglobulina G/inmunología , Limitación de la Movilidad , Factores de Edad , Autoanticuerpos , Diarrea , Electrodiagnóstico , Gangliósido G(M1)/inmunología , Síndrome de Guillain-Barré/fisiopatología , Síndrome de Guillain-Barré/terapia , Humanos , Pronóstico , Respiración Artificial , Estudios RetrospectivosRESUMEN
Infected or damaged tissues release multiple "alert" molecules such as alarmins and damage-associated molecular patterns (DAMPs) that are recognized by innate immune receptors, and induce tissue inflammation, regeneration, and repair. Recently, an extract from inflamed rabbit skin inoculated with vaccinia virus (Neurotropin®, NTP) was found to induce infarct tolerance in mice receiving permanent ischemic attack to the middle cerebral artery. Likewise, we report herein that NTP prevented the neurite retraction in PC12 cells by nerve growth factor (NGF) deprivation. This effect was accompanied by interaction of Fyn with high-affinity NGF receptor TrkA. Sucrose density gradient subcellular fractionation of NTP-treated cells showed heretofore unidentified membrane fractions with a high-buoyant density containing Trk, B subunit of cholera toxin-bound ganglioside, flotillin-1 and Fyn. Additionally, these new membrane fractions also contained Toll-like receptor 4 (TLR4). Inhibition of TLR4 function by TAK-242 prevented the formation of these unidentified membrane fractions and suppressed neuroprotection by NTP. These observations indicate that NTP controls TrkA-mediated signaling through the formation of clusters of new membrane microdomains, thus providing a platform for crosstalk between neurotrophic and innate immune receptors. Neuroprotective mechanisms through the interaction with innate immune systems may provide novel mechanism for neuroprotection.
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Inmunidad Innata/efectos de los fármacos , Polisacáridos/metabolismo , Receptor Cross-Talk/efectos de los fármacos , Animales , Gangliósidos/metabolismo , Inmunidad Innata/inmunología , Inmunidad Innata/fisiología , Microdominios de Membrana/metabolismo , Proteínas de la Membrana/metabolismo , Factor de Crecimiento Nervioso/metabolismo , Neuritas/metabolismo , Neuroprotección/efectos de los fármacos , Fármacos Neuroprotectores/metabolismo , Células PC12 , Fosforilación/efectos de los fármacos , Polisacáridos/inmunología , Proteínas Proto-Oncogénicas c-fyn/metabolismo , Ratas , Receptor Cross-Talk/inmunología , Receptor Cross-Talk/fisiología , Receptor trkA/inmunología , Receptor trkA/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Recently, the genetic variability in lysosomal storage disorders has been implicated in the pathogenesis of Parkinson's disease. Here, we found that variants in prosaposin (PSAP), a rare causative gene of various types of lysosomal storage disorders, are linked to Parkinson's disease. Genetic mutation screening revealed three pathogenic mutations in the saposin D domain of PSAP from three families with autosomal dominant Parkinson's disease. Whole-exome sequencing revealed no other variants in previously identified Parkinson's disease-causing or lysosomal storage disorder-causing genes. A case-control association study found two variants in the intronic regions of the PSAP saposin D domain (rs4747203 and rs885828) in sporadic Parkinson's disease had significantly higher allele frequencies in a combined cohort of Japan and Taiwan. We found the abnormal accumulation of autophagic vacuoles, impaired autophagic flux, altered intracellular localization of prosaposin, and an aggregation of α-synuclein in patient-derived skin fibroblasts or induced pluripotent stem cell-derived dopaminergic neurons. In mice, a Psap saposin D mutation caused progressive motor decline and dopaminergic neurodegeneration. Our data provide novel genetic evidence for the involvement of the PSAP saposin D domain in Parkinson's disease.