RESUMEN
Preterm infants often show pathologies of the cerebellum, which are associated with impaired motor performance, lower IQ and poor language skills at school ages. Using a mouse model of inflammation-induced encephalopathy of prematurity driven by systemic administration of pro-inflammatory IL-1ß, we sought to uncover causes of cerebellar damage. In this model, IL-1ß is administered between postnatal day (P) 1 to day 5, a timing equivalent to the last trimester for brain development in humans. Structural MRI analysis revealed that systemic IL-1ß treatment induced specific reductions in gray and white matter volumes of the mouse cerebellar lobules I and II (5% false discovery rate [FDR]) from P15 onwards. Preceding these MRI-detectable cerebellar volume changes, we observed damage to oligodendroglia, with reduced proliferation of OLIG2+ cells at P10 and reduced levels of the myelin proteins myelin basic protein (MBP) and myelin-associated glycoprotein (MAG) at P10 and P15. Increased density of IBA1+ cerebellar microglia were observed both at P5 and P45, with evidence for increased microglial proliferation at P5 and P10. Comparison of the transcriptome of microglia isolated from P5 cerebellums and cerebrums revealed significant enrichment of pro-inflammatory markers in microglia from both regions, but cerebellar microglia displayed a unique type I interferon signaling dysregulation. Collectively, these data suggest that perinatal inflammation driven by systemic IL-1ß leads to specific cerebellar volume deficits, which likely reflect oligodendrocyte pathology downstream of microglial activation. Further studies are now required to confirm the potential of protective strategies aimed at preventing sustained type I interferon signaling driven by cerebellar microglia as an important therapeutic target.
Asunto(s)
Enfermedades Cerebelosas , Enfermedades del Prematuro , Inflamación , Interferón Tipo I , Interleucina-1beta , Microglía , Animales , Encefalopatías/inducido químicamente , Encefalopatías/inmunología , Encefalopatías/patología , Enfermedades Cerebelosas/inducido químicamente , Enfermedades Cerebelosas/inmunología , Enfermedades Cerebelosas/patología , Cerebelo/efectos de los fármacos , Cerebelo/inmunología , Cerebelo/patología , Modelos Animales de Enfermedad , Femenino , Humanos , Recién Nacido , Recien Nacido Prematuro , Enfermedades del Prematuro/inducido químicamente , Enfermedades del Prematuro/inmunología , Enfermedades del Prematuro/patología , Inflamación/inducido químicamente , Inflamación/inmunología , Inflamación/patología , Interferón Tipo I/inmunología , Interleucina-1beta/efectos adversos , Interleucina-1beta/farmacología , Microglía/efectos de los fármacos , Microglía/inmunología , Microglía/patología , EmbarazoRESUMEN
Immune system dysfunction has been described in autism spectrum disorder. Here we tested the hypothesis that cerebellar defects are accompanied by immune dysfunction in adult mice lacking the autism-candidate gene Engrailed 2 (En2). Gene ontology analyses revealed that biological processes related to immune function were over-represented in the cerebellar transcriptome of En2-/- mice. Pro-inflammatory molecules and chemokines were reduced in the En2-/- cerebellum compared to controls. Conversely, pro-inflammatory molecules were increased in the peripheral blood of mutant mice. Our results suggest a link between immune dysfunction and cerebellar defects detected in En2-/- mice.
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Trastorno del Espectro Autista , Trastorno Autístico , Proteínas de Homeodominio , Proteínas del Tejido Nervioso , Animales , Trastorno Autístico/genética , Cerebelo/inmunología , Cerebelo/fisiopatología , Proteínas de Homeodominio/genética , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/genéticaRESUMEN
Heat stroke is a severe systemic inflammatory response disease caused by high fever, mainly with nervous system damage. Mesenchymal stem cells (MSCs) are currently believed to have anti-inflammation and immunomodulatory effects. Therefore, we aimed to explore the protective effect and mechanism of MSCs on heat stroke-induced excessive inflammation and neurological dysfunction. We established a heat stroke model in rats under conditions of continuous high temperature and high humidity. After modeling, rats were randomly divided into heat stroke model group, MSCs treatment group and normal temperature control group without any treatment. We performed survival analysis, neurological deficit score, histological staining of hippocampus and cerebellum, immunofluorescence staining of microglia, detection of inflammatory and chemokine levels in the hippocampus and cerebellum in each group. We found that MSCs treatment not only significantly reduced early (day 3) and late (day 28) mortality, but also prominently reduced nerve injury in heat stroke rats, and improved pathology and neuronal cell damage in the hippocampus and cerebellum. In addition, MSCs treatment can significantly inhibit the over-activation of hippocampal microglia in heat stroke rats and the levels of pro-inflammatory factors and chemokines in the hippocampus. Early treatment of MSCs can greatly promote the activation of cerebellar microglia in heat stroke rats. Meanwhile, MSCs treatment has an inhibitory effect on the level of chemokine in the cerebellum of rats in the early stage of heat stroke. In conclusion, the application of MSCs in the treatment of heat stroke in rats can significantly reduce mortality and neurological deficits and improve hippocampal damage, possibly by inhibiting the excessive activation of hippocampal microglia in heat stroke rats.
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Golpe de Calor/terapia , Hipocampo/patología , Trasplante de Células Madre Mesenquimatosas , Microglía , Animales , Cerebelo/inmunología , Cerebelo/patología , Citocinas/inmunología , Golpe de Calor/inmunología , Golpe de Calor/patología , Hipocampo/inmunología , Masculino , Células Madre Mesenquimatosas , Ratas Sprague-DawleyRESUMEN
The present study investigated the neuroprotective effect of taurine against the deleterious effects of chronic-recurrent neuroinflammation induced by LPS in the cerebellum of rats. Adult male Wistar rats were treated with taurine for 28 days. Taurine was administered at a dose of 30 or 100 mg/kg, by gavage. On days 7, 14, 21, and 28, the animals received LPS (250 µg/kg) intraperitoneally. The vehicle used was saline. The animals were divided into six groups: vehicle, taurine 30 mg/kg, taurine 100 mg/kg, LPS, LPS plus taurine 30 mg/kg, and LPS plus taurine 100 mg/kg. On day 29, the animals were euthanized, and the cerebellum was removed and prepared for immunofluorescence analysis using antibodies of GFAP, NeuN, CD11b, and cleaved caspase-3. LPS group showed a reduction in the immunoreactivity of GFAP in the arbor vitae and medullary center and of NeuN in the granular layer of the cerebellar cortex. LPS increased the immunoreactivity of CD11b in the arbor vitae and in the medullary center. Taurine protected against these effects induced by LPS in immunoreactivity of GFAP, NeuN, and CD11b, with the 100 mg/kg dose being the most effective. LPS induced an increase in the number of positive cleaved caspase-3 cells in the Purkinje cell layers, granular layer, arbor vitae, and medullary center. Taurine showed its antiapoptotic activity by reducing the cleaved caspase-3 cells in relation to the LPS group. Here, a potential neuroprotective role of taurine can be seen since this amino acid was effective in protecting the cerebellum of rats against cell death and changes in glial and neuronal cells in the face of chronic-recurrent neuroinflammation.
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Cerebelo/efectos de los fármacos , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Taurina/farmacología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Caspasa 3/análisis , Caspasa 3/metabolismo , Cerebelo/inmunología , Cerebelo/patología , Enfermedad Crónica , Modelos Animales de Enfermedad , Humanos , Lipopolisacáridos/administración & dosificación , Lipopolisacáridos/inmunología , Masculino , Microglía/efectos de los fármacos , Microglía/inmunología , Microglía/patología , Enfermedades Neuroinflamatorias/inmunología , Neuronas/efectos de los fármacos , Neuronas/inmunología , Neuronas/patología , Fármacos Neuroprotectores/uso terapéutico , Ratas , Ratas Wistar , Recurrencia , Taurina/uso terapéuticoRESUMEN
INTRODUCTION: AQP4 (aquaporin-4)-immunoglobulin G (IgG)-mediated neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease that affects the central nervous system, particularly the spinal cord and optic nerve; remyelination capacity in neuromyelitis optica is yet to be determined, as is the role of AQP4-IgG in cell differentiation. MATERIAL AND METHODS: We included three groups-a group of patients with AQP4-IgG-positive neuromyelitis optica, a healthy group, and a sham group. We analyzed differentiation capacity in cultures of neurospheres from the subventricular zone of mice by adding serum at two different times: early and advanced stages of differentiation. We also analyzed differentiation into different cell lines. RESULTS AND CONCLUSIONS: The effect of sera from patients with NMOSD on precursor cells differs according to the degree of differentiation, and probably affects oligodendrocyte progenitor cells from NG2 cells to a lesser extent than cells from the subventricular zone; however, the resulting oligodendrocytes may be compromised in terms of maturation and possibly limited in their ability to generate myelin. Furthermore, these cells decrease in number with age. It is very unlikely that the use of drugs favoring the migration and differentiation of oligodendrocyte progenitor cells in multiple sclerosis would be effective in the context of neuromyelitis optica, but cell therapy with oligodendrocyte progenitor cells seems to be a potential alternative.
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Acuaporina 4/inmunología , Autoanticuerpos/inmunología , Diferenciación Celular , Sistema Nervioso Central/patología , Inmunoglobulina G/inmunología , Neuromielitis Óptica/inmunología , Células Precursoras de Oligodendrocitos/patología , Animales , Autoanticuerpos/sangre , Estudios de Casos y Controles , Sistema Nervioso Central/inmunología , Cerebelo/inmunología , Cerebelo/patología , Femenino , Humanos , Masculino , Ratones Endogámicos BALB C , Persona de Mediana Edad , Neuromielitis Óptica/sangre , Neuromielitis Óptica/patología , Células Precursoras de Oligodendrocitos/inmunologíaRESUMEN
The brain is known to express many long noncoding RNAs (lncRNAs); however, whether and how these lncRNAs function in modulating synaptic stability remains unclear. Here, we report a cerebellum highly expressed lncRNA, Synage, regulating synaptic stability via at least two mechanisms. One is through the function of Synage as a sponge for the microRNA miR-325-3p, to regulate expression of the known cerebellar synapse organizer Cbln1. The other function is to serve as a scaffold for organizing the assembly of the LRP1-HSP90AA1-PSD-95 complex in PF-PC synapses. Although somewhat divergent in its mature mRNA sequence, the locus encoding Synage is positioned adjacent to the Cbln1 loci in mouse, rhesus macaque, and human, and Synage is highly expressed in the cerebella of all three species. Synage deletion causes a full-spectrum cerebellar ablation phenotype that proceeds from cerebellar atrophy, through neuron loss, on to synapse density reduction, synaptic vesicle loss, and finally to a reduction in synaptic activity during cerebellar development; these deficits are accompanied by motor dysfunction in adult mice, which can be rescued by AAV-mediated Synage overexpression from birth. Thus, our study demonstrates roles for the lncRNA Synage in regulating synaptic stability and function during cerebellar development.
Asunto(s)
Biología Celular/normas , Cerebelo/inmunología , ARN Largo no Codificante/genética , Sinapsis/genética , Animales , Humanos , RatonesRESUMEN
BACKGROUND: Bacterial meningitis is a fatal disease with a mortality up to 30% and neurological sequelae in one fourth of survivors. Available vaccines do not fully protect against this lethal disease. Here, we report the protective effect of synthetic oligodeoxynucleotides containing unmethylated cytosine-guanine motifs (CpG ODN) against the most frequent form of bacterial meningitis caused by Streptococcus pneumoniae. METHODS: Three days prior to the induction of meningitis by intracerebral injection of S. pneumoniae D39, wild-type and Toll-like receptor (TLR9)-/- mice received an intraperitoneal injection of 100 µg CpG ODN or vehicle. To render mice neutropenic, anti-Ly-6G monoclonal antibody was daily administrated starting 4 days before infection with a total of 7 injections. Kaplan-Meier survival analyses and bacteriological studies, in which mice were sacrificed 24 h and 36 h after infection, were performed. RESULTS: Pre-treatment with 100 µg CpG ODN prolonged survival of immunocompetent and neutropenic wild-type mice but not of TLR9-/- mice. There was a trend towards lower mortality in CpG ODN-treated immunocompetent and neutropenic wild-type mice. CpG ODN caused an increase of IL-12/IL-23p40 levels in the spleen and serum in uninfected animals. The effects of CpG ODN on bacterial concentrations and development of clinical symptoms were associated with an increased number of microglia in the CNS during the early phase of infection. Elevated concentrations of IL-12/IL-23p40 and MIP-1α correlated with lower bacterial concentrations in the blood and spleen during infection. CONCLUSIONS: Pre-conditioning with CpG ODN strengthened the resistance of neutropenic and immunocompetent mice against S. pneumoniae meningitis in the presence of TLR9. Administration of CpG ODN decreased bacterial burden in the cerebellum and reduced the degree of bacteremia. Systemic administration of CpG ODN may help to prevent or slow the progression to sepsis of bacterial CNS infections in healthy and immunocompromised individuals even after direct inoculation of bacteria into the intracranial compartments, which can occur after sinusitis, mastoiditis, open head trauma, and surgery, including placement of an external ventricular drain.
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Adyuvantes Inmunológicos/administración & dosificación , Inmunocompetencia/inmunología , Huésped Inmunocomprometido/inmunología , Meningitis Neumocócica/inmunología , Neutropenia/inmunología , Oligodesoxirribonucleótidos/administración & dosificación , Animales , Cerebelo/efectos de los fármacos , Cerebelo/inmunología , Cerebelo/metabolismo , Femenino , Inmunocompetencia/efectos de los fármacos , Huésped Inmunocomprometido/efectos de los fármacos , Inyecciones Intraventriculares , Masculino , Meningitis Neumocócica/tratamiento farmacológico , Meningitis Neumocócica/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neutropenia/metabolismo , Neutropenia/prevención & control , Bazo/efectos de los fármacos , Bazo/inmunología , Bazo/metabolismo , Streptococcus pneumoniae , Resultado del TratamientoAsunto(s)
Enfermedades Cerebelosas/diagnóstico , Fiebre/diagnóstico , Enfermedad Injerto contra Huésped/diagnóstico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Enfermedades Cerebelosas/inmunología , Cerebelo/diagnóstico por imagen , Cerebelo/inmunología , Femenino , Fiebre/inmunología , Fluorodesoxiglucosa F18/administración & dosificación , Enfermedad Injerto contra Huésped/inmunología , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radiofármacos/administración & dosificación , Trasplante Homólogo/efectos adversos , Adulto JovenRESUMEN
We xeno-transplanted human neural precursor cells derived from induced pluripotent stem cells into the cerebellum and brainstem of mice and rats during prenatal development or the first postnatal week. The transplants survived and started to differentiate up to 1 month after birth when they were rejected by both species. Extended survival and differentiation of the same cells were obtained only when they were transplanted in NOD-SCID mice. Transplants of human neural precursor cells mixed with the same cells after partial in vitro differentiation or with a cellular extract obtained from adult rat cerebellum increased survival of the xeno-graft beyond one month. These findings are consistent with the hypothesis that the slower pace of differentiation of human neural precursors compared to that of rodents restricts induction of immune-tolerance to human antigens expressed before completion of maturation of the immune system. With further maturation the transplanted neural precursors expressed more mature antigens before the graft were rejected. Supplementation of the immature cells suspensions with more mature antigens may help to induce immune-tolerance for those antigens expressed only later by the engrafted cells.
Asunto(s)
Diferenciación Celular , Cerebelo/inmunología , Supervivencia de Injerto , Células Madre Pluripotentes Inducidas/citología , Células-Madre Neurales/citología , Neuronas/trasplante , Trasplante de Células Madre/métodos , Animales , Células Cultivadas , Cerebelo/crecimiento & desarrollo , Femenino , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Neuronas/citología , Ratas , Ratas Wistar , Especificidad de la Especie , Trasplante HeterólogoRESUMEN
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder which manifests itself in early childhood and is distinguished by recurring behavioral patterns, and dysfunction in social/communication skills. Ubiquitous environmental pollutant, di-2-ethylhexyl phthalate (DEHP) is one of the most frequently used plasticizers in various industrial products, e.g. vinyl flooring, plastic toys, and medical appliances. DEHP gets easily released into the environment and leads to human exposure through various routes. DEHP has been described to be linked with oxidative stress in various organs in animal/human studies. Increased concentration of DEHP has also been detected in ASD children which indicates an association between phthalates exposure and ASD. However, effect of DEHP on autism-like behavior has not been investigated previously. Therefore, this study probed the effect of DEHP on autism-like behavior (marble burying, self-grooming and sociability) and innate immune cells (dendritic cells/neutrophils)/cerebellar oxidant-antioxidant balance (NFkB, iNOS, NADPH oxidase, nitrotyrosine, lipid peroxides, Nrf2, SOD, GPx) in BTBR and C57 mice. Our data show that DEHP treatment causes worsening of autism-like behavior in BTBR mice which is associated with enhancement of oxidative stress in innate immune cells and cerebellum with concomitant lack of antioxidant protection. DEHP also causes oxidative stress in C57 mice in both innate immune cells and cerebellar compartment, however there is Nrf2-mediated induction of enzymatic antioxidants which protects them from upregulated oxidative stress. This proposes the notion that ubiquitous environmental pollutants such as DEHP may be involved in the pathogenesis/progression of ASD through dysregulation of antioxidant-antioxidant balance in innate immune cells and cerebellum.
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Trastorno Autístico/inducido químicamente , Conducta Animal/efectos de los fármacos , Cerebelo/efectos de los fármacos , Dietilhexil Ftalato/toxicidad , Contaminantes Ambientales/toxicidad , Inmunidad Innata/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Plastificantes/toxicidad , Animales , Antioxidantes/metabolismo , Trastorno Autístico/enzimología , Trastorno Autístico/inmunología , Trastorno Autístico/psicología , Cerebelo/enzimología , Cerebelo/inmunología , Modelos Animales de Enfermedad , Aseo Animal/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Conducta SocialRESUMEN
Acquired cerebellar ataxia is a rare, in many cases immune-modulated and paraneoplastic illness. Acute and slowly progredient processes are possible. An early treatment is important for a good clinical outcome. Here we present the case of female patient in her 60s with an antirecoverin associated cerebellitis without retinopathia and neoplasia. After an immunosuppressive therapy with steroids and rituximab the symptoms improved, and the progression could be stopped.
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Autoanticuerpos/sangre , Ataxia Cerebelosa/diagnóstico , Ataxia de la Marcha/diagnóstico , Inmunosupresores/uso terapéutico , Recoverina/inmunología , Edad de Inicio , Autoanticuerpos/inmunología , Ataxia Cerebelosa/sangre , Ataxia Cerebelosa/tratamiento farmacológico , Ataxia Cerebelosa/inmunología , Cerebelo/diagnóstico por imagen , Cerebelo/inmunología , Tecnología de Seguimiento Ocular , Femenino , Ataxia de la Marcha/sangre , Ataxia de la Marcha/tratamiento farmacológico , Ataxia de la Marcha/inmunología , Glucocorticoides/uso terapéutico , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Imagen por Resonancia Magnética , Persona de Mediana Edad , Rituximab/uso terapéuticoRESUMEN
Combined checkpoint inhibition therapy targeting the programmed cell death 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 pathways has been a successful approach in the treatment of metastatic melanoma, leading to its investigation in the treatment of head and neck squamous cell carcinoma (HNSCC) with PD-L1 expression. Despite the potential for excellent responses, an increased rate of autoimmune neurological toxicity and paraneoplastic conditions has been observed when using these treatment modalities. We present the case of a patient with metastatic HNSCC treated with combination ipilimumab/nivolumab who experienced severe cerebellar ataxia with a positive screen for the anti-Zic4 antibody. This is the first case, to our knowledge, of anti-Zic4 antibody-mediated cerebellar toxicity reported in association with HNSCC. Although the patient experienced an impressive partial response with dual checkpoint inhibition, he suffered grade 4 neurotoxicity. Despite exciting advances in cancer immunotherapy, clinicians must be aware of the rare, debilitating and possibly previously undescribed paraneoplastic and autoimmune toxicities that may occur.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ataxia Cerebelosa/inmunología , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias Pulmonares/terapia , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Adulto , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Broncoscopía , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/inmunología , Ataxia Cerebelosa/sangre , Ataxia Cerebelosa/diagnóstico , Ataxia Cerebelosa/tratamiento farmacológico , Cerebelo/diagnóstico por imagen , Cerebelo/inmunología , Quimioradioterapia/efectos adversos , Quimioradioterapia/métodos , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Glucocorticoides/administración & dosificación , Humanos , Inmunoglobulinas Intravenosas/administración & dosificación , Ipilimumab/efectos adversos , Pulmón/diagnóstico por imagen , Pulmón/patología , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/secundario , Imagen por Resonancia Magnética , Masculino , Proteínas del Tejido Nervioso/inmunología , Nivolumab/efectos adversos , Uso Fuera de lo Indicado , Rituximab/administración & dosificación , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/secundario , Factores de Transcripción/inmunología , Resultado del TratamientoRESUMEN
Little is known about the effects of NPC1 deficiency in brain development and whether these effects contribute to neurodegeneration in Niemann-Pick disease type C (NPC). Degeneration of cerebellar Purkinje cells occurs at an earlier stage and to a greater extent in NPC; therefore, we analyzed the effect of NPC1 deficiency on microglia and on climbing fiber synaptic refinement during cerebellar postnatal development using the Npc1nmf164 mouse. Our analysis revealed that NPC1 deficiency leads to early phenotypic changes in microglia that are not associated with an innate immune response. However, the lack of NPC1 in Npc1nmf164 mice significantly affected the early development of microglia by delaying the radial migration, increasing the proliferation and impairing the differentiation of microglia precursor cells during postnatal development. Additionally, increased phagocytic activity of differentiating microglia was observed at the end of the second postnatal week in Npc1nmf164 mice. Moreover, significant climbing fiber synaptic refinement deficits along with an increased engulfment of climbing fiber synaptic elements by microglia were found in Npc1nmf164 mice, suggesting that profound developmental defects in microglia and synaptic connectivity might precede and predispose Purkinje cells to early neurodegeneration in NPC.
Asunto(s)
Cerebelo/crecimiento & desarrollo , Péptidos y Proteínas de Señalización Intracelular/deficiencia , Microglía/metabolismo , Microglía/patología , Enfermedad de Niemann-Pick Tipo C/metabolismo , Enfermedad de Niemann-Pick Tipo C/patología , Animales , Animales Recién Nacidos , Diferenciación Celular , Movimiento Celular , Proliferación Celular , Cerebelo/inmunología , Modelos Animales de Enfermedad , Inmunidad Innata , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones Endogámicos C57BL , Proteína Niemann-Pick C1 , Fagocitosis , Sinapsis/metabolismo , DesteteRESUMEN
Paraneoplastic cerebellar degeneration (PCD) is a rare immune-mediated disease that develops mostly in the setting of neoplasia and offers a unique prospect to explore the interplay between tumor immunity and autoimmunity. In PCD, the deleterious adaptive immune response targets self-antigens aberrantly expressed by tumor cells, mostly gynecological cancers, and physiologically expressed by the Purkinje neurons of the cerebellum. Highly specific anti-neuronal antibodies in the serum and cerebrospinal fluid represent key diagnostic biomarkers of PCD. Some anti-neuronal antibodies such as anti-Yo autoantibodies (recognizing the CDR2/CDR2L proteins) are only associated with PCD. Other anti-neuronal antibodies, such as anti-Hu, anti-Ri, and anti-Ma2, are detected in patients with PCD or other types of paraneoplastic neurological manifestations. Importantly, these autoantibodies cannot transfer disease and evidence for a pathogenic role of autoreactive T cells is accumulating. However, the precise mechanisms responsible for disruption of self-tolerance to neuronal self-antigens in the cancer setting and the pathways involved in pathogenesis within the cerebellum remain to be fully deciphered. Although the occurrence of PCD is rare, the risk for such severe complication may increase with wider use of cancer immunotherapy, notably immune checkpoint blockade. Here, we review recent literature pertaining to the pathophysiology of PCD and propose an immune scheme underlying this disabling disease. Additionally, based on observations from patients' samples and on the pre-clinical model we recently developed, we discuss potential therapeutic strategies that could blunt this cerebellum-specific autoimmune disease.
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Antígenos de Neoplasias/inmunología , Autoanticuerpos/inmunología , Autoinmunidad , Cerebelo/inmunología , Neoplasias/inmunología , Degeneración Cerebelosa Paraneoplásica/inmunología , Animales , Autoantígenos/inmunología , Autoantígenos/metabolismo , Cerebelo/metabolismo , Cerebelo/patología , Humanos , Inmunoterapia/efectos adversos , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias/terapia , Proteínas del Tejido Nervioso/inmunología , Proteínas del Tejido Nervioso/metabolismo , Degeneración Cerebelosa Paraneoplásica/metabolismo , Degeneración Cerebelosa Paraneoplásica/patología , Células de Purkinje/inmunología , Células de Purkinje/metabolismo , Células de Purkinje/patología , Factores de Riesgo , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
Myelin loss is the hallmark of the demyelinating disease multiple sclerosis (MS) and plays a significant role in multiple neurodegenerative diseases. A common factor in all neuropathologies is the central role of microglia, the intrinsic immune cells of the central nervous system (CNS). Microglia are activated in pathology and can have both pro- and anti-inflammatory functions. Here, we examined the effects of the flavonoid agathisflavone on microglia and remyelination in the cerebellar slice model following lysolecithin induced demyelination. Notably, agathisflavone enhances remyelination and alters microglial activation state, as determined by their morphology and cytokine profile. Furthermore, these effects of agathisflavone on remyelination and microglial activation were inhibited by blockade of estrogen receptor α. Thus, our results identify agathisflavone as a novel compound that may act via ER to regulate microglial activation and enhance remyelination and repair.
Asunto(s)
Antiinflamatorios/farmacología , Biflavonoides/farmacología , Cerebelo/efectos de los fármacos , Microglía/efectos de los fármacos , Vaina de Mielina/metabolismo , Neuroinmunomodulación/efectos de los fármacos , Oligodendroglía/efectos de los fármacos , Remielinización/efectos de los fármacos , Animales , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cerebelo/inmunología , Cerebelo/metabolismo , Cerebelo/patología , Citocinas/metabolismo , Receptor alfa de Estrógeno/efectos de los fármacos , Receptor alfa de Estrógeno/metabolismo , Femenino , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Lisofosfatidilcolinas/toxicidad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microglía/inmunología , Microglía/metabolismo , Microglía/patología , Oligodendroglía/inmunología , Oligodendroglía/metabolismo , Oligodendroglía/patología , Fenotipo , Técnicas de Cultivo de TejidosRESUMEN
Diacylglycerol kinase (DGK) plays a pivotal role in intracellular signaling pathways in mammals. Activated G protein-coupled receptor activates phospholipase C (PLC) through heterotrimeric G protein, following which PLC hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into diacylglycerol (DG) and inositol 1,4,5-trisphosphate (IP3). DGK catalyzes DG phosphorylation to produce phosphatidic acid. DG and phosphatidic acid function as second messengers and their intracellular concentrations are regulated by DGK; therefore, DGK plays an important role in regulating many biological processes. There are ten DGK isozymes, of which DGKη is classified as a type II DGK. Reports have shown that DGKη is associated with several diseases; for example, it is highly expressed in the hippocampus and cerebellum and is a key element in bipolar disorder. Although a DGKη-specific monoclonal antibody (mAb) is necessary to reveal the association between the expression of DGKη and diseases, an anti-DGKη mAb for immunohistochemistry has not yet been established. In this study, we established a specific anti-human DGKη (hDGKη) mAb, DhMab-4 (mouse IgG2b, kappa). DhMab-4 strongly stained Purkinje cells of human cerebellum in immunohistochemistry analysis. For epitope mapping of DhMab-4, we produced deletion or point mutants of hDGKη and performed western blotting to determine the binding epitope of DhMab-4. DhMab-4 reacted with dN745 mutant but not with dN750 mutant, indicating that the N-terminus of the DhMab-4 epitope is located between amino acids 745 and 750. More detailed analysis using point mutants demonstrated that five mutants, that is, D747A, P748A, F749A, G750A, and T752A, were not detected by DhMab-4. These results indicate that Asp747, Pro748, Phe749, Gly750, and Thr752 are important for DhMab-4 binding to hDGKη.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Diacilglicerol Quinasa/inmunología , Mapeo Epitopo/métodos , Animales , Cerebelo/inmunología , Cerebelo/patología , Diacilglicerol Quinasa/genética , Diacilglicerol Quinasa/metabolismo , Epítopos/metabolismo , Humanos , Inmunohistoquímica , Ratones Endogámicos , Mutación , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunologíaRESUMEN
Lead (Pb) is a heavy metal with a proven neurotoxic effect. Exposure is particularly dangerous to the developing brain in the pre- and neonatal periods. One postulated mechanism of its neurotoxicity is induction of inflammation. This study analyzed the effect of exposure of rat pups to Pb during periods of brain development on the concentrations of selected cytokines and prostanoids in the forebrain cortex, hippocampus and cerebellum. METHODS: Administration of 0.1% lead acetate (PbAc) in drinking water ad libitum, from the first day of gestation to postnatal day 21, resulted in blood Pb in rat pups reaching levels below the threshold considered safe for humans by the Centers for Disease Control and Prevention (10 µg/dL). Enzyme-linked immunosorbent assay (ELISA) method was used to determine the levels of interleukins IL-1ß, IL-6, transforming growth factor-ß (TGF-ß), prostaglandin E2 (PGE2) and thromboxane B2 (TXB2). Western blot and quantitative real-time PCR were used to determine the expression levels of cyclooxygenases COX-1 and COX-2. Finally, Western blot was used to determine the level of nuclear factor kappa B (NF-κB). RESULTS: In all studied brain structures (forebrain cortex, hippocampus and cerebellum), the administration of Pb caused a significant increase in all studied cytokines and prostanoids (IL-1ß, IL-6, TGF-ß, PGE2 and TXB2). The protein and mRNA expression of COX-1 and COX-2 increased in all studied brain structures, as did NF-κB expression. CONCLUSIONS: Chronic pre- and neonatal exposure to Pb induces neuroinflammation in the forebrain cortex, hippocampus and cerebellum of rat pups.
Asunto(s)
Cerebelo/inmunología , Encefalitis/inducido químicamente , Hipocampo/inmunología , Plomo/toxicidad , Efectos Tardíos de la Exposición Prenatal/inmunología , Prosencéfalo/inmunología , Animales , Animales Recién Nacidos , Biomarcadores/metabolismo , Cerebelo/efectos de los fármacos , Dinoprostona/metabolismo , Modelos Animales de Enfermedad , Encefalitis/inmunología , Femenino , Hipocampo/efectos de los fármacos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Embarazo , Prosencéfalo/efectos de los fármacos , Ratas , Tromboxano B2/metabolismo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
BACKGROUND: Patients with liver cirrhosis may develop hepatic encephalopathy. Rats with chronic hyperammonemia exhibit neurological alterations mediated by peripheral inflammation and neuroinflammation. Motor incoordination is due to increased TNF-a levels and activation of its receptor TNFR1 in the cerebellum. The aims were to assess (a) whether peripheral inflammation is responsible for TNF-a induction in hyperammonemic rats, (b) the cell type(s) in which TNF-a is increased, (c) whether this increase is associated with increased nuclear NF-κB and TNFR1 activation, (d) the time course of TNF-a induction, and (e) if TNF-a is induced in the Purkinje neurons of patients who die with liver cirrhosis. METHODS: We analyzed the level of TNF-a mRNA and NF-κB in microglia, astrocytes, and Purkinje neurons in the cerebellum after 1, 2, and 4 weeks of hyperammonemia. We assessed whether preventing peripheral inflammation by administering an anti-TNF-a antibody prevents TNF-a induction. We tested whether TNF-a induction is reversed by R7050, which inhibits the TNFR1-NF-κB pathway, in ex vivo cerebellar slices. RESULTS: Hyperammonemia induced microglial and astrocyte activation at 1 week. This was followed by TNF-a induction in both glial cell types at 2 weeks and in Purkinje neurons at 4 weeks. The level of TNF-a mRNA increased in parallel with the TNF-a protein level, indicating that TNF-a was synthesized in Purkinje cells. This increase was associated with increased NF-κB nuclear translocation. The nuclear translocation of NF-κB and the increase in TNF-a were reversed by R7050, indicating that they were mediated by the activation of TNFR1. Preventing peripheral inflammation with an anti-TNF-a antibody prevents TNF-a induction. CONCLUSION: Sustained (4 weeks) but not short-term hyperammonemia induces TNF-a in Purkinje neurons in rats. This is mediated by peripheral inflammation. TNF-a is also increased in the Purkinje neurons of patients who die with liver cirrhosis. The results suggest that hyperammonemia induces TNF-a in glial cells and that TNF-a released by glial cells activates TNFR1 in Purkinje neurons, leading to NF-κB nuclear translocation and the induction of TNF-a expression, which may contribute to the neurological alterations observed in hyperammonemia and hepatic encephalopathy.
Asunto(s)
Cerebelo/metabolismo , Hiperamonemia/metabolismo , Células de Purkinje/metabolismo , Transducción de Señal/fisiología , Factor de Necrosis Tumoral alfa/metabolismo , Anciano , Animales , Cerebelo/inmunología , Humanos , Hiperamonemia/complicaciones , Hiperamonemia/inmunología , Cirrosis Hepática/complicaciones , Cirrosis Hepática/inmunología , Cirrosis Hepática/metabolismo , Masculino , Persona de Mediana Edad , FN-kappa B/inmunología , FN-kappa B/metabolismo , Neuroglía/inmunología , Neuroglía/metabolismo , Células de Purkinje/inmunología , Ratas , Ratas Wistar , Receptores Tipo I de Factores de Necrosis Tumoral/inmunología , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
BACKGROUND: Activated microglia, which can be detected in vivo by 11C-PBR28 positron emission tomography (PET), represent a main component of MS pathology in the brain. Their role in the cerebellum is still unexplored, although cerebellar involvement in MS is frequent and accounts for disability progression. OBJECTIVES: We aimed at characterizing cerebellar neuroinflammation in MS patients compared to healthy subjects by combining 11C-PBR28 MRI-Positron Emission Tomography (MR-PET) with 7 Tesla (T) MRI and assessing its relationship with brain neuroinflammation and clinical outcome measures. METHODS: Twenty-eight MS patients and 16 healthy controls underwent 11C-PBR28 MR-PET to measure microglia activation in normal appearing cerebellum and lesions segmented from 7 T scans. Patients were evaluated using the Expanded Disability Status Scale and Symbol Digit Modalities Test. 11C-PBR28 binding was assessed in regions of interest using 60-90 minutes standardized uptake values normalized by a pseudo-reference region in the brain normal appearing white matter. Multilinear regression was used to compare tracer uptake in MS and healthy controls and assess correlations with clinical scores. RESULTS: In all cerebellar regions examined, MS patients showed abnormally increased tracer uptake, which correlated with cognitive and neurological disability. CONCLUSION: Neuroinflammation is widespread in the cerebellum of patients with MS and related to neurological disability and cognitive impairment.
Asunto(s)
Cerebelo , Inflamación , Microglía , Esclerosis Múltiple , Neuroimagen , Pirimidinas/farmacocinética , Sustancia Blanca , Adulto , Cerebelo/diagnóstico por imagen , Cerebelo/inmunología , Cerebelo/metabolismo , Cerebelo/patología , Femenino , Humanos , Inflamación/diagnóstico por imagen , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Imagen Multimodal , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Tomografía de Emisión de Positrones , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/inmunología , Sustancia Blanca/metabolismo , Sustancia Blanca/patologíaRESUMEN
BACKGROUND: According to the views of psychoneuroendocrinoimmunology, many interactions exist between nervous, endocrine and immune system the purpose of which is to achieve adaptive measures restoring an internal equilibrium (homeostasis) following stress conditions. The center where these interactions converge is the hypothalamus. This is a center of the autonomic nervous system that controls the visceral systems, including the immune system, through both the nervous and neuroendocrine mechanisms. The nervous mechanisms are based on nervous circuits that bidirectionally connect hypothalamic neurons and neurons of the sympathetic and parasympathetic system; the neuroendocrine mechanisms are based on the release by neurosecretory hypothalamic neurons of hormones that target the endocrine cells and on the feedback effects of the hormones secreted by these endocrine cells on the same hypothalamic neurons. Moreover, the hypothalamus is an important subcortical center of the limbic system that controls through nervous and neuroendocrine mechanisms the areas of the cerebral cortex where the psychic functions controlling mood, emotions, anxiety and instinctive behaviors take place. Accordingly, various studies conducted in the last decades have indicated that hypothalamic diseases may be associated with immune and/or psychic disorders. OBJECTIVE: Various researches have reported that the hypothalamus is controlled by the cerebellum through a feedback nervous circuit, namely the hypothalamocerebellar circuit, which bi-directionally connects regions of the hypothalamus, including the immunoregulatory ones, and related regions of the cerebellum. An objective of the present review was to analyze the anatomical bases of the nervous and neuroendocrine mechanisms for the control of the immune system and, in particular, of the interaction between hypothalamus and cerebellum to achieve the immunoregulatory function. CONCLUSION: Since the hypothalamus represents the link through which the immune functions may influence the psychic functions and vice versa, the cerebellum, controlling several regions of the hypothalamus, could be considered as a primary player in the regulation of the multiple functional interactions postulated by psychoneuroendocrinoimmunology.