RESUMO
Anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) encephalitis, a rare subtype of autoimmune encephalitis, was first reported by Lai et al. The AMPAR antibodies target against extracellular epitopes of the GluA1 or GluA2 subunits of the receptor. AMPARs are expressed throughout the central nervous system, especially in the hippocampus and other limbic regions. Anti-AMPAR encephalitis was more common in middle-aged women and most patients had an acute or subacute onset. Limbic encephalitis, a classic syndrome of anti-AMPAR encephalitis, was clinically characterized by a subacute disturbance of short-term memory loss, confusion, abnormal behavior and seizure. Magnetic resonance imaging often showed T2/fluid-attenuated inversion-recovery hyperintensities in the bilateral medial temporal lobe. For suspected patients, paired serum and cerebrospinal fluid (CSF) testing with cell-based assay were recommended. CSF specimen was preferred given its higher sensitivity. Most patients with anti-AMPAR encephalitis were complicated with tumors, such as thymoma, small cell lung cancer, breast cancer, and ovarian cancer. First-line treatments included high-dose steroids, intravenous immunoglobulin and plasma exchange. Second-line treatments, including rituximab and cyclophosphamide, can be initiated in patients who were non-reactive to first-line treatment. Most patients with anti-AMPAR encephalitis showed a partial neurologic response to immunotherapy.
Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Encefalite/diagnóstico , Encefalite/etiologia , Receptores de Glutamato/imunologia , Animais , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/etiologia , Doenças Autoimunes/metabolismo , Autoimunidade , Biomarcadores , Terapia Combinada , Diagnóstico Diferencial , Diagnóstico por Imagem , Gerenciamento Clínico , Encefalite/metabolismo , Encefalite/terapia , Humanos , Fenótipo , Prognóstico , Avaliação de Sintomas , Resultado do TratamentoRESUMO
Crustaceans are major constituents of aquatic ecosystems and, as such, changes in their behavior and the structure and function of their bodies can serve as indicators of alterations in their immediate environment, such as those associated with climate change and anthropogenic contamination. We have used bioinformatics and a de novo transcriptome assembly approach to identify potential targets for developing specific antibodies to serve as nervous system function markers for freshwater prawns of the Macrobrachium spp. Total RNA was extracted from brain ganglia of Macrobrachium carcinus freshwater prawns and Illumina Next Generation Sequencing was performed using an Eel Pond mRNA Seq Protocol to construct a de novo transcriptome. Sequencing yielded 97,202,662 sequences: 47,630,546 paired and 1,941,570 singletons. Assembly with Trinity resulted in 197,898 assembled contigs from which 30,576 were annotated: 9,600 by orthology, 17,197 by homology, and 3,779 by transcript families. We looked for glutamate receptors contigs, due to their main role in crustacean excitatory neurotransmission, and found 138 contigs related to ionotropic receptors, 32 related to metabotropic receptors, and 18 to unidentified receptors. After performing multiple sequence alignments within different biological organisms and antigenicity analysis, we were able to develop antibodies for prawn AMPA ionotropic glutamate receptor 1, metabotropic glutamate receptor 1 and 4, and ionotropic NMDA glutamate receptor subunit 2B, with the expectation that the availability of these antibodies will help broaden knowledge regarding the underlying structural and functional mechanisms involved in prawn behavioral responses to environmental impacts. The Macrobrachium carcinus brain transcriptome can be an important tool for examining changes in many other nervous system molecules as a function of developmental stages, or in response to particular conditions or treatments.
Assuntos
Anticorpos/imunologia , Encéfalo/metabolismo , Ecossistema , Anotação de Sequência Molecular/métodos , Palaemonidae/genética , Receptores de Glutamato/genética , Animais , Perfilação da Expressão Gênica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Palaemonidae/metabolismo , Receptores de Glutamato/imunologia , Receptores de Glutamato/metabolismo , TranscriptomaRESUMO
Autoimmune encephalitis (AIE) poses a diagnostic challenge due to its heterogeneous clinical presentation, which overlaps with various neurological and psychiatric diseases. During the diagnostic work-up, cerebrospinal fluid (CSF) is routinely obtained, allowing for differential diagnostics as well as for the determination of antibody subclasses and specificities. In this monocentric cohort study, we describe initial and serial CSF findings of 33 patients diagnosed with antibody-associated AIE (LGI1 (n=8), NMDA (n=7), CASPR2 (n=3), IgLON5 (n=3), AMPAR (n=1), GAD65/67 (n=4), Yo (n=3), Ma-1/2 (n=2), CV2 (n=2)). Routine CSF parameters of 12.1% of AIE patients were in normal ranges, while 60.6% showed elevated protein levels and 45.4% had intrathecal oligoclonal bands (OCBs). Repeated CSF analyses showed a trend towards normalization of initial pathological CSF findings, while relapses were more likely to be associated with increased cell counts and total protein levels. OCB status conversion in anti-NMDARE patients coincided with clinical improvement. In summary, we show that in routine CSF analysis at diagnosis, a considerable number of patients with AIE did not exhibit alteration in the CSF and therefore, diagnosis may be delayed if antibody testing is not performed. Moreover, OCB status in anti-NMDAR AIE patients could represent a potential prognostic biomarker, however further studies are necessary to validate these exploratory findings.
Assuntos
Autoanticorpos/líquido cefalorraquidiano , Doenças Autoimunes do Sistema Nervoso/líquido cefalorraquidiano , Encefalite/líquido cefalorraquidiano , Imunoglobulina G/líquido cefalorraquidiano , Autoanticorpos/imunologia , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/imunologia , Moléculas de Adesão Celular Neuronais/imunologia , Encefalite/diagnóstico , Encefalite/imunologia , Feminino , Humanos , Imunoglobulina G/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Estudos Longitudinais , Masculino , Proteínas de Membrana/imunologia , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/imunologia , Receptores de Glutamato/imunologia , Receptores de N-Metil-D-Aspartato/imunologia , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
INTRODUCTION: : Anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) is a subtype of glutamate receptor that mediates most of the fast excitatory neurotransmission in the brain. Anti-AMPAR encephalitis is an autoimmune-mediated neurological disorder, frequently accompanied by the presence of neoplasms, comprising a spectrum of paraneoplastic syndrome. PATIENT CONCERNS: A 56-year-old man was admitted for deterioration in memory and aberrant psychological behaviors, which lasted for at least 20âdays. DIAGNOSIS: The patient was diagnosed as anti-AMPAR encephalitis and 4 months later, he was diagnosed with small cell lung cancer. INTERVENTIONS: Once diagnosis for anti-AMPAR encephalitis was confirmed, methylprednisolone was prescribed with initial dose 500âmg/d for 14âdays until the patient returned to pre-illness state. Then he was discharged with oral treatment with corticosteroids. Following the diagnosis of small cell lung cancer, he received 5 rounds of chemotherapy, including carboplatin and etoposide. OUTCOMES: After taken the prescription of Methylprednisolone for anti-AMPAR encephalitis, he returned to pre-illness state and was discharged. In April 21, 2017, after symptoms of respiratory system showed up, he was diagnosed with small cell lung cancer and he eventually died of respiratory failure. CONCLUSION: Though progress has been made in recent years in diagnosis and treatment for autoimmune encephalitis, it is challenging to diagnose due to the similarity in clinical findings with other autoimmune or infectious encephalitis. In addition, it is necessary for these patients to regularly have tumor screening, considering AMPAR antibody encephalitis is closely associated with neoplasm, and the incidence of paraneoplastic syndrome is 63% to 70%.
Assuntos
Autoanticorpos/imunologia , Encefalite/imunologia , Doença de Hashimoto/imunologia , Neoplasias Pulmonares/imunologia , Receptores de Glutamato/imunologia , Carcinoma de Pequenas Células do Pulmão/imunologia , Evolução Fatal , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Limbic encephalitis (LE) is a clinically defined syndrome characterised by an acute or subacute impairment of short-term memory, seizures and psychiatric symptoms (i.e. depression, anxiety and hallucination). LE could come from certain conditions where the neuropsychiatric systemic lupus erythematosus (NPSLE) of the multiple central nervous system is layered. In this report, we describe a 46-year-old Japanese female with SLE that suddenly presented with seizures, sensory aphasia and pseudobulbar affect. She was diagnosed with severe NPSLE presenting clinical LE (LE-SLE) by excluding malignancies, infectious encephalitis and symptomatic epilepsy using diffusion-weighted magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT). The patient showed a rapid response to treatment with methylprednisolone pulses followed by high-dose prednisolone and intravenous cyclophosphamide. She had elevated anti-glutamate receptor antibodies (anti-GluRs) in her serum and cerebrospinal fluid (CSF) on admission, and the titres decreased to a normal range at a one-year follow up. Our case highlights the importance of measuring anti-neuron antibodies including anti-GluRs in NPSLE patients, and suggests that the reduction of these pathogenic autoantibodies in serum or CSF could be a prognostic marker.
Assuntos
Ciclofosfamida , Glucocorticoides , Encefalite Límbica , Lúpus Eritematoso Sistêmico , Administração Intravenosa , Anticorpos/sangue , Anticorpos/líquido cefalorraquidiano , Ciclofosfamida/administração & dosagem , Feminino , Glucocorticoides/uso terapêutico , Humanos , Encefalite Límbica/tratamento farmacológico , Lúpus Eritematoso Sistêmico/complicações , Pessoa de Meia-Idade , Receptores de Glutamato/imunologia , Resultado do TratamentoRESUMO
Epilepsy affects ~50 million people. In ~30% of patients the etiology is unknown, and ~30% are unresponsive to anti-epileptic drugs. Intractable epilepsy often leads to multiple seizures daily or weekly, lasting for years, and accompanied by cognitive, behavioral, and psychiatric problems. This multidisciplinary scientific (not clinical) 'Perspective' article discusses Autoimmune Epilepsy from immunological, neurological and basic-science angles. The article includes summaries and novel discoveries, ideas, insights and recommendations. We summarize the characteristic features of the respective antigens, and the pathological activity in vitro and in animal models of autoimmune antibodies to: Glutamate/AMPA-GluR3, Glutamate/NMDA-NR1, Glutamate/NMDA-NR2, GAD-65, GABA-R, GLY-R, VGKC, LGI1, CASPR2, and ß2 GP1, found in subpopulations of epilepsy patients. Glutamate receptor antibodies: AMPA-GluR3B peptide antibodies, seem so far as the most exclusive and pathogenic autoimmune antibodies in Autoimmune Epilepsy. They kill neural cells by three mechanisms: excitotoxicity, Reactive-Oxygen-Species, and complement-fixation, and induce and/or facilitate brain damage, seizures, and behavioral impairments. In this article we raise and discuss many more topics and new insights related to Autoimmune Epilepsy. 1. Few autoimmune antibodies tilt the balance between excitatory Glutamate and inhibitory GABA, thereby promoting neuropathology and epilepsy; 2. Many autoantigens are synaptic, and have extracellular domains. These features increase the likelihood of autoimmunity against them, and the ease with which autoimmune antibodies can reach and harm these self-proteins. 3. Several autoantigens have 'frenetic character'- undergoing dynamic changes that can increase their antigenicity; 4. The mRNAs of the autoantigens are widely expressed in multiple organs outside the brain. If translated by default to proteins, broad spectrum detrimental autoimmunity is expected; 5. The autoimmunity can precede seizures, cause them, and be detrimental whether primary or epiphenomenon; 6. Some autoimmune antibodies induce, and associate with, cognitive, behavioral and psychiatric impairments; 7. There are evidences for epitope spreading in Autoimmune Epilepsy; 8. T cells have different 'faces' in the brain, and in Autoimmune Epilepsy: Normal T cells are needed for the healthy brain. Normal T cells are damaged by autoimmune antibodies to Glutamate/AMPA GluR3, which they express, and maybe by additional autoantibodies to: Dopamine-R, GABA-R, Ach-R, Serotonin-R, and Adrenergic-R, present in various neurological diseases (summarized herein), since T cells express all these Neurotransmitter receptors. However, autoimmune and/or cytotoxic T cells damage the brain; 9. The HLA molecules are important for normal brain function. The HLA haplotype can confer susceptibility or protection from Autoimmune Epilepsy; 10. There are several therapeutic strategies for Autoimmune Epilepsy.
Assuntos
Autoimunidade/imunologia , Epilepsia/imunologia , Autoanticorpos/imunologia , Autoantígenos/imunologia , Ácido Glutâmico/imunologia , Humanos , Receptores de Glutamato/imunologia , Convulsões/imunologia , Linfócitos T Citotóxicos/imunologiaRESUMO
BACKGROUND: The clinical spectrum of glucose transporter type 1 deficiency syndrome (GLUT1DS) has broadened, with increasing recognition of a milder phenotype. Antibodies targeting the subunits of glutamate receptors (GluRs), including GluN1, GluN2B, and GluD2, have been detected in various neurological disorders. Anti-GluD2 antibodies in particular may be associated with cerebellar symptoms. CASE REPORT: A 3-year-5-month-old boy with normal development exhibited myoclonus refractory to antiepileptic drugs from one year ago. He developed tremor and ataxia. Cerebrospinal fluid (CSF) revealed fasting-state glucose 50 mg/dl (CSF/blood glucose ratio of 0.50). Single photon emission computed tomography with 123I-iodoamphetamine revealed hypoperfusion in the cerebellum. At age 4 years and 5 months, treatment with intravenous methylprednisolone (IVMP) relieved his symptoms and improved the cerebellar hypoperfusion. However, his symptoms reappeared at age 5 years and 1 month. Treatment with IVMP was repeated, resulting in transient disappearance of symptoms. At age 6 years and 9 months, he was diagnosed with GLUT1DS by genetic analysis, and treatment with modified Atkins diet was started with efficacy. Levels of anti-GluN1, -GluN2B, and -GluD2 antibodies in the serum and CSF were measured 4 times. All antibodies in the CSF were elevated over 2 standard deviations above controls, and the levels fluctuated along with the severity of his symptoms. The level of anti-GluD2 antibodies in CSF declined to the normal range only after starting the modified Atkins diet. CONCLUSION: Treatment with IVMP transiently improved this patient's symptoms. Levels of anti-GluR antibodies may be associated with symptom severity.
Assuntos
Erros Inatos do Metabolismo dos Carboidratos/genética , Erros Inatos do Metabolismo dos Carboidratos/imunologia , Proteínas de Transporte de Monossacarídeos/deficiência , Receptores de Glutamato/imunologia , Ataxia/fisiopatologia , Autoanticorpos/imunologia , Erros Inatos do Metabolismo dos Carboidratos/metabolismo , Ataxia Cerebelar/fisiopatologia , Criança , Pré-Escolar , Transportador de Glucose Tipo 1/metabolismo , Humanos , Masculino , Proteínas de Transporte de Monossacarídeos/genética , Proteínas de Transporte de Monossacarídeos/imunologia , Proteínas de Transporte de Monossacarídeos/metabolismo , Mioclonia/metabolismo , Mioclonia/fisiopatologia , Doenças do Sistema Nervoso , Receptores de Glutamato/genéticaAssuntos
Autoanticorpos/líquido cefalorraquidiano , Síndrome de Kleine-Levin/diagnóstico , Receptores de N-Metil-D-Aspartato/imunologia , Adolescente , Antimaníacos/uso terapêutico , Eletroencefalografia/métodos , Humanos , Síndrome de Kleine-Levin/líquido cefalorraquidiano , Síndrome de Kleine-Levin/tratamento farmacológico , Síndrome de Kleine-Levin/imunologia , Encefalite Límbica/líquido cefalorraquidiano , Encefalite Límbica/diagnóstico , Carbonato de Lítio/uso terapêutico , Masculino , Receptores de Glutamato/imunologia , Receptores de N-Metil-D-Aspartato/análise , Resultado do TratamentoRESUMO
Various central nervous system (CNS) complications may occur after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which can result in severe clinical problems. Diagnosis is often difficult, as distinctive clinical symptoms may be absent and different neurological disorders may exhibit similar symptoms. Despite the fact that antibodies responding to brain cell surface antigens have become well recognized in several CNS disorders, cases of autoimmune CNS disorders after allo-HSCT have rarely been reported. Here, we report on a patient who developed encephalitis associated with antibodies against N-methyl-D-aspartate (NMDA)-type glutamate receptor (GluR) after allo-HSCT. To the best of our knowledge, this is the first report of the involvement of antibodies against NMDA-type GluR in post-transplantation encephalitis. Autoimmunity to NMDA-type GluR may have contributed to neurological complications after transplantation in unresolved cases.
Assuntos
Autoanticorpos/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Encefalite Límbica/etiologia , Encefalite Límbica/imunologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/imunologia , Receptores de Glutamato/imunologia , Receptores de N-Metil-D-Aspartato/imunologia , Autoimunidade , Feminino , Humanos , Pessoa de Meia-Idade , Transplante Homólogo/efeitos adversosRESUMO
Immune-mediated inflammation of the brain has been recognized for more than 50 years, although the initial descriptions were mainly thought to be secondary to an underlying neoplasm. Some of these paraneoplastic encephalitides express serum antibodies, but these were not thought to be pathogenic but instead have a T-cell-mediated pathophysiology. Over the last two decades, several pathogenic antibodies against neuronal surface antigens have been described in autoimmune encephalitis, which are amenable to immunotherapy. Several of these antibodies are directed against glutamate receptors (GluRs). NMDAR encephalitis (NMDARE) is the most common of these antibodies, and patients often present with psychosis, hallucinations, and reduced consciousness. Patients often progress on to develop confusion, seizures, movement disorders, autonomic instability, and respiratory depression. Although initially described as exclusively occurring secondary to ovarian teratoma (and later other tumors), non-paraneoplastic forms are increasingly common, and other triggers like viral infections are now well recognized. AMPAR encephalitis is relatively less common than NMDARE but is more likely to paraneoplastic. AMPAR antibodies typically cause limbic encephalitis, with patients presenting with confusion, disorientation, memory loss, and often seizures. The syndromes associated with the metabotropic receptor antibodies are much rarer and often can be paraneoplastic-mGluR1 (cerebellar degeneration) and mGluR5 (Ophelia syndrome) being the ones described in literature.With the advance in molecular biology techniques, it is now possible to detect these antibodies using cell-based assays with high sensitivity and specificity, especially when coupled with brain tissue immunohistochemistry and binding to live cell-based neurons. The rapid and reliable identification of these antibodies aids in the timely treatment (either in the form of identifying/removing the underlying tumor or instituting immunomodulatory therapy) and has significantly improved clinical outcome in this otherwise devastating group of conditions.
Assuntos
Autoanticorpos/imunologia , Doenças Autoimunes/imunologia , Doenças do Sistema Nervoso Central/imunologia , Receptores de AMPA/imunologia , Receptores de Glutamato/imunologia , Receptores de N-Metil-D-Aspartato/imunologia , Autoanticorpos/metabolismo , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Doenças Autoimunes/terapia , Doenças do Sistema Nervoso Central/metabolismo , Doenças do Sistema Nervoso Central/patologia , Doenças do Sistema Nervoso Central/terapia , Humanos , Testes Imunológicos/métodos , ImunoterapiaRESUMO
Antibody-mediated encephalitis defines a class of diseases wherein antibodies directed at cell-surface receptors are associated with behavioral and cognitive disturbances. One such recently described encephalitis is due to antibodies directed at alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR). This entity is exceptionally rare and its clinical phenotype incompletely described. We present findings from two cases of AMPAR encephalitis that exemplify variability in the disease spectrum, and summarize findings in published cases derived from a systematic literature review. When all patients are considered together, the presence of psychiatric symptoms at presentation portended a poor outcome and was associated with the presence of a tumor. Furthermore, we provide evidence to suggest that the topography of magnetic resonance imaging abnormalities in reported cases mirrors the distribution of AMPARs in the human brain. The potential for neurological improvement following immunomodulatory therapy together with the favorable outcome reported in most cases emphasizes the importance of testing for autoantibodies against neuronal cell-surface proteins, including AMPAR, in patients with clinical and neuroimaging findings suggestive of autoimmune encephalitis. Close attention to the clinical phenotype may inform the presence of malignancy and long-term prognosis.
Assuntos
Doenças Autoimunes do Sistema Nervoso , Encefalite , Receptores de Glutamato/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes do Sistema Nervoso/diagnóstico por imagem , Doenças Autoimunes do Sistema Nervoso/imunologia , Doenças Autoimunes do Sistema Nervoso/patologia , Doenças Autoimunes do Sistema Nervoso/fisiopatologia , Encefalite/diagnóstico por imagem , Encefalite/imunologia , Encefalite/patologia , Encefalite/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Neuroimagem , Adulto JovemRESUMO
OBJECTIVE: To identify neuronal surface antibodies in opsoclonus myoclonus ataxia syndrome (OMAS) using contemporary antigen discovery methodology. METHODS: OMAS patient serum immunoglobulin G immunohistochemistry using age-equivalent rat cerebellar tissue was followed by immunoprecipitation, gel electrophoresis, and mass spectrometry. Data are available via ProteomeXchange (identifier PXD009578). This generated a list of potential neuronal surface cerebellar autoantigens. Live cell-based assays were used to confirm membrane-surface antigens and adsorb antigen-specific immunoglobulin Gs. The serologic results were compared to the clinical data. RESULTS: Four of the 6 OMAS sera tested bound rat cerebellar sections. Two of these sera with similar immunoreactivities were used in immunoprecipitation experiments using cerebellum from postnatal rat pups (P18). Mass spectrometry identified 12 cell-surface proteins, of which glutamate receptor δ2 (GluD2), a predominately cerebellar-expressed protein, was found at a 3-fold-higher concentration than the other 11 proteins. Antibodies to GluD2 were identified in 14/16 (87%) OMAS samples, compared with 5/139 (5%) pediatric and 1/38 (2.6%) adult serum controls (p < 0.0001), and in 2/4 sera from patients with neuroblastoma without neurologic features. Adsorption of positive OMAS sera against GluD2-transfected cells substantially reduced but did not eliminate reactivity toward cerebellar sections. CONCLUSION: Autoantibodies to GluD2 are common in patients with OMAS, bind to surface determinants, and are potentially pathogenic.
Assuntos
Anticorpos/sangue , Síndrome de Opsoclonia-Mioclonia/sangue , Receptores de Glutamato/imunologia , Adolescente , Animais , Animais Recém-Nascidos , Cerebelo/metabolismo , Criança , Pré-Escolar , Encefalite/sangue , Líquido Extracelular/metabolismo , Feminino , Células HEK293 , Humanos , Imunoprecipitação , Lactente , Masculino , Espectrometria de Massas , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Síndrome de Opsoclonia-Mioclonia/patologia , Proteômica/métodos , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/imunologia , Receptores de Glutamato/genética , TransfecçãoRESUMO
BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with mast cell-mediated inflammation and heightened oxidant stress. Kynurenine (KYN), an endogenous tryptophan metabolite, can promote allergen-induced mast cell activation through the aryl hydrocarbon receptor (AhR). OBJECTIVES: We sought to determine the role of the KYN/AhR axis and oxidant stress in mast cell activation and the development of CRSwNP. METHODS: We measured the expression of indoleamine 2,3-dioxygenase 1, tryptophan 2,3-dioxygenase, KYN, and oxidized calmodulin-dependent protein kinase II (ox-CaMKII) in nasal polyps and controls. KYN-potentiated ovalbumin (OVA)-induced ROS generation, cell activation, and ox-CaMKII expression were investigated in wild-type and AhR-deficient (AhR-/-) mast cells. The role of ox-CaMKII in mast cell activation was further investigated. RESULTS: Nasal polyps in CRSwNP showed an increased expression of indoleamine 2,3-dioxygenase 1, tryptophan2,3-dioxygenase, and KYN compared with controls. AhR was predominantly expressed in mast cells in nasal polyps. Activated mast cells and local IgE levels were substantially increased in eosinophilic polyps compared with noneosinophilic polyps and controls. Furthermore, KYN potentiated OVA-induced ROS generation, intracellular Ca2+ levels, cell activation, and expression of ox-CaMKII in wild-type, but not in AhR-/- mast cells. Compared with noneosinophilic polyps and controls, eosinophilic polyps showed increased expression of ox-CaMKII in mast cells. Mast cells from ROS-resistant CaMKII MMVVδ mice or pretreated with CaMKII inhibitor showed protection against KYN-promoted OVA-induced mast cell activation. CONCLUSIONS: These studies support a potentially critical but previously unidentified function of the KYN/AhR axis in regulating IgE-mediated mast cell activation through ROS and ox-CaMKII in CRSwNP.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Pólipos Nasais/imunologia , Receptores de Hidrocarboneto Arílico/imunologia , Receptores de Glutamato/imunologia , Rinite/imunologia , Sinusite/imunologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/imunologia , Doença Crônica , Eosinófilos/imunologia , Eosinófilos/patologia , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Mastócitos/imunologia , Mastócitos/patologia , Camundongos , Camundongos Knockout , Pólipos Nasais/genética , Pólipos Nasais/patologia , Receptores de Hidrocarboneto Arílico/genética , Receptores de Glutamato/genética , Rinite/genética , Rinite/patologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Sinusite/genética , Sinusite/patologiaRESUMO
It may be challenging to distinguish autoimmune encephalitis associated with anti-neuronal autoantibodies from primary psychiatric disorders. Here, serum was drawn from patients with a first-episode psychosis (n=70) or a clinical high-risk for psychosis (n=6) and controls (n=34). We investigated the serum prevalence of 24 anti-neuronal autoantibodies: IgG antibodies for anti-N-methyl-d-aspartate-type glutamate receptor (anti-NMDAR), glutamate and γ-aminobutyric acid alpha and beta receptors (GABA-a, GABA-b), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA), glycine receptor (GlyR), metabotropic glutamate receptor 1 and 5 (mGluR1, mGluR5), anti-Tr/Delta/notch-like epidermal growth factor-related receptor (DNER), contactin-associated protein-like 2 (CASPR2), myelin oligodendrocyte glycoprotein (MOG), glutamic acid decarboxylase-65 (GAD65), collapsin response mediator protein 5/crossveinless-2 (CV2), aquaporin-4 (AQP4), anti-dipeptidyl-peptidase-like protein-6 (DPPX), type 1 anti-neuronal nuclear antibody (ANNA-1, Hu), Ri, Yo, IgLON5, Ma2, zinc finger protein 4 (ZIC4), Rho GTPase-activating protein 26, amphiphysin, and recoverin, as well as IgA and IgM for dopamine-2-receptor (DRD2). Anti-NMDA IgG antibodies were positive with serum titer 1:320 in one patient with a clinical high risk for psychosis. He did not receive a diagnosis of encephalitis after comprehensive neurological evaluation. All other antineuronal autoantibodies were negative and there were no additional findings with immunohistochemistry of brain issues.
Assuntos
Autoanticorpos/sangue , Sintomas Prodrômicos , Transtornos Psicóticos/sangue , Transtornos Psicóticos/imunologia , Receptores de Glutamato/imunologia , Adolescente , Adulto , Aquaporina 4 , Feminino , Seguimentos , Humanos , Masculino , Proteínas de Membrana/imunologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Proteínas do Tecido Nervoso/imunologia , Escalas de Graduação Psiquiátrica , Receptores de GABA/imunologia , Receptores de Glicina/imunologia , Estudos Retrospectivos , Adulto JovemRESUMO
Glutamate receptor δ2 (GluRδ2) is expressed in the neuronal postsynaptic densities at the junctions between the Purkinje cells and the parallel fibers. Recent reports have described patients with opsoclonus who possess anti-GluRδ2 antibodies. We report the case of a 53-year-old man with opsoclonus whose cerebrospinal fluid was positive for anti-GluRδ2 antibodies. Electronystagmography revealed abnormal sinusoidal eye movements, which were definitively identified as opsoclonus. The frequency and amplitude of saccadic oscillations diminished after plasmapheresis (PE). The patient's opsoclonus was altered after PE, suggesting that anti-GluRδ2 antibodies may act on the saccade generator in the brainstem via the cerebellum and that they may be involved in the onset of opsoclonus.
Assuntos
Transtornos da Motilidade Ocular/imunologia , Transtornos da Motilidade Ocular/terapia , Plasmaferese/métodos , Receptores de Glutamato/imunologia , Animais , Autoanticorpos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The incidence of neurological disorders is growing in developed countries together with increased lifespan. Nowadays, there are still no effective treatments for neurodegenerative pathologies, which make necessary to search for new therapeutic agents. Natural products, most of them used in traditional medicine, are considered promising alternatives for the treatment of neurodegenerative diseases. Honokiol is a natural bioactive phenylpropanoid compound, belonging to the class of neolignan, found in notable amounts in the bark of Magnolia tree, and has been reported to exert diverse pharmacological properties including neuroprotective activities. Honokiol can permeate the blood brain barrier and the blood-cerebrospinal fluid to increase its bioavailability in neurological tissues. Diverse studies have provided evidence on the neuroprotective effect of honokiol in the central nervous system, due to its potent antioxidant activity, and amelioration of the excitotoxicity mainly related to the blockade of glutamate receptors and reduction in neuroinflammation. In addition, recent studies suggest that honokiol can attenuate neurotoxicity exerted by abnormally aggregated Aß in Alzheimer's disease. The present work summarizes what is currently known concerning the neuroprotective effects of honokiol and its potential molecular mechanisms of action, which make it considered as a promising agent in the treatment and management of neurodegenerative diseases. © 2017 BioFactors, 43(6):760-769, 2017.
Assuntos
Antioxidantes/farmacologia , Compostos de Bifenilo/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Lignanas/farmacologia , Magnolia/química , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/imunologia , Antioxidantes/isolamento & purificação , Antioxidantes/farmacocinética , Produtos Biológicos/química , Transporte Biológico , Compostos de Bifenilo/isolamento & purificação , Compostos de Bifenilo/farmacocinética , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/metabolismo , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/patologia , Citocinas/antagonistas & inibidores , Citocinas/genética , Citocinas/imunologia , Regulação da Expressão Gênica , Humanos , Lignanas/isolamento & purificação , Lignanas/farmacocinética , Fatores de Crescimento Neural/antagonistas & inibidores , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/imunologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/patologia , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacocinética , Casca de Planta/química , Receptores de Glutamato/genética , Receptores de Glutamato/imunologiaRESUMO
N-methyl-d-aspartate receptors (NMDARs) are heterotetrameric ion channels assembled as diheteromeric or triheteromeric complexes. Here, we report structures of the triheteromeric GluN1/GluN2A/GluN2B receptor in the absence or presence of the GluN2B-specific allosteric modulator Ro 25-6981 (Ro), determined by cryogenic electron microscopy (cryo-EM). In the absence of Ro, the GluN2A and GluN2B amino-terminal domains (ATDs) adopt "closed" and "open" clefts, respectively. Upon binding Ro, the GluN2B ATD clamshell transitions from an open to a closed conformation. Consistent with a predominance of the GluN2A subunit in ion channel gating, the GluN2A subunit interacts more extensively with GluN1 subunits throughout the receptor, in comparison with the GluN2B subunit. Differences in the conformation of the pseudo-2-fold-related GluN1 subunits further reflect receptor asymmetry. The triheteromeric NMDAR structures provide the first view of the most common NMDA receptor assembly and show how incorporation of two different GluN2 subunits modifies receptor symmetry and subunit interactions, allowing each subunit to uniquely influence receptor structure and function, thus increasing receptor complexity.
Assuntos
Multimerização Proteica , Receptores de Glutamato/química , Receptores de N-Metil-D-Aspartato/química , Proteínas de Xenopus/química , Regulação Alostérica , Animais , Anticorpos Monoclonais , Microscopia Crioeletrônica , Modelos Moleculares , Plasticidade Neuronal , Domínios Proteicos , Receptores de Glutamato/imunologia , Receptores de Glutamato/ultraestrutura , Receptores de N-Metil-D-Aspartato/imunologia , Receptores de N-Metil-D-Aspartato/ultraestrutura , Proteínas de Xenopus/imunologia , Proteínas de Xenopus/ultraestrutura , Xenopus laevisRESUMO
Emerging epidemiology studies indicate that maternal immune activation (MIA) resulting from inflammatory stimuli such as viral or bacterial infections during pregnancy serves as a risk factor for multiple neurodevelopmental disorders including autism spectrum disorders and schizophrenia. Although alterations in the cortex and hippocampus of MIA offspring have been described, less evidence exists on the impact on the cerebellum. Here, we report altered expression of cytokines and chemokines in the cerebellum of MIA offspring, including increase in the neuroinflammatory cytokine TNFα and its receptor TNFR1. We also report reduced expression of the synaptic organizing proteins cerebellin-1 and GluRδ2. These synaptic protein alterations are associated with a deficit in the ability of cerebellar neurons to form synapses and an increased number of dendritic spines that are not in contact with a presynaptic terminal. These impairments are likely contributing to the behavioral deficits in the MIA exposed offspring.
Assuntos
Cerebelo/imunologia , Citocinas/imunologia , Proteínas do Tecido Nervoso/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Precursores de Proteínas/imunologia , Receptores de Glutamato/imunologia , Sinapses/imunologia , Animais , Cerebelo/metabolismo , Citocinas/biossíntese , Feminino , Masculino , Exposição Materna/efeitos adversos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/biossíntese , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Biossíntese de Proteínas/fisiologia , Precursores de Proteínas/biossíntese , Receptores de Glutamato/biossíntese , Sinapses/metabolismoRESUMO
Anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) encephalitis positive for additional onconeural antibodies is rarely reported. Here we report the clinical features of a patient who developed limbic encephalitis with both glutamate receptor 2 (GluR2) and collapsin response mediator protein 5 (CRMP5) antibodies. Brain magnetic resonance imaging revealed multifocal encephalopathy. Chest computed tomography showed a highly suspicious malignant thymoma. He experienced rapid neurological deterioration during hospitalization. This report indicates that the clinical diversity of anti-AMPAR encephalitis and the presence of onconeural antibodies may lead to poor prognosis.
Assuntos
Doenças Autoimunes do Sistema Nervoso , Encefalite , Proteínas do Tecido Nervoso/imunologia , Receptores de Glutamato/imunologia , Timoma/diagnóstico por imagem , Neoplasias do Timo/diagnóstico por imagem , Adulto , Doenças Autoimunes do Sistema Nervoso/imunologia , Doenças Autoimunes do Sistema Nervoso/patologia , Doenças Autoimunes do Sistema Nervoso/fisiopatologia , Encefalite/imunologia , Encefalite/patologia , Encefalite/fisiopatologia , Humanos , Hidrolases , Masculino , Proteínas Associadas aos MicrotúbulosRESUMO
Over the last few year, antibodies to various central nervous system receptors, particularly the glutamate and γ-aminobutyric acid (GABA) receptors, have been found to be associated with autoimmune neurologic disorders. The receptors include the N-methyl-d-aspartate receptor (NMDAR), the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), the metabotropic glutamate receptors (mGluRs), and GABA type A and B receptors (respectively GABAAR and GABABR). Compared to the previously described paraneoplastic antibodies directed at intracellular targets, the patients with receptor antibodies are often younger, they less frequently have malignancies, and they respond better to immunotherapy. Many of the patients have limbic encephalitis with amnesia, disorientation, seizures, and psychological or psychiatric symptoms, but those with NMDAR antibodies usually develop a more widespread form of encephalitis, often leading to a decrease in consciousness and requirement for long-term intensive care treatment. The autoantibodies bind directly to the synaptic or extrasynaptic receptors on the membrane surface, and have direct effects on signal transduction in central synapses. These conditions are very important to recognize as the symptoms and complications can be fatal when not treated in time, whereas with immunotherapy many patients recover considerably.