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1.
Ann Neurol ; 92(6): 1090-1101, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36053822

RESUMO

BACKGROUND AND OBJECTIVES: We sought to determine clinical significance of neuronal septin autoimmunity and evaluate for potential IgG effects. METHODS: Septin-IgGs were detected by indirect immunofluorescence assays (IFAs; mouse tissue and cell based) or Western blot. IgG binding to (and internalization of) extracellular septin epitopes were evaluated for by live rat hippocampal neuron assay. The impact of purified patient IgGs on murine cortical neuron function was determined by recording extracellular field potentials in a multielectrode array platform. RESULTS: Septin-IgGs were identified in 23 patients. All 8 patients with septin-5-IgG detected had cerebellar ataxia, and 7 had prominent eye movement disorders. One of 2 patients with co-existing septin-7-IgG had additional psychiatric phenotype (apathy, emotional blunting, and poor insight). Fifteen patients had septin-7 autoimmunity, without septin-5-IgG detected. Disorders included encephalopathy (11; 2 patients with accompanying myelopathy, and 2 were relapsing), myelopathy (3), and episodic ataxia (1). Psychiatric symptoms (≥1 of agitation, apathy, catatonia, disorganized thinking, and paranoia) were prominent in 6 of 11 patients with encephalopathic symptoms. Eight of 10 patients with data available (from 23 total) improved after immunotherapy, and a further 2 patients improved spontaneously. Staining of plasma membranes of live hippocampal neurons produced by patient IgGs (subclasses 1 and 2) colocalized with pre- and post-synaptic markers. Decreased spiking and bursting behavior in mixed cultures of murine glutamatergic and GABAergic cortical neurons produced by patient IgGs were attributable to neither antigenic crosslinking and internalization nor complement activation. INTERPRETATION: Septin-IgGs are predictive of distinct treatment-responsive autoimmune central nervous system (CNS) disorders. Live neuron binding and induced electrophysiologic effects by patient IgGs may support septin-specific pathophysiology. ANN NEUROL 2022;92:1090-1101.


Assuntos
Encefalopatias , Doenças da Medula Espinal , Animais , Ratos , Camundongos , Septinas/metabolismo , Autoimunidade , Neurônios/metabolismo , Imunoglobulina G/metabolismo
2.
Ann Neurol ; 81(2): 298-309, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28120349

RESUMO

OBJECTIVE: A novel autoimmune central nervous system (CNS) disorder with glial fibrillary acidic protein (GFAP)-IgG as biomarker was recently characterized. Here, 102 patients with GFAP-IgG positivity are described. METHODS: The 102 included patients had: (1) serum, cerebrospinal fluid (CSF), or both that yielded a characteristic astrocytic pattern of mouse tissue immunostaining; (2) confirmation of IgG reactive with specific GFAP isoforms (α, ɛ, or κ) by cell-based assays; and (3) clinical data available. Control specimens (n = 865) were evaluated by tissue (n = 542) and cell-based (n = 323) assays. RESULTS: Median symptom onset age was 44 years (range = 8-103), and 54% were women. The predominant phenotype (83 patients; 81%) was inflammation of meninges, brain, spinal cord, or all 3 (meningoencephalomyelitis). Among patients, highest specificity for those phenotypes was observed for CSF testing (94%), and highest sensitivity was for the GFAPα isoform (100%). Rare GFAP-IgG positivity was encountered in serum controls by tissue-based assay (0.5%) or cell-based assay (1.5%), and in CSF controls by cell-based assay (0.9%). Among patients, striking perivascular radial enhancement was found on brain magnetic resonance imaging in 53%. Although cases frequently mimicked vasculitis, angiography was uniformly negative, and spinal imaging frequently demonstrated longitudinally extensive myelitic lesions. Diverse neoplasms encountered were found prospectively in 22%. Ovarian teratoma was most common and was predicted best when both N-methyl-D-aspartate receptor-IgG and aquaporin-4-IgG coexisted (71%). Six patients with prolonged follow-up had brisk corticosteroid response, but required additional immunosuppression to overcome steroid dependency. INTERPRETATION: GFAPα-IgG, when detected in CSF, is highly specific for an immunotherapy-responsive autoimmune CNS disorder, sometimes with paraneoplastic cause. Ann Neurol 2017;81:298-309.


Assuntos
Astrócitos/patologia , Autoanticorpos/líquido cefalorraquidiano , Doenças Autoimunes do Sistema Nervoso/líquido cefalorraquidiano , Proteína Glial Fibrilar Ácida/imunologia , Síndromes Paraneoplásicas do Sistema Nervoso/líquido cefalorraquidiano , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Biomarcadores/líquido cefalorraquidiano , Criança , Feminino , Humanos , Imunoglobulina G , Imageamento por Ressonância Magnética , Masculino , Camundongos , Pessoa de Meia-Idade , Adulto Jovem
3.
Artigo em Inglês | MEDLINE | ID: mdl-32461352

RESUMO

OBJECTIVE: To determine serologic characteristics, frequency, phenotype, paraneoplastic associations, and electrodiagnostic and histopathologic features accompanying contactin-1 autoimmunity. METHODS: Archived sera known to produce synaptic tissue-based immunofluorescence patterns were reevaluated, and contactin-1 specificity was confirmed by recombinant protein assays. Screening of 233 chronic/relapsing demyelinating neuropathies for additional cases was performed. RESULTS: We identified 10 contactin-1 IgG seropositive cases. Frequency of contactin-1 immunoglobulin (Ig) G among tested Mayo Clinic chronic/relapsing demyelinating neuropathies was 2%. Sensory predominant presentations (n = 9, 90%), neuropathic pain (n = 6, 60%), and subacute progression (n = 5, 50%) were commonly encountered among contactin-1 neuropathies. Two patients had chronic immune sensory polyradiculopathy-like phenotype at presentation. Electrodiagnostic studies were consistent with demyelination (slowed conduction velocities and/or prolonged distal latencies) without conduction block. Markedly elevated CSF protein (median 222 mg/dL, range 69-960 mg/dL), thickening/gadolinium enhancement of nerve roots (4/5), and subperineural edema on nerve biopsy (4/4) were other characteristic features. Three cases were diagnosed with paraneoplastic demyelinating neuropathies (thymoma, n = 1; breast cancer, n = 1; plasmacytoma, n = 1). Four of the 9 patients treated with IV immunoglobulin demonstrated initial clinical improvement, but the favorable response was sustained in only 1 case (median follow-up, 60 months). Sustained clinical stabilization or improvement was observed among 3 of the 6 cases in whom second-line therapies (rituximab, cyclophosphamide, and azathioprine) were used. CONCLUSION: Contactin-1 IgG has a distinct sensory predominant presentation commonly associated with neuropathic pain, with demyelinating changes on electrophysiologic studies. A paraneoplastic cause should be considered. Testing of contactin-1 IgG among cases with similar presentations may guide immunotherapy selection, especially second-line immunotherapy consideration.


Assuntos
Autoanticorpos/sangue , Doenças Autoimunes do Sistema Nervoso , Contactina 1/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/metabolismo , Doenças Autoimunes do Sistema Nervoso/patologia , Doenças Autoimunes do Sistema Nervoso/fisiopatologia , Eletrodiagnóstico , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
4.
Neurology ; 93(10): e954-e963, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31371564

RESUMO

OBJECTIVE: To describe phenotypes, treatment response, and outcomes of autoimmunity targeting a synaptic vesicle coat protein, the neuronal (B2) form of adaptor protein-3 (AP3). METHODS: Archived serum and CSF specimens (from 616,025 screened) harboring unclassified synaptic antibodies mimicking amphiphysin-immunoglobulin G (IgG) on tissue-based indirect immunofluorescence assay (IFA) were re-evaluated for novel IgG staining patterns. Autoantigens were identified by western blot and mass spectrometry. Recombinant western blot and cell-binding assay (CBA) were used to confirm antigen specificity. Clinical data were obtained retrospectively. RESULTS: Serum (10) and CSF (6) specimens of 10 patients produced identical IFA staining patterns throughout mouse nervous system tissues, most prominently in cerebellum (Purkinje neuronal perikarya, granular layer synapses, and dentate regions), spinal cord gray matter, dorsal root ganglia, and sympathetic ganglia. The antigen revealed by mass spectrometry analysis and confirmed by recombinant assays (western blot and CBA) was AP3B2 in all. Of 10 seropositive patients, 6 were women; median symptom onset age was 42 years (range 24-58). Clinical information was available for 9 patients, all with subacute onset and rapidly progressive gait ataxia. Neurologic manifestations were myeloneuropathy (3), peripheral sensory neuropathy (2), cerebellar ataxia (2), and spinocerebellar ataxia (2). Five patients received immunotherapy; none improved, but they did not worsen over the follow-up period (median 36 months; range 3-94). Two patients (both with cancer) died. One of 50 control sera was positive by western blot only (but not by IFA or CBA). CONCLUSION: AP3B2 (previously named ß-neuronal adaptin-like protein) autoimmunity appears rare, is accompanied by ataxia (sensory or cerebellar), and is potentially treatable.


Assuntos
Complexo 3 de Proteínas Adaptadoras/metabolismo , Subunidades beta do Complexo de Proteínas Adaptadoras/metabolismo , Autoimunidade/fisiologia , Transtornos Neurológicos da Marcha/diagnóstico por imagem , Transtornos Neurológicos da Marcha/metabolismo , Imunoglobulina G/metabolismo , Adulto , Animais , Autoanticorpos/sangue , Autoanticorpos/líquido cefalorraquidiano , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Células Cultivadas , Ataxia Cerebelar/diagnóstico por imagem , Ataxia Cerebelar/metabolismo , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Ratos
5.
Neurol Neuroimmunol Neuroinflamm ; 5(5): e474, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29998156

RESUMO

OBJECTIVE: To report a form of autoimmune cerebellar ataxia in which antibodies target septin-5, a guanosine triphosphate (GTP)-binding neural protein involved in neurotransmitter exocytosis. METHODS: Archived sera and CSF specimens with unclassified synaptic antibodies were re-evaluated by tissue-based indirect immunofluorescence assay. Autoantigens were identified by Western blot and mass spectrometry. Recombinant protein assays (Western blot, cell based, and protein screening array) confirmed antigen specificity. RESULTS: Serum and CSF from 6 patients produced identical synaptic immunoglobulin G (IgG) staining patterns of synaptic regions (neuropil) of the mouse cerebrum and cerebellum. The molecular layer of the cerebellum and the thalamus demonstrated stronger immunoreactivity than the midbrain, hippocampus, cortex, and basal ganglia. The antigen revealed by mass spectrometry analysis of immunoprecipitated cerebellar proteins and confirmed by recombinant protein assays was septin-5. All 4 patients with records available had subacute onset of cerebellar ataxia with prominent eye movement symptoms (oscillopsia or vertigo). None had cancer detected. Improvements occurred after immunotherapies (2) or spontaneously (1). One patient died. CONCLUSION: Septin-5 IgG represents a biomarker for a potentially fatal but treatable autoimmune ataxia.

6.
Neurol Neuroimmunol Neuroinflamm ; 4(5): e385, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28761904

RESUMO

OBJECTIVE: To describe the phenotypes, treatment response, and outcome of IgLON5 autoimmunity. METHODS: Archived serum and CSF specimens from 367 patients known to harbor unclassified antibodies which stained neural synapses diffusely (mimicking amphiphysin-IgG) were reevaluated by indirect immunofluorescence assay (IFA) using a composite of mouse tissues and recombinant IgLON5-transfected cell-based assay (CBA, Euroimmun). RESULTS: Available specimens (serum, 25; CSF, 9) from 26/367 patients (7%) had identical IFA appearance and robust IgLON5 CBA positivity. Clinical information was available for 20/26 patients; 13 were women. Median disease-onset age was 62 years (range, 46-75 years). Most patients had insidious onset and progression of neurological symptoms affecting movement and sleep predominantly. Sleep disorders were sleep-disordered breathing (11) and parasomnias (3). Brainstem disorders were gait instability (14), dysphagia (10), abnormal eye movements (7), respiratory dysfunction (6), ataxia (5), craniocervical dystonia (3), and dysarthria (3). Findings compatible with hyperexcitability included myoclonus (3), cramps (3), fasciculations (2), and exaggerated startle (2). Neuropsychiatric disorders included cognitive dysfunction (6), psychiatric symptoms (5), and seizures (1). Dysautonomia, in 9, affected bladder function (7), gastrointestinal motility (3), thermoregulation (3), and orthostatic tolerance (1). Just 2 patients had coexisting autoimmune disease. Brain MRI findings were nonspecific and CSF was noninflammatory in all tested. Seven of 9 immunotherapy-treated patients improved: 6 of those 7 were stable at last follow-up. Three untreated patients died. Each IgLON5-IgG subclass (1-4) was readily detectable in ≥80% of specimens using CBA. CONCLUSIONS: IgLON5-IgG is diagnostic of a potentially treatable neurological disorder, where autoimmune clues are otherwise lacking.

7.
PLoS One ; 12(11): e0187215, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29107957

RESUMO

Oxidative stress and mitochondrial dysfunction are important determinants of neurodegeneration in secondary progressive multiple sclerosis (SPMS). We previously showed that febuxostat, a xanthine oxidase inhibitor, ameliorated both relapsing-remitting and secondary progressive experimental autoimmune encephalomyelitis (EAE) by preventing neurodegeneration in mice. In this study, we investigated how febuxostat protects neuron in secondary progressive EAE. A DNA microarray analysis revealed that febuxostat treatment increased the CNS expression of several mitochondria-related genes in EAE mice, most notably including GOT2, which encodes glutamate oxaloacetate transaminase 2 (GOT2). GOT2 is a mitochondrial enzyme that oxidizes glutamate to produce α-ketoglutarate for the Krebs cycle, eventually leading to the production of adenosine triphosphate (ATP). Whereas GOT2 expression was decreased in the spinal cord during the chronic progressive phase of EAE, febuxostat-treated EAE mice showed increased GOT2 expression. Moreover, febuxostat treatment of Neuro2a cells in vitro ameliorated ATP exhaustion induced by rotenone application. The ability of febuxostat to preserve ATP production in the presence of rotenone was significantly reduced by GOT2 siRNA. GOT2-mediated ATP synthesis may be a pivotal mechanism underlying the protective effect of febuxostat against neurodegeneration in EAE. Accordingly, febuxostat may also have clinical utility as a disease-modifying drug in SPMS.


Assuntos
Aspartato Aminotransferase Mitocondrial/metabolismo , Encefalomielite Autoimune Experimental/prevenção & controle , Febuxostat/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Animais , Aspartato Aminotransferase Mitocondrial/genética , Linhagem Celular , Encefalomielite Autoimune Experimental/enzimologia , Metabolismo Energético , Febuxostat/farmacologia , Humanos , Camundongos , Mitocôndrias/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Rotenona/farmacologia , Xantina Oxidase/antagonistas & inibidores
8.
Ann Clin Transl Neurol ; 2(1): 56-66, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25642435

RESUMO

OBJECTIVES: The intestinal microflora affects the pathogenesis of several autoimmune diseases by influencing immune system function. Some bacteria, such as lactic acid bacteria, have been reported to have beneficial effects on immune function. However, little is known about the effects of yeasts. Here, we aimed to investigate the effects of various dietary yeasts contained in fermented foods on experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), and to elucidate the mechanisms underlying these effects. METHODS: The effects of eight yeasts selected from 18 types of yeasts contained in fermented foods were examined using an EAE model. Of these, Candida kefyr was investigated by analyzing the intestinal microflora and its effects on intestinal and systemic immune states. RESULTS: Administration of C. kefyr ameliorated the severity of EAE. Reduced numbers of Th17 cells, suppressed interleukin (IL)-6 production by intestinal explants, and increased Tregs and CD103-positive regulatory dendritic cells in mesenteric lymph nodes (MLNs) were observed. Analysis of 16s-rDNA from feces of C. kefyr-treated mice demonstrated increased Lactobacillales and decreased Bacteroides compared to control flora. Transfer of intestinal microbiota also resulted in decreased Bacteroides and ameliorated symptoms of EAE. Thus, oral administration of C. kefyr ameliorated EAE by altering the microflora, accompanied by increased Tregs and CD103-positive regulatory dendritic cells in MLNs and decreased Th17 cells in the intestinal lamina propria. INTERPRETATION: Oral ingestion of C. kefyr may have beneficial effects on MS by modifying microflora. In addition, our findings also suggested the potential health benefits of dietary yeasts.

9.
PLoS One ; 6(11): e27644, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22110705

RESUMO

BACKGROUND: Certain intestinal microflora are thought to regulate the systemic immune response. Lactic acid bacteria are one of the most studied bacteria in terms of their beneficial effects on health and autoimmune diseases; one of which is Multiple sclerosis (MS) which affects the central nervous system. We investigated whether the lactic acid bacterium Pediococcus acidilactici, which comprises human commensal bacteria, has beneficial effects on experimental autoimmune encephalomyelitis (EAE), an animal model of MS. METHODOLOGY/PRINCIPAL FINDINGS: P. acidilactici R037 was orally administered to EAE mice to investigate the effects of R037. R037 treatment suppressed clinical EAE severity as prophylaxis and therapy. The antigen-specific production of inflammatory cytokines was inhibited in R037-treated mice. A significant increase in the number of CD4(+) Interleukin (IL)-10-producing cells was observed in the mesenteric lymph nodes (MLNs) and spleens isolated from R037-treated naive mice, while no increase was observed in the number of these cells in the lamina propria. Because only a slight increase in the CD4(+)Foxp3(+) cells was observed in MLNs, R037 may primarily induce Foxp3(-) IL10-producing T regulatory type 1 (Tr1) cells in MLNs, which contribute to the beneficial effect of R037 on EAE. CONCLUSIONS/SIGNIFICANCE: An orally administered single strain of P. acidilactici R037 ameliorates EAE by inducing IL10-producing Tr1 cells. Our findings indicate the therapeutic potential of the oral administration of R037 for treating multiple sclerosis.


Assuntos
Encefalopatias/imunologia , Encefalopatias/microbiologia , Doença de Hashimoto/imunologia , Doença de Hashimoto/microbiologia , Interleucina-10/biossíntese , Ácido Láctico/biossíntese , Pediococcus/fisiologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/microbiologia , Administração Oral , Animais , Encefalopatias/metabolismo , Encefalopatias/terapia , Encefalite , Feminino , Doença de Hashimoto/metabolismo , Doença de Hashimoto/terapia , Camundongos , Pediococcus/metabolismo
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