RESUMO
Inflammation drives the pathology of many neurological diseases. d-mannose has been found to exert an antiinflammatory effect in peripheral diseases, but its effects on neuroinflammation and inflammatory cells in the central nervous system have not been studied. We aimed to determine the effects of d-mannose on key macrophage/microglial functions-oxidative stress and phagocytosis. In murine experimental autoimmune encephalomyelitis (EAE), we found d-mannose improved EAE symptoms compared to phosphate-buffered saline (PBS)-control mice, while other monosaccharides did not. Multiagent molecular MRI performed to assess oxidative stress (targeting myeloperoxidase [MPO] using MPO-bis-5-hydroxytryptamide diethylenetriaminepentaacetate gadolinium [Gd]) and phagocytosis (using cross-linked iron oxide [CLIO] nanoparticles) in vivo revealed that d-mannose-treated mice had smaller total MPO-Gd+ areas than those of PBS-control mice, consistent with decreased MPO-mediated oxidative stress. Interestingly, d-mannose-treated mice exhibited markedly smaller CLIO+ areas and much less T2 shortening effect in the CLIO+ lesions compared to PBS-control mice, revealing that d-mannose partially blocked phagocytosis. In vitro experiments with different monosaccharides further confirmed that only d-mannose treatment blocked macrophage phagocytosis in a dose-dependent manner. As phagocytosis of myelin debris has been known to increase inflammation, decreasing phagocytosis could result in decreased activation of proinflammatory macrophages. Indeed, compared to PBS-control EAE mice, d-mannose-treated EAE mice exhibited significantly fewer infiltrating macrophages/activated microglia, among which proinflammatory macrophages/microglia were greatly reduced while antiinflammatory macrophages/microglia increased. By uncovering that d-mannose diminishes the proinflammatory response and boosts the antiinflammatory response, our findings suggest that d-mannose, an over-the-counter supplement with a high safety profile, may be a low-cost treatment option for neuroinflammatory diseases such as multiple sclerosis.
Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Manose/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Animais , Avaliação Pré-Clínica de Medicamentos , Feminino , Manose/farmacologia , Camundongos Endogâmicos C57BL , Imagem MolecularAssuntos
Acidentes por Quedas , Dor nas Costas , Rigidez Muscular Espasmódica , Adulto , Feminino , Humanos , Dor nas Costas/etiologia , Diagnóstico Diferencial , Perna (Membro) , Rigidez Muscular Espasmódica/complicações , Rigidez Muscular Espasmódica/diagnóstico , Rigidez Muscular Espasmódica/imunologia , Rigidez Muscular Espasmódica/terapia , Espasmo/etiologiaAssuntos
Autoanticorpos/sangue , Doenças Autoimunes/diagnóstico , Moléculas de Adesão Celular Neuronais/antagonistas & inibidores , Imunoterapia , Doenças Neurodegenerativas/etiologia , Idoso , Doenças Autoimunes/terapia , Diagnóstico Diferencial , Transtornos Neurológicos da Marcha/etiologia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Masculino , Doença dos Neurônios Motores/etiologia , Transtornos do Sono-Vigília/etiologiaRESUMO
Seizures are a well-recognized and often prominent manifestation of autoimmune encephalitic syndromes. Progress in detection of pathogenic neural autoantibodies has led to increased awareness of autoimmune causes of seizures. Clinical studies of patients with these autoantibodies have improved our understanding of the seizure characteristics, treatments, and seizure prognosis in these disorders. The International League Against Epilepsy (ILAE) Autoimmunity and Inflammation Taskforce proposes conceptual definitions for two main diagnostic entities: (a) acute symptomatic seizures secondary to autoimmune encephalitis, and (b) autoimmune-associated epilepsy, the latter of which suggests an enduring predisposition to seizures. Such a distinction is relevant when discussing the pathophysiology, treatment, prognosis, and social consequences of these disorders. We discuss the role of biomarkers in the application of these conceptual definitions and illustrate their use in patients cared for by members of the task force.
Assuntos
Encefalite/sangue , Encefalite/diagnóstico , Epilepsia/sangue , Epilepsia/diagnóstico , Doença de Hashimoto/sangue , Doença de Hashimoto/diagnóstico , Convulsões/sangue , Convulsões/diagnóstico , Doença Aguda , Adolescente , Adulto , Autoanticorpos/sangue , Biomarcadores/sangue , Encefalite/complicações , Epilepsia/complicações , Feminino , Doença de Hashimoto/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Convulsões/etiologia , Adulto JovemAssuntos
Encefalite/diagnóstico , Doença de Hashimoto/diagnóstico , Hiponatremia/etiologia , Idoso , Braço/fisiopatologia , Análise Química do Sangue , Diagnóstico Diferencial , Discinesias/etiologia , Encefalite/complicações , Encefalite/tratamento farmacológico , Face/fisiopatologia , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Glucocorticoides/uso terapêutico , Doença de Hashimoto/complicações , Doença de Hashimoto/tratamento farmacológico , Humanos , Síndrome de Secreção Inadequada de HAD/diagnóstico , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Metilprednisolona/uso terapêutico , Concentração Osmolar , Sódio/sangueRESUMO
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, É, 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 JovemRESUMO
Autoimmune disorders are becoming increasingly recognized within the broader field of neurology. The discovery of multiple, novel, neutrally targeted autoantibodies over the past decade and their translation into commercially available testing, in particular, has aided in the more rapid diagnosis of these disorders. When considering imaging in autoimmune neurologic disorders, it is important, when possible, to visualize the autoimmune process itself, as well as to make sure that the patient does not have an associated malignancy driving the overall process. Positron emission tomographic scans can aid in the detection of small tumors with limited spread, as well as in the visualization of autoimmune processes affecting the brain and/or spinal cord. In autoimmune disorders of the central nervous system, imaging abnormalities can appear within the limbic system, extralimbic areas, and spinal cord. Such imaging abnormalities can serve as objective markers to follow over time to assess patients' responses to treatment. It is important to recognize that overlapping syndromes (for instance, both demyelinating and autoimmune or both infectious and autoimmune) exist and that inflammatory disorders can leave behind sequelae that can be recognized on subsequent imaging. Work is currently underway to develop more specific imaging techniques for autoimmune neurologic disorders.
Assuntos
Autoanticorpos/imunologia , Doenças Autoimunes do Sistema Nervoso/diagnóstico por imagem , Doenças Autoimunes/diagnóstico por imagem , Sistema Nervoso Central/diagnóstico por imagem , Doenças Desmielinizantes/imunologia , Doenças Autoimunes do Sistema Nervoso/imunologia , Sistema Nervoso Central/imunologia , Doenças Desmielinizantes/patologia , Humanos , Miosite/imunologia , Miosite/terapiaRESUMO
The understanding of the manifestations, mechanisms, and management of autoimmune encephalitis has expanded dramatically in recent decades. Immune-mediated encephalitides are comparable in incidence and prevalence to infectious etiologies, and are associated with significant morbidity, especially when there is a delay in recognition and treatment. As such, clinicians from many specialties must develop a functional understanding of these disorders. Herein we provide an overview of the autoimmune and paraneoplastic encephalitides, including those associated with either intracellular or cell surface/synaptic neuronal autoantibodies. After briefly reviewing the current understanding of the pathobiology of autoimmune encephalitis, we combine a neuroanatomical approach with specific antibody syndromes to provide the reader with a clinically relevant review of these disorders. The clinical manifestations, diagnosis, and management of autoimmune encephalitis are reviewed, with an emphasis on clinical relevance. We also introduce updates in the field, including autoimmune encephalitis associated with novel cancer immunotherapies, infectious triggers of autoimmune encephalitis, and autoimmune encephalitis with demyelinating overlap syndromes.
Assuntos
Autoanticorpos/imunologia , Encefalite/terapia , Doença de Hashimoto/terapia , Imunoterapia , Síndromes Paraneoplásicas/terapia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/imunologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/terapia , Encefalite/imunologia , Doença de Hashimoto/imunologia , Humanos , Neurônios , Síndromes Paraneoplásicas/imunologiaRESUMO
Currently, there is no stable and flexible method to label and track cytotoxic T lymphocytes (CTLs) in vivo in CTL immunotherapy. We aimed to evaluate whether the sulfo-hydroxysuccinimide (NHS)-biotin-streptavidin (SA) platform could chemically modify the cell surface of CTLs for in vivo tracking. CD8+ T lymphocytes were labeled with sulfo-NHS-biotin under different conditions and then incubated with SA-Alexa647. Labeling efficiency was proportional to sulfo-NHS-biotin concentration. CD8+ T lymphocytes could be labeled with higher efficiency with sulfo-NHS-biotin in DPBS than in RPMI (P < 0.05). Incubation temperature was not a key factor. CTLs maintained sufficient labeling for at least 72 h (P < 0.05), without altering cell viability. After co-culturing labeled CTLs with mouse glioma stem cells (GSCs) engineered to present biotin on their surface, targeting CTLs could specifically target biotin-presenting GSCs and inhibited cell proliferation (P < 0.01) and tumor spheres formation. In a biotin-presenting GSC brain tumor model, targeting CTLs could be detected in biotin-presenting gliomas in mouse brains but not in the non-tumor-bearing contralateral hemispheres (P < 0.05). In vivo fluorescent molecular tomography imaging in a subcutaneous U87 mouse model confirmed that targeting CTLs homed in on the biotin-presenting U87 tumors but not the control U87 tumors. PET imaging with 89Zr-deferoxamine-biotin and SA showed a rapid clearance of the PET signal over 24 h in the control tumor, while only minimally decreased in the targeted tumor. Thus, sulfo-NHS-biotin-SA labeling is an efficient method to noninvasively track the migration of adoptive transferred CTLs and does not alter CTL viability or interfere with CTL-mediated cytotoxic activity.
Assuntos
Biotinilação/métodos , Imunoterapia/métodos , Linfócitos T Citotóxicos/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Humanos , CamundongosRESUMO
Herpes simplex virus (HSV) encephalitis can induce an autoimmune encephalitis mediated by autoantibodies against the N-methyl-D-aspartate receptor (NMDAR). Post-HSV NMDAR encephalitis and de novo NMDAR encephalitis have been more commonly described in children and young adults. We describe the case of a 67-year-old woman with post-HSV NMDAR encephalitis and review the relevant literature. Clinical, serological, neurophysiological, and imaging evaluations were undertaken in the evaluation of this patient. A literature review was performed. Nearly 2 months after a typical course of HSV encephalitis confirmed by HSV polymerase chain reaction studies from the spinal fluid and treated with intravenous acyclovir, a 67-year-old woman suffered neurological deterioration. There was no evidence of active HSV infection, but NMDAR antibodies were found in her serum and spinal fluid. The patient improved after initiation of immunosuppressive therapy. All patients who experience new or recurrent neurological symptoms following recovery from HSV encephalitis should be evaluated for post-infectious autoimmune encephalitis, including NMDAR encephalitis.
Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato/virologia , Antivirais/uso terapêutico , Encefalite por Herpes Simples/virologia , Imunossupressores/uso terapêutico , Aciclovir/uso terapêutico , Idoso , Encefalite Antirreceptor de N-Metil-D-Aspartato/tratamento farmacológico , Encefalite Antirreceptor de N-Metil-D-Aspartato/etiologia , Encefalite Antirreceptor de N-Metil-D-Aspartato/patologia , Autoanticorpos/líquido cefalorraquidiano , DNA Polimerase Dirigida por DNA/líquido cefalorraquidiano , DNA Polimerase Dirigida por DNA/genética , Encefalite por Herpes Simples/complicações , Encefalite por Herpes Simples/tratamento farmacológico , Encefalite por Herpes Simples/patologia , Feminino , Expressão Gênica , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Rituximab/uso terapêutico , Simplexvirus/genética , Simplexvirus/crescimento & desenvolvimento , Simplexvirus/patogenicidade , Proteínas Virais/líquido cefalorraquidiano , Proteínas Virais/genéticaRESUMO
Autoimmune neurology is a rapidly evolving new subspecialty driven by the discovery of novel neural- (neuronal- or glial-) specific autoantibodies and their target antigens. The neurologic manifestations affecting the central nervous system include encephalitis, dementia, epilepsy, and movement and sleep disorders. Laboratory testing is now available for most of these neural-specific autoantibodies, which serve as diagnostic markers, in some instances directing the physician toward specific cancer types (e.g., N-methyl-D-aspartic acid receptor antibodies for teratoma, collapsin response mediator protein 5 for small-cell lung cancer) and assisting in therapeutic decision making. Antibodies targeting intracellular proteins serve as markers of cytotoxic effector T-cell-mediated injury, which is generally poorly responsive to immunotherapy. By contrast, antibodies targeting extracellular plasma membrane proteins may act as pathogenic effectors and often infer good responses to immunotherapy. Diagnosing these conditions and implementing treatment as early into the clinical course as possible ensures the best possible clinical outcomes. An adequate immunotherapy trial to assess maximum reversibility of symptoms, as assessed through objective functional measures, is crucial and can help to determine whether maintenance therapy is needed.
Assuntos
Autoanticorpos , Doenças do Sistema Nervoso Central/imunologia , Imunoterapia , Doenças do Sistema Nervoso Central/diagnóstico , Doenças do Sistema Nervoso Central/terapia , Encefalite , Epilepsia , HumanosRESUMO
In the past few years, many autoimmune encephalitides have been identified, with specific clinical syndromes and associated antibodies against neuronal surface antigens. There is compelling evidence that many of these antibodies are pathogenic and most of these encephalitides are highly responsive to immunotherapies. The clinical spectra of some of these antibody-mediated syndromes, especially those reported in only a few patients, are evolving. Others, such as anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, are well characterized. Diagnosis involves recognizing the specific syndromes and identifying the antibody in a patient's cerebrospinal fluid (CSF) and/or serum. These syndromes are associated with variable abnormalities in CSF, magnetic resonance imaging, and electroencephalography. Treatment is often multidisciplinary and should be focused upon neutralizing the effects of antibodies and eliminating their source. Overlapping disorders have been noted, with some patients having more than one neurologic autoimmune disease. In other patients, viral infections such as herpes simplex virus encephalitis trigger robust antineuronal autoimmune responses.
Assuntos
Autoanticorpos , Doenças Autoimunes do Sistema Nervoso/imunologia , Encefalopatias/imunologia , Encefalite/imunologia , Doença de Hashimoto/imunologia , Humanos , Neurônios/imunologiaRESUMO
Although they are relatively rare, the diagnosis of paraneoplastic neurologic syndromes (PNS) can be aided by the identification of neural autoantibodies in patients' serum and cerebrospinal fluid (CSF). They often clinically manifest as characteristic syndromes, including limbic encephalitis, opsoclonus-myoclonus syndrome, paraneoplastic cerebellar degeneration, and paraneoplastic encephalomyelitis. The antibodies are directed either toward intracellular targets, or epitopes on the cell surface. As compared to cell surface antibodies, intracellular paraneoplastic autoantibodies are more classically associated with cancer, most often lung, breast, thymoma, gynecologic, testicular, and/or neuroendocrine cancers. The malignancies themselves tend to be small and regionally contained, attesting to the strength of the immune system in cancer immunosurveillance. Typically, the intracellular antibodies are not directly pathogenic and tend to be associated with PNS that are poorly responsive to treatment. With some notable exceptions, including patients with PNS associated with testicular cancer, patients with intracellular antibodies are typically older individuals, in their 7th decade of life and beyond. Many of them are current or former smokers. Treatment strategies include tumor removal as well as immunotherapy to treat the concomitant PNS. Newer technologies and the ever-broadening use of cancer immunotherapies are contributing to the continued identification of novel intracellularly targeted autoantibodies.
Assuntos
Encefalite Límbica , Síndromes Paraneoplásicas do Sistema Nervoso , Neoplasias Testiculares , Masculino , Humanos , Feminino , Síndromes Paraneoplásicas do Sistema Nervoso/terapia , Autoanticorpos , ImunoterapiaRESUMO
Purkinje cell cytoplasmic autoantibody type 1 (PCA1), also known as anti-Yo, is a 'high-risk' paraneoplastic antibody, associated with rapidly progressive cerebellar syndrome. In patients with this syndrome, various MRI abnormalities have been documented, including atrophy in the cerebellum and brainstem, T2 hyperintensity in the brainstem and spinal cord, and cranial nerve enhancement. This report introduces an imaging finding, cerebellar leptomeningeal enhancement, which was observed in all three cases at early stages. Despite neurological deterioration, all patients underwent immunotherapy, and subsequent follow-up MRI revealed resolution of the leptomeningeal enhancement, suggesting that this feature is distinct from meningeal carcinomatosis.
Assuntos
Doenças Cerebelares , Degeneração Paraneoplásica Cerebelar , Síndromes Paraneoplásicas , Humanos , Degeneração Paraneoplásica Cerebelar/diagnóstico por imagem , Degeneração Paraneoplásica Cerebelar/metabolismo , Células de Purkinje/metabolismo , Autoanticorpos , Proteínas do Tecido Nervoso , Cerebelo/metabolismo , Doenças Cerebelares/diagnóstico por imagem , Doenças Cerebelares/metabolismoRESUMO
BACKGROUND: Patients with paraneoplastic syndromes (PNS) are excluded from clinical trials involving immune checkpoint inhibitors (ICIs) due to safety concerns. Moreover, real-world data on efficacy and safety is scarce. METHODS: In this retrospective study, data were collected on patients with PNS and solid tumors receiving ICI between 2015 and 2022 at nine institutions. Patients were classified into: Cohort 1 (pre-existing PNS before ICI initiation), cohort 2 (PNS during ICI treatment), and cohort 3 (PNS after ICI discontinuation). Patients with metastatic non-small cell lung cancer (NSCLC) (mNSCLC) from cohort 1 were matched to patients who were PNS-free at each institution up to a 1:3 ratio for age, sex, type of ICI, use of concurrent chemotherapy, and number of lines of systemic therapy prior to ICI initiation. Kaplan-Meier method was used to assess overall survival (OS) and time-to-next treatment (TTNT). RESULTS: Among 109 patients with PNS treated with ICIs, median age at ICI initiation was 67 years (IQR: 58-74). The most represented cancer type was NSCLC (n=39, 36%). In cohort 1 (n=55), PNS exacerbations occurred in 16 (29%) patients with median time to exacerbation after ICI of 1.1 months (IQR: 0.7-3.3). Exacerbation or de novo PNS prompted temporary/permanent interruption of ICIs in 14 (13%) patients. For cohort 2 (n=16), median time between ICI initiation and de novo PNS was 1.2 months (IQR: 0.4-3.5). Treatment-related adverse events (trAEs) occurred in 43 (39%) patients. Grade ≥3 trAEs occurred in 18 (17%) patients. PNS-directed immunosuppressive therapy was required in 55 (50%) patients. We matched 18 patients with mNSCLC and PNS (cohort 1) to 40 without PNS, treated with ICIs. There was no significant difference in OS or TTNT between patients with mNSCLC with and without PNS, although a trend was seen towards worse outcomes in patients with PNS. TrAEs occurred in 6/18 (33%) and 14/40 (35%), respectively. Grade ≥3 trAEs occurred in 4 (22%) patients with PNS and 7 (18%) patients without PNS. CONCLUSIONS: Exacerbations of pre-existing PNS occurred in 29% of patients treated with ICIs and both exacerbations and de novo PNS occur early in the ICI course. TrAE from ICIs were similar between patients with and without PNS. Our data suggest that pre-existing PNS should not preclude consideration of ICI therapy although patients may not derive the same clinical benefit compared with patients without PNS.