Asunto(s)
Autoanticuerpos , Imagen por Resonancia Magnética , Glicoproteína Mielina-Oligodendrócito , Neuritis Óptica , Humanos , Femenino , Glicoproteína Mielina-Oligodendrócito/inmunología , Neuritis Óptica/inmunología , Neuritis Óptica/diagnóstico , Preescolar , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Diagnóstico Diferencial , Nervio Óptico/patología , Nervio Óptico/inmunologíaRESUMEN
Although researched extensively the understanding regarding mechanisms underlying glaucoma pathogenesis remains limited. Further, the exact mechanism behind neuronal death remains elusive. The role of neuroinflammation in retinal ganglion cell (RGC) death has been prominently theorised. This review provides a comprehensive summary of neuroinflammatory responses in glaucoma. A systematic search of Medline and Embase for articles published up to 8th March 2023 yielded 32 studies using post-mortem tissues from glaucoma patients. The raw data were extracted from tables and text to calculate the standardized mean differences (SMDs). These studies utilized post-mortem tissues from glaucoma patients, totalling 490 samples, compared with 380 control samples. Among the included studies, 27 reported glial cell activation based on changes to cellular morphology and molecular staining. Molecular changes were predominantly attributed to astrocytes (62.5%) and microglia (15.6%), with some involvement of Muller cells. These glial cell changes included amoeboid microglial cells with increased CD45 or HLA-DR intensity and hypertrophied astrocytes with increased glial fibrillary acidic protein labelling. Further, changes to extracellular matrix proteins like collagen, galectin, and tenascin-C suggested glial cells' influence on structural changes in the optic nerve head. The activation of DAMPs-driven immune response and the classical complement cascade was reported and found to be associated with activated glial cells in glaucomatous tissue. Increased pro-inflammatory markers such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were also linked to glial cells. Glial cell activation was also associated with mitochondrial, vascular, metabolic and antioxidant component disruptions. Association of the activated glial cells with pro-inflammatory responses, dysregulation of homeostatic components and antigen presentation indicates that glial cell responses influence glaucoma progression. However, the exact mechanism triggering these responses and underlying interactions remains unexplored. This necessitates further research using human samples for an increased understanding of the precise role of neuroinflammation in glaucoma progression.
Asunto(s)
Glaucoma , Neuroglía , Nervio Óptico , Humanos , Autopsia , Glaucoma/inmunología , Glaucoma/patología , Glaucoma/metabolismo , Neuroglía/inmunología , Neuroglía/patología , Neuroglía/metabolismo , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/patología , Nervio Óptico/patología , Nervio Óptico/inmunología , Retina/inmunología , Retina/patología , Células Ganglionares de la Retina/patología , Células Ganglionares de la Retina/inmunologíaRESUMEN
The eye, an anatomical extension of the central nervous system (CNS), exhibits many molecular and cellular parallels to the brain. Emerging research demonstrates that changes in the brain are often reflected in the eye, particularly in the retina1. Still, the possibility of an immunological nexus between the posterior eye and the rest of the CNS tissues remains unexplored. Here, studying immune responses to herpes simplex virus in the brain, we observed that intravitreal immunization protects mice against intracranial viral challenge. This protection extended to bacteria and even tumours, allowing therapeutic immune responses against glioblastoma through intravitreal immunization. We further show that the anterior and posterior compartments of the eye have distinct lymphatic drainage systems, with the latter draining to the deep cervical lymph nodes through lymphatic vasculature in the optic nerve sheath. This posterior lymphatic drainage, like that of meningeal lymphatics, could be modulated by the lymphatic stimulator VEGFC. Conversely, we show that inhibition of lymphatic signalling on the optic nerve could overcome a major limitation in gene therapy by diminishing the immune response to adeno-associated virus and ensuring continued efficacy after multiple doses. These results reveal a shared lymphatic circuit able to mount a unified immune response between the posterior eye and the brain, highlighting an understudied immunological feature of the eye and opening up the potential for new therapeutic strategies in ocular and CNS diseases.
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Encéfalo , Ojo , Sistema Linfático , Animales , Femenino , Humanos , Masculino , Ratones , Conejos , Bacterias/inmunología , Encéfalo/anatomía & histología , Encéfalo/inmunología , Dependovirus/inmunología , Ojo/anatomía & histología , Ojo/inmunología , Glioblastoma/inmunología , Herpesvirus Humano 2/inmunología , Inyecciones Intravítreas , Sistema Linfático/anatomía & histología , Sistema Linfático/inmunología , Vasos Linfáticos/anatomía & histología , Vasos Linfáticos/inmunología , Macaca mulatta , Meninges/inmunología , Nervio Óptico/inmunología , Porcinos , Pez Cebra , Factor C de Crecimiento Endotelial Vascular/inmunología , Factor C de Crecimiento Endotelial Vascular/metabolismo , Factor C de Crecimiento Endotelial Vascular/farmacologíaRESUMEN
OBJECTIVE: To investigate the optic nerve and macular parameters of children who recovered from COVID-19 compared with healthy children using optical coherence tomography (OCT). DESIGN: Cohort study. SETTING: Hospital Clinico San Carlos, Madrid. PATIENTS: Children between 6 and 18 years old who recovered from COVID-19 with laboratory-confirmed SARS-CoV-2 infection and historical controls were included. INTERVENTIONS: All patients underwent an ophthalmological examination, including macular and optic nerve OCT. Demographic data, medical history and COVID-19 symptoms were noted. MAIN OUTCOME MEASURES: Peripapillary retinal nerve fibre layer thickness, macular retinal nerve fibre layer thickness, macular ganglion cell layer thickness and retinal thickness. RESULTS: 90 patients were included: 29 children who recovered from COVID-19 and 61 controls. Patients with COVID-19 presented an increase in global peripapillary retinal nerve fibre layer thickness (mean difference 7.7; 95% CI 3.4 to 12.1), temporal superior (mean difference 11.0; 95% CI 3.3 to 18.6), temporal inferior (mean difference 15.6; 95% CI 6.5 to 24.7) and nasal (mean difference 9.8; 95% CI 2.9 to 16.7) sectors. Macular retinal nerve fibre layer analysis showed decreased thickness in the nasal outer (p=0.011) and temporal inner (p=0.036) sectors in patients with COVID-19, while macular ganglion cell layer thickness increased in these sectors (p=0.001 and p=0.015, respectively). No differences in retinal thickness were noted. CONCLUSIONS: Children with recent history of COVID-19 present significant changes in peripapillary and macular OCT analyses.
Asunto(s)
COVID-19/complicaciones , Fibras Nerviosas/patología , Nervio Óptico/diagnóstico por imagen , Células Ganglionares de la Retina/patología , Adolescente , COVID-19/inmunología , COVID-19/virología , Estudios de Casos y Controles , Niño , Estudios de Cohortes , Voluntarios Sanos , Humanos , Mácula Lútea/citología , Mácula Lútea/diagnóstico por imagen , Mácula Lútea/inmunología , Mácula Lútea/patología , Masculino , Fibras Nerviosas/inmunología , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/inmunología , Enfermedades del Sistema Nervioso/patología , Nervio Óptico/inmunología , Nervio Óptico/patología , Tamaño de los Órganos , Células Ganglionares de la Retina/inmunología , SARS-CoV-2/inmunología , Tomografía de Coherencia Óptica/estadística & datos numéricosRESUMEN
Neuromyelitis optica spectrum disorder (NMOSD), a relapsing autoimmune disease of the central nervous system, mainly targets the optic nerve and spinal cord. To date, all attempts at the establishment of NMOSD animal models have been based on neuromyelitis optica immunoglobulin G antibody (NMO-IgG) and mimic the disease in part. To solve this problem, we developed a rodent model by opening the blood-brain barrier (BBB) with low frequency ultrasound, followed by injection of NMO-IgG from NMOSD patients and complement to mice suffering pre-existing neuroinflammation produced by experimental autoimmune encephalomyelitis (EAE). In this study, we showed that ultrasound with NMO-IgG and complement caused marked inflammation and demyelination of both spinal cords and optic nerves compared to blank control group, as well as glial fibrillary acidic protein (GFAP) and aquaporin-4 (AQP4) loss of spinal cords and optic nerves compared to EAE mice and EAE mice with only BBB opening. In addition, magnetic resonance imaging (MRI) revealed optic neuritis with spinal cord lesions. We further demonstrated eye segregation defects in the dorsal lateral geniculate nucleus (dLGN) of these NMOSD mice.
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Proteínas del Sistema Complemento/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Inmunoglobulina G/inmunología , Neuromielitis Óptica/inmunología , Animales , Acuaporina 4/metabolismo , Barrera Hematoencefálica/metabolismo , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/diagnóstico por imagen , Encefalomielitis Autoinmune Experimental/metabolismo , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Imagen por Resonancia Magnética , Ratones Endogámicos C57BL , Neuromielitis Óptica/diagnóstico por imagen , Neuromielitis Óptica/metabolismo , Nervio Óptico/diagnóstico por imagen , Nervio Óptico/inmunología , Nervio Óptico/metabolismo , Médula Espinal/diagnóstico por imagen , Médula Espinal/inmunología , Médula Espinal/metabolismo , Ondas UltrasónicasRESUMEN
NMOSD is a rare but severe relapsing remitting demyelinating disease that affects both adults and children. Most patients have pathogenic antibodies that target the central nervous system AQP4 protein. This review provides an update on our current understanding of the disease pathophysiology and describes the clinical, paraclinical features and therapeutic management of the disease.
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Anticuerpos/inmunología , Acuaporina 4/genética , Inmunoglobulina G/genética , Neuromielitis Óptica/genética , Anticuerpos/genética , Acuaporina 4/inmunología , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/patología , Humanos , Inmunoglobulina G/inmunología , Neuromielitis Óptica/inmunología , Neuromielitis Óptica/patología , Nervio Óptico/inmunología , Nervio Óptico/patología , Médula Espinal/inmunología , Médula Espinal/patologíaRESUMEN
Neuroinflammation has been put forward as a mechanism triggering axonal regrowth in the mammalian central nervous system (CNS), yet little is known about the underlying cellular and molecular players connecting these two processes. In this study, we provide evidence that MMP2 is an essential factor linking inflammation to axonal regeneration by using an in vivo mouse model of inflammation-induced axonal regeneration in the optic nerve. We show that infiltrating myeloid cells abundantly express MMP2 and that MMP2 deficiency results in reduced long-distance axonal regeneration. However, this phenotype can be rescued by restoring MMP2 expression in myeloid cells via a heterologous bone marrow transplantation. Furthermore, while MMP2 deficiency does not affect the number of infiltrating myeloid cells, it does determine the coordinated expression of pro- and anti-inflammatory molecules. Altogether, in addition to its role in axonal regeneration via resolution of the glial scar, here, we reveal a new mechanism via which MMP2 facilitates axonal regeneration, namely orchestrating the expression of pro- and anti-inflammatory molecules by infiltrating innate immune cells.
Asunto(s)
Axones/inmunología , Trasplante de Médula Ósea , Metaloproteinasa 2 de la Matriz/genética , Regeneración Nerviosa/inmunología , Traumatismos del Nervio Óptico/inmunología , Nervio Óptico/inmunología , Animales , Antígenos Ly/genética , Antígenos Ly/inmunología , Axones/ultraestructura , Receptor 1 de Quimiocinas CX3C/genética , Receptor 1 de Quimiocinas CX3C/inmunología , Movimiento Celular , Proteína GAP-43/genética , Proteína GAP-43/inmunología , Regulación de la Expresión Génica , Inmunidad Innata , Inflamación , Antígenos Comunes de Leucocito/genética , Antígenos Comunes de Leucocito/inmunología , Metaloproteinasa 2 de la Matriz/deficiencia , Metaloproteinasa 2 de la Matriz/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Mieloides/citología , Células Mieloides/inmunología , Regeneración Nerviosa/genética , Nervio Óptico/metabolismo , Traumatismos del Nervio Óptico/genética , Traumatismos del Nervio Óptico/patología , Retina/inmunología , Retina/lesiones , Retina/metabolismo , Trasplante Heterólogo , Irradiación Corporal TotalRESUMEN
AIM: To investigate the effects of resveratrol on oxidative stress and inflammation parameters and histological alterations in cisplatin-induced optic nerve damage in a mouse model. MATERIAL AND METHOD: Thirty-six albino Wistar male rats were divided into three groups as control, 5 mg/kg cisplatin-administered (Cis) and 5 mg/kg cisplatin + 25 mg/kg resveratrol-administered (Cis + Res) animals. At the end of the experimental period, the rats were sacrificed with high-dose (50 mg/kg) thiopental sodium, and their optic nerves were dissected. Malondialdehyde (MDA), total glutathione (tGSH), total oxidant status (TOS), total antioxidant status (TAS), tumour necrosis factor alpha (TNF-α), nuclear factor kappa B (NF-KB) levels, and histopathological findings were assessed using the optic nerve tissues. RESULTS: In the Cis + Res group, the MDA, TOS, OSI, TNF-a and NFK-B levels were significantly lower and the tGSH and TAS levels were significantly higher compared with the Cis group (P = 0.001). In histological evaluations, there were dilated and congested blood vessels, destruction, oedema, degeneration, haemorrhage, and proliferating capillaries indicating the presence of inflammation and damage only in the Cis-administered group. However, in the Cis + Res group, the histological findings were very similar to the healthy controls. CONCLUSION: Resveratrol is a promising neuroprotective agent for cisplatin-induced optic nerve toxicity with its anti-oxidant and anti-inflammatory effects. Further investigations are needed to evaluate the possible therapeutic effects on other optic nerve toxicities.
Asunto(s)
Cisplatino/efectos adversos , Fármacos Neuroprotectores/administración & dosificación , Traumatismos del Nervio Óptico/tratamiento farmacológico , Nervio Óptico/efectos de los fármacos , Resveratrol/administración & dosificación , Animales , Modelos Animales de Enfermedad , Humanos , Masculino , Nervio Óptico/inmunología , Nervio Óptico/patología , Traumatismos del Nervio Óptico/inducido químicamente , Traumatismos del Nervio Óptico/inmunología , Traumatismos del Nervio Óptico/patología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/inmunología , RatasRESUMEN
Neuromyelitis optica (NMO) is an immune-mediated demyelinative disorder of the central nervous system affecting mainly the optical nerves and the spinal cord. The recurrent course of the disease, with exacerbations and incomplete remissions, causes accumulating disability, which has a profound impact upon patients' quality of life. The discovery of antibodies against aquaporin 4 (AQP4) and their leading role in NMO etiology and the formulation of diagnostic criteria have improved appropriate recognition of the disease. In recent years, there has been rapid progress in understanding the background of NMO, leading to an increasing range of treatment options. On the basis of a review of the relevant literature, the authors present currently available therapeutic strategies for NMO as well as ongoing research in this field, with reference to key points of immune-mediated processes involved in the background of the disease.
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Acuaporina 4/inmunología , Neuromielitis Óptica/inmunología , Neuromielitis Óptica/terapia , Nervio Óptico/inmunología , Médula Espinal/inmunología , Acuaporina 4/metabolismo , Autoanticuerpos/inmunología , Humanos , Inmunoglobulina G/inmunología , Glicoproteína Mielina-Oligodendrócito/inmunología , Neuromielitis Óptica/metabolismo , Nervio Óptico/metabolismo , Calidad de Vida , Recurrencia , Médula Espinal/metabolismoRESUMEN
The complete features of the neurological complications of coronavirus disease 2019 (COVID-19) still need to be elucidated, including associated cranial nerve involvement. In the present study we describe cranial nerve lesions seen in magnetic resonance imaging (MRI) of six cases of confirmed COVID-19, involving the olfactory bulb, optic nerve, abducens nerve, and facial nerve. Cranial nerve involvement was associated with COVID-19, but whether by direct viral invasion or autoimmunity needs to be clarified. The development of neurological symptoms after initial respiratory symptoms and the absence of the virus in the cerebrospinal fluid (CSF) suggest the possibility of autoimmunity.
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Nervio Abducens/diagnóstico por imagen , COVID-19/diagnóstico por imagen , Enfermedades de los Nervios Craneales/diagnóstico por imagen , Nervio Facial/diagnóstico por imagen , Bulbo Olfatorio/diagnóstico por imagen , Nervio Óptico/diagnóstico por imagen , Nervio Abducens/inmunología , Nervio Abducens/patología , Nervio Abducens/virología , Adulto , Anciano , Autoinmunidad , COVID-19/inmunología , COVID-19/patología , COVID-19/virología , Enfermedades de los Nervios Craneales/inmunología , Enfermedades de los Nervios Craneales/patología , Enfermedades de los Nervios Craneales/virología , Nervio Facial/inmunología , Nervio Facial/patología , Nervio Facial/virología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Neuroimagen , Bulbo Olfatorio/inmunología , Bulbo Olfatorio/patología , Bulbo Olfatorio/virología , Nervio Óptico/inmunología , Nervio Óptico/patología , Nervio Óptico/virología , SARS-CoV-2/patogenicidadRESUMEN
BACKGROUND: Several neuroimaging studies demonstrated that optic neuritis (ON) leads to functional and anatomical architecture changes in the brain. The alterations of interhemispheric functional connectivity (IFC) in patients with AQP4-ON and myelin oligodendrocyte glycoprotein (MOG)-ON are not well understood. PURPOSE: To investigate the differential patterns of VMHC in patients with AQP4-ON and MOG-ON. MATERIAL AND METHODS: Twenty-one patients with AQP4-ON, 11 patients with MOG-ON, and 34 healthy controls underwent resting-state MRI scans. One-way ANOVA was used to identify regions in which the zVMHC differed among the three groups. Post hoc two-sample t-tests were then conducted to compare zVMHC values between pairs of groups. Pearson correlation analysis was conducted to reveal relationships between mean zVMHC values and clinical variables in the AQP4-ON and MOG-ON groups. RESULTS: The results revealed significant differences in zVMHC values in the PreCG among the three groups. Compared to the control group: the AQP4-ON group showed significantly lower VMHC values in the superior temporal gyrus, inferior frontal gyrus, and PreCG; and the MOG-ON group showed significantly higher zVMHC values in the PostCG. Compared to the AQP4-ON group, the MOG-ON group showed significantly lower zVMHC values in the PreCG/PostCG (voxel-level P<0.01, GRF correction, cluster-level P<0.05). CONCLUSION: Patients with AQP4-ON and those with MOG-ON showed abnormal VMHC in the motor cortices, sensorimotor cortices, and frontal lobe, possibly indicating impaired sensorimotor function in patients with ON. Moreover, differential patterns of VMHC in patients with AQP4-ON, compared to patients with MOG-ON, might serve as a clinical indicator for classification of ON.
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Acuaporina 4/inmunología , Imagen por Resonancia Magnética/métodos , Glicoproteína Mielina-Oligodendrócito/inmunología , Neuritis Óptica/diagnóstico por imagen , Neuritis Óptica/inmunología , Adulto , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Nervio Óptico/diagnóstico por imagen , Nervio Óptico/inmunologíaRESUMEN
Antitumour necrosis factor alpha agents are important treatments in many inflammatory conditions including rheumatoid arthritis, psoriatic arthritis and the inflammatory bowel diseases. However, there have been case reports of optic neuritis and other demyelinating diseases as complications of these agents. This case report presents a patient with ulcerative colitis on infliximab who presented with sudden onset mono-ocular visual field loss and highlights the diagnosis and management of infliximab-induced optic neuritis.
Asunto(s)
Ceguera/inmunología , Colitis Ulcerosa/tratamiento farmacológico , Fármacos Gastrointestinales/efectos adversos , Infliximab/efectos adversos , Neuritis Óptica/inmunología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Ceguera/diagnóstico , Ceguera/tratamiento farmacológico , Colitis Ulcerosa/inmunología , Sustitución de Medicamentos , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Nervio Óptico/diagnóstico por imagen , Nervio Óptico/efectos de los fármacos , Nervio Óptico/inmunología , Neuritis Óptica/complicaciones , Neuritis Óptica/diagnóstico , Neuritis Óptica/tratamiento farmacológico , Prednisolona/uso terapéutico , Tomografía de Coherencia Óptica , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/inmunología , Agudeza Visual , Pruebas del Campo Visual , Campos VisualesRESUMEN
Transected axons typically fail to regenerate in the central nervous system (CNS), resulting in chronic neurological disability in individuals with traumatic brain or spinal cord injury, glaucoma and ischemia-reperfusion injury of the eye. Although neuroinflammation is often depicted as detrimental, there is growing evidence that alternatively activated, reparative leukocyte subsets and their products can be deployed to improve neurological outcomes. In the current study, we identify a unique granulocyte subset, with characteristics of an immature neutrophil, that had neuroprotective properties and drove CNS axon regeneration in vivo, in part via secretion of a cocktail of growth factors. This pro-regenerative neutrophil promoted repair in the optic nerve and spinal cord, demonstrating its relevance across CNS compartments and neuronal populations. Our findings could ultimately lead to the development of new immunotherapies that reverse CNS damage and restore lost neurological function across a spectrum of diseases.
Asunto(s)
Axones/metabolismo , Comunicación Celular , Sistema Nervioso Central/citología , Sistema Nervioso Central/metabolismo , Regeneración Nerviosa , Neuronas/metabolismo , Neutrófilos/metabolismo , Animales , Biomarcadores , Plasticidad de la Célula/inmunología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/inmunología , Sistema Nervioso Central/inmunología , Péptidos y Proteínas de Señalización Intercelular/biosíntesis , Ratones , Infiltración Neutrófila/inmunología , Neutrófilos/inmunología , Nervio Óptico/inmunología , Nervio Óptico/metabolismo , Receptores de Interleucina-8B/metabolismo , Médula Espinal/citología , Médula Espinal/metabolismo , Transcriptoma , Zimosan/metabolismo , Zimosan/farmacologíaRESUMEN
Glaucoma is a complex neurodegenerative disease involving RGC axons, somas, and synapses at dendrites and axon terminals. Recent research advancements in the field have revealed a bigger picture of glaucomatous neurodegeneration that encompasses multiple stressors, multiple injury sites, multiple cell types, and multiple signaling pathways for asynchronous degeneration of RGCs during a chronic disease period. Optic nerve head is commonly viewed as the critical site of injury in glaucoma, where early injurious insults initiate distal and proximal signaling for axonal and somatic degeneration. Despite compartmentalized processes for degeneration of RGC axons and somas, there are intricate interactions between the two compartments and mechanistic overlaps between the molecular pathways that mediate degeneration in axonal and somatic compartments. This review summarizes the recent progress in the molecular understanding of RGC degeneration in glaucoma and highlights various etiological paths with biomechanical, metabolic, oxidative, and inflammatory components. Through this growing body of knowledge, the glaucoma community moves closer toward causative treatment of this blinding disease.
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Glaucoma , Inflamación , Degeneración Nerviosa , Nervio Óptico , Células Ganglionares de la Retina , Animales , Glaucoma/inmunología , Glaucoma/metabolismo , Glaucoma/patología , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Degeneración Nerviosa/inmunología , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Nervio Óptico/inmunología , Nervio Óptico/metabolismo , Nervio Óptico/patología , Células Ganglionares de la Retina/inmunología , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/patologíaRESUMEN
A 30-year-old woman presented with recurrent hiccups, vomiting and painful diminution of vision and gait instability for 1 day. She had one-and-a-half syndrome, bilateral seventh cranial nerve paresis with bilateral symptomatic optic neuritis and left-sided ataxic haemiparesis. We described her disorder as the 'twenty syndrome' (11/2+7+7+2+2+½=20). MRI of her brain revealed demyelination predominantly in right posterolateral aspect of pons, medulla and bilateral optic nerves. Serum antiaquaporin-4 antibody came out positive. Thus, she was diagnosed as neuromyelitis optica spectrum disorder (NMOSD). She responded brilliantly to immunosuppressive therapy. This is the first ever reported case of the 'twenty syndrome' secondary to cerebral NMOSD.
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Ataxia Cerebelosa/inmunología , Parálisis Facial/inmunología , Inmunosupresores/uso terapéutico , Neuromielitis Óptica/diagnóstico , Trastornos de la Motilidad Ocular/inmunología , Neuritis Óptica/inmunología , Adulto , Acuaporina 4/inmunología , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Ataxia Cerebelosa/sangre , Ataxia Cerebelosa/diagnóstico , Ataxia Cerebelosa/tratamiento farmacológico , Parálisis Facial/sangre , Parálisis Facial/diagnóstico , Parálisis Facial/tratamiento farmacológico , Femenino , Humanos , Imagen por Resonancia Magnética , Neuromielitis Óptica/sangre , Neuromielitis Óptica/complicaciones , Neuromielitis Óptica/inmunología , Trastornos de la Motilidad Ocular/sangre , Trastornos de la Motilidad Ocular/diagnóstico , Trastornos de la Motilidad Ocular/tratamiento farmacológico , Nervio Óptico/diagnóstico por imagen , Nervio Óptico/inmunología , Neuritis Óptica/sangre , Neuritis Óptica/diagnóstico , Neuritis Óptica/tratamiento farmacológico , Tegmento Pontino/diagnóstico por imagen , Tegmento Pontino/inmunología , Síndrome , Resultado del TratamientoRESUMEN
Glaucoma is identified by an irreversible retinal ganglion cell (RGC) loss and optic nerve damage. Over the past few years, the immune system gained importance in its genesis. In a glaucoma-like animal model with intraocular S100B injection, RGC death occurs at 14 days. In an experimental autoimmune glaucoma model with systemic S100B immunization, a loss of RGCs is accompanied by a decreased synaptic signal at 28 days. Here, we aimed to study synaptic alterations in these two models. In one group, rats received a systemic S100B immunization (n = 7/group), while in the other group, S100B was injected intraocularly (n = 6-7/group). Both groups were compared to appropriate controls and investigated after 14 days. While inhibitory post-synapses remained unchanged in both models, excitatory post-synapses degenerated in animals with intraocular S100B injection (p = 0.03). Excitatory pre-synapses tendentially increased in animals with systemic S100B immunization (p = 0.08) and significantly decreased in intraocular ones (p = 0.04). Significantly more n-methyl-d-aspartate (NMDA) receptors (both p ≤ 0.04) as well as gamma-aminobutyric acid (GABA) receptors (both p < 0.03) were observed in S100B animals in both models. We assume that an upregulation of these receptors causes the interacting synapse types to degenerate. Heightened levels of excitatory pre-synapses could be explained by remodeling followed by degeneration.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Glaucoma/inmunología , Receptores de GABA/inmunología , Receptores de N-Metil-D-Aspartato/inmunología , Subunidad beta de la Proteína de Unión al Calcio S100/toxicidad , Sinapsis/inmunología , Animales , Enfermedades Autoinmunes/inducido químicamente , Enfermedades Autoinmunes/patología , Modelos Animales de Enfermedad , Glaucoma/inducido químicamente , Glaucoma/patología , Presión Intraocular/efectos de los fármacos , Masculino , Nervio Óptico/inmunología , Nervio Óptico/patología , Ratas , Ratas Endogámicas Lew , Ratas Wistar , Células Ganglionares de la Retina/inmunología , Células Ganglionares de la Retina/patología , Subunidad beta de la Proteína de Unión al Calcio S100/inmunología , Sinapsis/patologíaRESUMEN
Optomotor response is increasingly used in preclinical research for evaluating the visual function in rodents. However, the most suitable measuring protocol for specific scientific questions is not always established. We aimed to determine the optimal parameters for visual function analysis in experimental autoimmune encephalomyelitis optic neuritis (EAEON), an animal model for multiple sclerosis. Contrast sensitivity as well as spatial frequency both had a low variance and a good test-retest reliability. Also, both parameters were able to differentiate between the EAEON and the control group. Correlations with the retinal degeneration, assessed by optical coherence tomography, the infiltration of immune cells, and the clinical disability score revealed that spatial frequency was superior to contrast sensitivity analysis. We therefore conclude that spatial frequency testing is better suited as visual acuity assessment in C57Bl/6 J EAEON mice. Furthermore, contrast sensitivity measurements are more time consuming, possibly leading to more stress for the animals.
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Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Nervio Óptico/inmunología , Nervio Óptico/patología , Tomografía de Coherencia Óptica/métodos , Agudeza Visual/fisiología , Animales , Encefalomielitis Autoinmune Experimental/diagnóstico por imagen , Femenino , Ratones , Ratones Endogámicos C57BL , Estimulación LuminosaRESUMEN
Dry eye disease (DED) is a multifactorial disease of the ocular surface, characterized by loss of tear film homeostasis and ocular symptoms, in which neurosensory abnormalities have recently been shown to play an etiological role. Although the role of inflammation has been widely studied in DED, the kinetics of immune cells of the ocular surface in this complex disease are hereto unclear. Herein, we utilized intravital multiphoton imaging on transgenic mice to investigate the 3D morphology and kinetics of conventional dendritic cells (cDCs) and the role of ocular surface sensory nerves in regulating them in both the naïve state and experimental DED. Mice with DED had significantly lower tear secretion (p < 0.01), greater corneal fluorescein staining (p < 0.001), and higher cDC density in the ocular surface (p < 0.05), compared to naïve mice. cDCs in DED mice showed morphological alterations in the limbus, exhibiting smaller surface area (p < 0.001) and volume (p < 0.001) compared to naïve mice. Furthermore, corneal cDCs showed greater sphericity in DED mice compared to naïve mice (p < 0.01). In addition, limbal cDCs displayed significantly increased migratory kinetics in DED, including mean track speed, 3D instantaneous velocity, track length, and displacement, compared to naïve mice (all p < 0.05). In mice with DED, cDCs showed a higher meandering index in the limbus compared to central cornea (p < 0.05). In DED, cDCs were less frequently found in contact with nerves in the limbus, peripheral, and central cornea (p < 0.05). cDCs in contact with nerves demonstrated a larger surface area (p < 0.001) and volume (p < 0.001), however, they exhibited less sphericity (p < 0.05) as compared to cDCs not in contact with nerves in naïve mice. Importantly, cDCs in contact with nerves during DED had a decreased track length, displacement, mean track speed, and 3D instantaneous velocity compared to those not in contact with nerves (all p < 0.05). Taken together, we present in vivo evidence of altered cDC kinetics and 3D morphology in DED. Furthermore, apparent neuronal contact significantly alters cDC kinetics and morphological characteristics, suggesting that ocular surface nerves may play a direct role in mediating immune responses in DED.
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Células Dendríticas/inmunología , Síndromes de Ojo Seco/diagnóstico por imagen , Síndromes de Ojo Seco/inmunología , Microscopía Intravital/métodos , Limbo de la Córnea/diagnóstico por imagen , Limbo de la Córnea/inmunología , Microscopía de Fluorescencia por Excitación Multifotónica/métodos , Animales , Movimiento Celular/inmunología , Modelos Animales de Enfermedad , Femenino , Cinética , Limbo de la Córnea/inervación , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Nervio Óptico/inmunologíaRESUMEN
Autoimmune optic neuritis (AON), a model of multiple sclerosis-associated optic neuritis, is accompanied by degeneration of retinal ganglion cells (RGCs) and optic nerve demyelination and axonal loss. In order to investigate the role of N-methyl-d-aspartate (NMDA) receptors in mediating RGC degeneration, upstream changes in the optic nerve actin cytoskeleton and associated deterioration in visual function, we induced AON in Brown Norway rats by immunization with myelin oligodendrocyte glycoprotein. Subsequently, visual acuity was assessed by recording visual evoked potentials and electroretinograms prior to extraction of optic nerves for western blot analysis and retinas for quantification of RGCs. As previously reported, in Brown Norway rats RGC degeneration is observed prior to onset of immune cell infiltration and demyelination of the optic nerves. However, within the optic nerve, destabilization of the actin cytoskeleton could be seen as indicated by an increase in the globular to filamentous actin ratio. Interestingly, these changes could be mimicked by intravitreal injection of glutamate, and similarly blocked by application of the NMDA receptor blocker MK-801, leading us to propose that prior to optic nerve lesion formation, NMDA receptor activation within the retina leads to retinal calcium accumulation, actin destabilization within the optic nerve as well as a deterioration of visual acuity during AON.
Asunto(s)
Neuritis Óptica/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Retina/metabolismo , Animales , Maleato de Dizocilpina/farmacología , Encefalomielitis Autoinmune Experimental/inducido químicamente , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Potenciales Evocados Visuales/efectos de los fármacos , Potenciales Evocados Visuales/fisiología , Antagonistas de Aminoácidos Excitadores/farmacología , Femenino , Glicoproteína Mielina-Oligodendrócito/toxicidad , Nervio Óptico/efectos de los fármacos , Nervio Óptico/inmunología , Nervio Óptico/metabolismo , Neuritis Óptica/inducido químicamente , Neuritis Óptica/inmunología , Ratas , Ratas Endogámicas BN , Receptores de N-Metil-D-Aspartato/inmunología , Retina/efectos de los fármacos , Retina/inmunologíaRESUMEN
Studies have suggested an involvement of the immune system in glaucoma. Hence, a rat experimental autoimmune glaucoma model (EAG) was developed to investigate the role of the immune response. Here, we transferred this model into mice. Either 0.8 mg/mL of the optic nerve antigen homogenate (ONA; ONA 0.8) or 1.0 mg/mL ONA (ONA 1.0) were injected in 129/Sv mice. Controls received sodium chloride. Before and 6 weeks after immunization, the intraocular pressure (IOP) was measured. At 6 weeks, retinal neurons, glia cells, and synapses were analyzed via immunohistology and quantitative real-time PCR (RT-qPCR). Additionally, optic nerves were examined. The IOP stayed in the normal physiological range throughout the study (p > 0.05). A significant reduction of retinal ganglion cells (RGCs) was noted in both immunized groups (p < 0.001). Remodeling of glutamatergic and GABAergic synapses was seen in ONA 1.0 retinas. Furthermore, both ONA groups revealed optic nerve degeneration and macrogliosis (all: p < 0.001). An increase of activated microglia was noted in ONA retinas and optic nerves (p < 0.05). Both ONA concentrations led to RGC loss and optic nerve degeneration. Therefore, the EAG model was successfully transferred from rats to mice. In further studies, transgenic knockout mice can be used to investigate the pathomechanisms of glaucoma more precisely.