Complement-independent retinal pathology produced by intravitreal injection of neuromyelitis optica immunoglobulin G

Felix, Carol; Levin, Marc H.; Verkman, A. S.

doi:10.1186/s12974-016-0746-9

Cited by 64 publications

(50 citation statements)

References 38 publications

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“…In addition, intravitreally injected AQP4-IgG was found to deposit on Müller cells and lead to inflammation and retinal pathology. 37 It is also important to note that the distinct patterns of ERG changes in AQP4þ and AQP4À patients suggest these 2 NMOSD subgroups may have different mechanisms with regard to the involvement of astrocytes. 29 It is well known that Müller cells in the human macula have unique morphology compared with those in the peripheral retina.…”

Section: Discussionmentioning

confidence: 99%

Evidence of Müller Glial Dysfunction in Patients with Aquaporin-4 Immunoglobulin G–Positive Neuromyelitis Optica Spectrum Disorder

et al. 2019

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Purpose: To compare functional and structural changes in the retina in patients with aquaporin-4 immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). Design: Cross-sectional study; biochemical study of human retinas. Participants: A total of 181 participants, including 22 consecutive patients (44 eyes) with NMOSD, 131 patients (262 eyes) with multiple sclerosis (MS), and 28 normal subjects (56 eyes). In addition, 8 eyeballs from healthy donors were used for biochemical analysis. Methods: Full-field electroretinography (ERG) and spectral-domain OCT were performed in all the subjects. Topography of AQP4 expression and Müller glial distribution were analyzed using Western blotting and immunohistochemistry. Main Outcome Measures: Full-field ERG parameters, including amplitudes and peak times. Tissue volume of each of the retinal layers at the fovea by OCT segmentation. Levels of AQP4 expression at different retinal regions. Results: The b-wave amplitude was significantly reduced in patients with AQP4-IgGþ NMOSD in scotopic ERGs (compared with AQP4-IgG-subjects, patients with MS, and normal controls) but not in photopic ERGs. Further analysis showed that this b-wave change was mainly caused by reduction of the slow PII component, suggesting specific Müller cell dysfunction. We also found thinning of specific retinal layers at the fovea in patients with AQP4-IgGþ NMOSD, in the Henle fiber outer nuclear layer (HFONL) and the inner segment (IS) layer, but not in the inner nuclear layer (INL), outer plexiform layer (OPL), or outer segment (OS) layer. Furthermore, there was a significant association between foveal HFONL-IS complex thinning and scotopic b-wave amplitude reduction (P ¼ 0.005w0.01, fixed-effects model). Western blotting demonstrated that Müller cellespecific AQP4 was expressed at a higher level at the fovea than the peripheral retina. Immunohistochemical studies revealed that the specific foveal thinning reflected the topography of AQP4 expression and Müller glial distribution in the human macula. Conclusions: This study provides in vivo structural and functional evidence of Müller glial dysfunction in eyes of patients with AQP4-IgGþ NMOSD. Topography of retinal structural change is supported by distribution of Müller cells and patterns of AQP4 expression. The study suggests that visual electrophysiology and retinal imaging could be useful biomarkers to assess the potential retinal astrocytopathy in

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Section: Discussionmentioning

confidence: 99%

Evidence of Müller Glial Dysfunction in Patients with Aquaporin-4 Immunoglobulin G–Positive Neuromyelitis Optica Spectrum Disorder

et al. 2019

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“…This aggravates neuroinflammation which involves microglia activation and parenchymal infiltration of macrophages, granulocytes and natural killer cells from the peripheral circulation. These activated immune cells with Fc receptors can lead to astrocyte cytotoxicity via ADCC [12,31,32]. The protective effect of memantine on astrocytes likely attenuated the release of proinflammatory cytokines and chemokines from astrocytes triggered by AQP4-IgG binding, hence reduced microglia activation.…”

Section: Discussionmentioning

confidence: 99%

Memantine ameliorates motor impairments and pathologies in a mouse model of neuromyelitis optica spectrum disorders.

Yick

Tang

Ka-Fai

et al. 2020

Preprint

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Background: Neuromyelitis optica spectrum disorders (NMOSD) are central nervous system (CNS) autoimmune inflammatory demyelinating diseases characterized by recurrent episodes of acute optic neuritis and transverse myelitis. Aquaporin-4 immunoglobulin G (AQP4-IgG) autoantibodies, which target the water channel aquaporin-4 (AQP4) on astrocytic membrane, are pathogenic in NMOSD. Glutamate excitotoxicity, which is triggered by internalization of AQP4-glutamate transporter complex after AQP4-IgG binding to astrocytes, is involved in early NMOSD pathophysiologies. We studied the effects of memantine, a N-methyl-D-aspartate (NMDA) receptor antagonist, on motor impairments and spinal cord pathologies in mice which received human AQP4-IgG. Methods: Purified IgG from AQP4-IgG-seropositive NMOSD patients were passively transferred to adult C57BL/6 mice with disrupted blood-brain barrier. Memantine was administered by oral gavage. Motor impairments of the mice were assessed by beam walking test. Spinal cords of the mice were assessed by immunofluorescence and ELISA. Results: Oral administration of memantine ameliorated the motor impairments induced by AQP4-IgG, no matter the treatment was initiated before (preventive) or after (therapeutic) disease flare. Memantine profoundly reduced AQP4 and astrocyte loss, and attenuated demyelination and axonal loss in the spinal cord of mice which had received AQP4-IgG. The protective effects of memantine were associated with inhibition of apoptosis and suppression of neuroinflammation, with decrease in microglia activation and neutrophil infiltration and reduction of increase in levels of proinflammatory cytokines including interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF- α). In addition, memantine elevated growth factors including brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF) in the spinal cord. Conclusions: Our findings support that glutamate excitotoxicity and neuroinflammation plays important roles in complement-independent pathophysiology during early development of NMOSD lesions, and highlight the potential of oral memantine as a therapeutic agent in NMOSD acute attacks.

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“…In a study done using rats that attempted to produce NMO optic neuritis or retinitis, AQP4‐IgG (without complement) was delivered to the eye by a single intravitreal injection . AQP4‐IgG deposition was seen on retinal Müller cells.…”

Section: Passive Transfer Models Of Nmomentioning

confidence: 99%

Experimental animal models of aquaporin‐4‐IgG‐seropositive neuromyelitis optica spectrum disorders: progress and shortcomings

Duan

2019

Brain Pathology

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Neuromyelitis optica spectrum disorders (NMOSD) is a heterogeneous group of neuroinflammatory conditions associated with demyelination primarily in spinal cord and optic nerve, and to a lesser extent in brain. Most NMOSD patients are seropositive for IgG autoantibodies against aquaporin-4 (AQP4-IgG), the principal water channel in astrocytes. There has been interest in establishing experimental animal models of seropositive NMOSD (herein referred to as NMO) in order to elucidate NMO pathogenesis mechanisms and to evaluate drug candidates. An important outcome of early NMO animal models was evidence for a pathogenic role of AQP4-IgG. However, available animal models of NMO, based largely on passive transfer to rodents of AQP4-IgG or transfer of AQP4-sensitized T cells, often together with pro-inflammatory maneuvers, only partially recapitulate the clinical and pathological features of human NMO, and are inherently biased toward humoral or cellular immune mechanisms. This review summarizes current progress and shortcomings in experimental animal models of seropositive NMOSD, and opines on the import of advancing animal models.

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Complement-independent retinal pathology produced by intravitreal injection of neuromyelitis optica immunoglobulin G

Cited by 64 publications

References 38 publications

Evidence of Müller Glial Dysfunction in Patients with Aquaporin-4 Immunoglobulin G–Positive Neuromyelitis Optica Spectrum Disorder

Evidence of Müller Glial Dysfunction in Patients with Aquaporin-4 Immunoglobulin G–Positive Neuromyelitis Optica Spectrum Disorder

Memantine ameliorates motor impairments and pathologies in a mouse model of neuromyelitis optica spectrum disorders.

Experimental animal models of aquaporin‐4‐IgG‐seropositive neuromyelitis optica spectrum disorders: progress and shortcomings

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