Dataset Information

Impact of the anti-aquaporin-4 autoantibody on inner retinal structure, function and structure-function associations in Japanese patients with optic neuritis.

ABSTRACT:

Purpose

An autoantibody against aquaporin-4 (AQP4 Ab) is highly specific for neuromyelitis optica spectrum disorder and plays a pathogenic role in this disease. The purpose of this study was to investigate the impact of AQP4 Ab on inner retinal structure, function, and the structure-function relationships in eyes with optic neuritis.

Methods

Thirty five eyes from 25 cases who had received visual function tests and RTVue optical coherence tomography (OCT) measurement at least six months after the latest episode of optic neuritis were enrolled. Patients with multiple sclerosis were excluded. AQP4 Ab was measured using a cell-based assay. Visual acuity, mean deviation (MD) of the Humphrey visual field SITA standard 30-2 tests, retinal nerve fiber layer (RNFL), ganglion cell complex (GCC) thicknesses, and other clinical variables were compared between the AQP4 Ab-positive and -negative groups. Parameters associated with visual functions were evaluated by generalized estimating equation (GEE) models.

Results

The AQP4 Ab-positive group (20 eyes from 12 cases) had a higher proportion of bilateral involvement and longer duration of follow-up than the AQP4 Ab-negative group (15 eyes from 13 cases). Linear mixed effect models revealed worse MD and visual acuity in AQP4 Ab-positive eyes than those in AQP4 Ab-negative eyes after adjusting for within-patient inter-eye dependence, whereas there were no differences in RNFL and GCC thickness between the two groups. In seropositive eyes, GEE regression analyses revealed that depending on age and the number of recurrences of ON episodes, OCT parameters correlated strongly with MD and more weakly with visual acuity.

Conclusions

Reductions in RNFL and GCC thickness were proportional to the visual field defect in eyes with AQP4 Ab but not in eyes without AQP4 Ab. The presence of AQP4 Ab probably plays a critical role in retinal ganglion cell loss in optic neuritis.

SUBMITTER: Matsumoto Y

PROVIDER: S-EPMC5310877 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

Impact of the anti-aquaporin-4 autoantibody on inner retinal structure, function and structure-function associations in Japanese patients with optic neuritis.

Matsumoto Yoshiko Y Mori Sotaro S Ueda Kaori K Kurimoto Takuji T Kanamori Akiyasu A Yamada Yuko Y Nakashima Ichiro I Nakamura Makoto M

PloS one 20170215 2

<h4>Purpose</h4>An autoantibody against aquaporin-4 (AQP4 Ab) is highly specific for neuromyelitis optica spectrum disorder and plays a pathogenic role in this disease. The purpose of this study was to investigate the impact of AQP4 Ab on inner retinal structure, function, and the structure-function relationships in eyes with optic neuritis.<h4>Methods</h4>Thirty five eyes from 25 cases who had received visual function tests and RTVue optical coherence tomography (OCT) measurement at least six m ...[more]

PMID: 28199381

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Project description:BackgroundOptic neuritis (ON) is a common manifestation of aquaporin-4 (AQP4) antibody seropositive neuromyelitis optica (NMO). The extent of tissue damage is frequently severe, often leading to loss of visual function, and there is no curative treatment for this condition. To develop a novel therapeutic strategy, elucidating the underlying pathological mechanism using a clinically relevant experimental ON model is necessary. However, previous ON animal models have only resulted in mild lesions with limited functional impairment. In the present study, we attempted to establish a feasible ON model with severe pathological and functional manifestations using a high-affinity anti-AQP4 antibody. Subsequently, we aimed to address whether our model is suitable for potential drug evaluation by testing the effect of minocycline, a well-known microglia/macrophage inhibitor.MethodsAQP4-immunoglobulin G (IgG)-related ON in rats was induced by direct injection of a high-affinity anti-AQP4 monoclonal antibody, E5415A. Thereafter, the pathological and functional characterizations were performed, and the therapeutic potential of minocycline was investigated.ResultsWe established an experimental ON model that reproduces the histological characteristics of ON in seropositive NMO, such as loss of AQP4/glial fibrillary acidic protein immunoreactivity, immune cell infiltration, and extensive axonal damage. We also observed that our rat model exhibited severe visual dysfunction. The histological analysis showed prominent accumulation of macrophages/activated microglia in the lesion site in the acute phase. Thus, we investigated the possible effect of the pharmacological inhibition of macrophages/microglia activation by minocycline and revealed that it effectively ameliorated axonal damage and functional outcome.ConclusionsWe established an AQP4-IgG-induced ON rat model with severe functional impairments that reproduce the histological characteristics of patients with NMO. Using this model, we revealed that minocycline treatment ameliorates functional and pathological outcomes, highlighting the usefulness of our model for evaluating potential therapeutic drugs for ON in NMO.

Project description:The exact mechanisms and temporal sequence of neurodegeneration in multiple sclerosis are still unresolved. The visual pathway including its unmyelinated retinal axons, can serve as a prototypic model of neurodegeneration in experimental optic neuritis. We conducted a longitudinal study combining retinal imaging through optical coherence tomography (OCT) with immunohistochemical analyses of retinal and optic nerve tissue at various time points in experimental autoimmune encephalomyelitis (EAE).Inner retinal layer (IRL) thickness was measured in 30 EAE and 14 healthy control C57BL/6?J mice using OCT. Distribution of marker proteins was assessed by immunofluorescence staining and retinal mRNA levels were assayed using real-time PCR. Histological morphology was evaluated on light and electron microscopy images.Signs of inflammatory edema 11?days post immunisation coincided with IRL thickening, while neuro-axonal degeneration throughout the disease course contributed to IRL thinning observed after 20?days post immunisation. Retinal pathology, including axonal transport impairment, was observed early, prior to cellular infiltration (i.e. T-cells) in the optic nerve 11?days post immunisation. Yet, the effects of early retinal damage on OCT-derived readouts were outweighed by the initial inflammatory edema. Early microglial activation and astrocytosis was detected in the retina prior to retinal ganglion cell loss and persisted until 33?days post immunisation. Müller cell reactivity (i.e. aquaporin-4 and glutamine synthetase decrease) presented after 11?days post immunisation in the IRL. Severe neuro-axonal degeneration was observed in the optic nerve and retina until 33?days post immunisation.Initial signs of retinal pathology subsequent to early glial activity, suggests a need for prophylactic treatment of optic neuritis. Following early inflammation, Müller cells possibly respond to retinal pathology with compensatory mechanisms. Although the majority of the IRL damage observed is likely due to retrograde degeneration following optic neuritis, initial pathology, possibly due to gliosis, may contribute further to IRL thinning. These results add morphological substrate to our OCT findings. The extent and rapid onset of axonal and neuronal damage in this model appears relevant for testing interventions scaled to human optic neuritis.

Dataset Information

Impact of the anti-aquaporin-4 autoantibody on inner retinal structure, function and structure-function associations in Japanese patients with optic neuritis.

Purpose

Methods

Results

Conclusions

Publications

Impact of the anti-aquaporin-4 autoantibody on inner retinal structure, function and structure-function associations in Japanese patients with optic neuritis.

Similar Datasets

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