Abstract
Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD) are antibody mediated CNS disorders mostly affecting the optic nerve and spinal cord with potential severe impact on the visual pathway. Here, we investigated inflammation and degeneration of the visual system in a spontaneous encephalomyelitis animal model. We used double-transgenic (2D2/Th) mice which develop a spontaneous opticospinal encephalomyelitis (OSE). Retinal morphology and its function were evaluated via spectral domain optical coherence tomography (SD-OCT) and electroretinography (ERG) in 6- and 8-week-old mice. Immunohistochemistry of retina and optic nerve and examination of the retina via RT-qPCR were performed using markers for inflammation, immune cells and the complement pathway. OSE mice showed clinical signs of encephalomyelitis with an incidence of 75% at day 38. A progressive retinal thinning was detected in OSE mice via SD-OCT. An impairment in photoreceptor signal transmission occurred. This was accompanied by cellular infiltration and demyelination of optic nerves. The number of microglia/macrophages was increased in OSE optic nerves and retinas. Analysis of the retina revealed a reduced retinal ganglion cell number and downregulated Pou4f1 mRNA expression in OSE retinas. RT-qPCR revealed an elevation of microglia markers and the cytokines Tnfa and Tgfb. We also documented an upregulation of the complement system via the classical pathway. In summary, we describe characteristics of inflammation and degeneration of the visual system in a spontaneous encephalomyelitis model, characterized by coinciding inflammatory and degenerative mechanisms in both retina and optic nerve with involvement of the complement system.
Highlights
Chronic inflammatory diseases of the central nervous system (CNS) have profound implications for patients due to the potential development of disability
We show that the retina loses function in accordance with progressive neurodegeneration of retinal ganglion cells (RGCs) in line with inflammation and Abbreviations: AQP4, Aquaporin-4; CNS, Central nervous system; ERG, Electroretinography; ganglion cell layer (GCL), Ganglion cell layer; GFAP, Glial fibrillary acidic protein; H&E, Hematoxylin and eosin; inner nuclear layer (INL), Inner nuclear layer; inner plexiform layer (IPL), Inner plexiform layer; luxol fast blue (LFB), Luxol fast blue; MAC, Membrane attack complex; myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD), Myelin oligodendrocyte glycoprotein-antibody-associated disease; myelin oligodendrocyte glycoprotein (MOG), Myelin oligodendrocyte glycoprotein; MS, Multiple Sclerosis; NMOSD, Neuromyelitis optica spectrum disorder; OCT, Optical coherence tomography; outer nuclear layer (ONL), Outer nuclear layer; opticospinal encephalomyelitis (OSE), Opticospinal encephalomyelitis; RGC, Retinal ganglion cell; retinal nerve fiber layer (RNFL), Retinal nerve fiber layer; RT-qPCR, Quantitative real-time reverse transcription polymerase chain reaction
We provide evidence that early on during OSE, mice are affected by severe damage of the visual system with reduced function, retinal thinning, and severe inflammation with involvement of both the adaptive and innate immunity as well as activation of the complement system
Summary
Chronic inflammatory diseases of the central nervous system (CNS) have profound implications for patients due to the potential development of disability. While Multiple Sclerosis (MS) is the most common cause [1], there is a spectrum of relatively rare neuroinflammatory and neurodegenerative diseases such as Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein (MOG)-IgG antibody associated disease (MOGAD). 25% of patients with a NMOSD phenotype present with autoantibodies directed against MOG [2]. A robust association of anti-MOG IgG has been found with optic neuritis, myelitis and brainstem encephalitis, as well as with acute disseminated encephalomyelitis (ADEM)-like presentations [3]. MOGAD is considered as distinct disease entity with differing pathophysiological features compared to NMOSD [3, 4]. The target of MOG antibodies are oligodendrocytes; the pathogenesis in MOG+ patients is different from the astrocytopathy in aquaporin4+ (APQ4+) NMOSD [6, 7]
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