Characterizing Visual Manifestations in NMOSD and MOGAD Mouse Models

Vision loss is one of the debilitating consequences of autoimmune diseases affecting the central nervous system. Inflammatory attacks on the optic nerve can cause sudden and severe visual impairment, yet long-term outcomes vary dramatically between patients. While some recover nearly normal vision, others are left in permanent blindness.

Two diseases that illustrate this contrast are Neuromyelitis Optica Spectrum Disorder (NMOSD) and Myelin Oligodendrocyte Glycoprotein (MOG) Antibody–Associated Disease (MOGAD). Both frequently present with Optic Neuritis, but follow markedly different clinical trajectories. NMOSD often results in severe and irreversible vision loss despite treatment, whereas patients with MOGAD typically regain much of their vision, even after pronounced inflammation.

What drives these opposing outcomes remains unclear. Since the underlying disease mechanisms cannot easily be studied in patients, researchers rely on animal models to investigate why these diseases lead to such different visual outcomes.

At the Translational Neuroimmunology Group at the University Hospital Bern, Anke Salmen and Jana Remlinger sought to answer this question using antibody-driven Experimental Autoimmune Encephalomyelitis (EAE). EAE is the most widely used animal model for studying autoimmune disorders of the Central Nervous System (CNS), particularly multiple sclerosis. Traditionally induced through active immunization with myelin-derived peptides, the model can be adapted to reproduce key pathological features of diseases such as MOGAD and NMOSD. Across these disease models, optic neuritis is a common manifestation, providing a valuable preclinical platform for investigating visual dysfunction and tissue injury. Using these models, the researchers sought to determine whether disease-specific EAE variants could reproduce the contrasting visual outcomes observed in patients and reveal distinct patterns of visual dysfunction, retinal injury, and optic nerve damage.

Understanding NMOSD and MOGAD in the Clinical Context

Although NMOSD and MOGAD are both autoimmune conditions affecting the CNS, they target different cellular proteins.

In NMOSD, AQP4-IgG1 antibodies target aquaporin-4 channels on astrocyte end-feet and retinal Müller cells. This interaction triggers complement-dependent cytotoxicity, leading to astrocyte death, secondary demyelination, and often devastating, permanent visual disability. By contrast, MOGAD is driven by igG1 antibodies directed against MOG, resulting in primary demyelination and oligodendrocyte loss.  Although Optic neuritis is common in both diseases, patients with MOGAD generally experience substantially better visual recovery.

Visual Function and Retinal Structure Show Limited Disease-Specific Differences

If these models accurately mimic human disease, should they not also recapitulate the striking differences in visual outcomes observed in patients? To answer this question, the researchers assessed visual acuity throughout disease progression using Striatech’s OptoDrum and monitored retinal structure using Optical Coherence Tomography (OCT).

Surprisingly, both antibody models showed very similar visual deficits. Rather than reproducing the severe visual loss characteristic for NMOSD and the comparatively favorable recovery seen in MOGAD, both groups exhibited pronounced reductions in visual acuity. OCT imaging likewise displayed thinning of the ganglion cell complex (GCC) and loss of retinal ganglion cells in both disease models, with no clear disease-specific differences.

One finding nevertheless stood out. Across all animals, GCC thinning closely correlated with impaired mobility during the chronic disease phase. This association suggests that retinal degeneration reflects overall neurological disability, highlighting OCT as a potential non-invasive biomarker of neurodegeneration.

Histological Analysis Reveals Subtle Differences

Although functional vision and retinal structure appeared remarkably similar, histological analyses revealed subtle distinctions between the disease models.

The NMOSD-like model exhibited earlier optic nerve inflammation and greater immune cell infiltration than the MOGAD-like model. However, these differences did not translate into distinct retinal pathologies. Lesions lacked disease-specific characteristics, and Müller cell activation, the hallmark of AQP4-mediated astrocyte injury, did not differ significantly between the two groups.

The authors suggest that this may reflect a limitation of the model itself. Because antibodies were administered systemically, complement activation and AQP4 loss remained limited, potentially preventing the development of the compartmentalized astrocyte pathology that characterizes human NMOSD.

What Can These Models Teach Us?

Rather than reproducing the divergent visual trajectories observed in patients, the antibody-driven EAE models showed broadly similar patterns of retinal degeneration and visual dysfunction. The strong T-cell-mediated inflammatory environment triggered by the initial immunization with the MOG35–55 peptide may simply overshadow the more subtle differences between astrocyte-targeted and myelin-targeted disease mechanisms.

Importantly, however, the study also highlights the value of retinal imaging beyond disease modelling. The close association between retinal ganglion cell loss, GCC thinning, and mobility impairment supports the growing view that the retina offers an accessible window into neurodegeneration. As OCT is already widely used in clinical practice, retinal measurements may prove valuable for monitoring disease progression across inflammatory disorders of the CNS.

Remlinger and colleagues provide one of the most comprehensive characterizations of visual pathology in antibody-driven EAE models to date. Although further refinement will be necessary to better capture the distinct biology of NMOSD and MOGAD, their work reinforces the translational importance of the visual system, not only as a target of autoimmune disease, but also as a valuable biomarker for CNS damage.

Abbreviation glossary:

NMOSD – Neuromyelitis Optica Spectrum Disorder
MOGAD – MOG Antibody–Associated Disease
EAE – Experimental Autoimmune Encephalomyelitis
CNS – Central nervous system
MOG – Myelin Oligodendrocyte Glycoprotein
GCC – Ganglion Cell Complex
OCT – Optical Coherence Tomography

Source material:

1. Remlinger J, Bagnoud M, Meli I, Massy M, Linington C, Chan A, Bennett JL, Hoepner R, Enzmann V, Salmen A. Modelling MOG antibody-associated disorder and neuromyelitis optica spectrum disorder in animal models: spinal cord manifestations. Mult Scler Relat Disord. 2023;78:104892. doi:10.1016/j.msard.2023.104892​

Original source:

Remlinger J, Bagnoud M, Meli I, Massy M, Hoepner R, Linington C, Chan A, Bennett JL, Enzmann V, Salmen A. Modeling MOG antibody-associated disorder and neuromyelitis optica spectrum disorder in animal models: visual system manifestations. Neurol Neuroimmunol Neuroinflamm. 2023;10(5):e200141. doi:10.1212/NXI.0000000000200141

Blog author: Emilia Kawecka, Technical University of Munich, Student Assistant at Striatech