Neuromyelitis optica IgG in the cerebrospinal fluid induces astrocytopathy in optic nerve

Background: Serum immunoglobulin G targeting the astrocyte water channel aquaporin-4

(AQP4) in the central nervous system (CNS) is a biomarker for neuromyelitis optica spectrum

disease (NMOSD). Optic neuritis (ON) is believed to be immune-mediated and is associated with

AQP4-IgG in NMOSD-ON. The predilection of the optic nerve in NMOSD may partly be explained

by the dense expression of AQP4 in the optic nerve. We previously reported that AQP4-IgG in

cerebrospinal fluid (CSF) becomes widely distributed in the brain and causes complementdependent

astrocyte injury in periventricular areas and brain parenchyma.

Objective: To examine the pathogenicity of CSF AQP4-IgG on the optic nerve.

Materials and methods: Purified AQP4-IgG from an NMOSD patient was given to naïve mice as

a single intrathecal injection into CSF at the cisterna magna with human complement (C) +/- antiregulatory

protein CD59a antibody (anti-CD59a). A total of five mice received AQP4-IgG + C +

anti-CD59a, four mice received normal-IgG + C + anti-CD59a, four mice received AQP4-IgG+ C

and one normal-IgG + C. Mice were killed four days later. The optic nerves were isolated and

fixed in paraformaldehyde. Paraffin embedded optic nerves were cut into sections of 6μm, and

immunostaining was performed1. Histological changes were scored semiquantitatively 0-31.

Results: Intrathecal injection of AQP4-IgG + C induced focal astrocyte pathology with loss of

AQP4 and glial fibrillary acidic protein (GFAP) in optic nerves from all mice, which was coincident

with deposition of complement. Histopathological lesions were markedly enhanced with

extensive/long-segment astrocytopathy of optic nerve and optic chiasm involvement in AQP4-

IgG+ C + anti-CD59a treated mice. Such pathology was not seen in mice receiving normal

human IgG, C and anti-CD59a.

Conclusion: We describe the induction of ON in an animal model for NMOSD, utilizing the

intrathecal route for antibody administration, which mimics a physiological approach for the

presence of antibody in the CSF.

Reference:

1- Asgari N, Khorooshi R, Lillevang ST, Owens T. Complement-dependent pathogenicity of

brain-specific antibodies in cerebrospinal fluid. Journal of neuroimmunology 2013;254:76-82.