Experimental mouse model of optic neuritis with inflammatory demyelination produced by passive transfer of neuromyelitis optica-immunoglobulin G

Nithi Asavapanumas,Julien Ratelade,Marc H Levin,Jeffrey L Bennett,Marios C Papadopoulos,Alan S Verkman

doi:10.1186/1742-2094-11-16

Abstract

BackgroundAlthough optic neuritis (ON) is a defining feature of neuromyelitis optica (NMO), appropriate animal models of NMO ON are lacking. Most NMO patients are seropositive for immunoglobulin G autoantibodies (NMO-IgG) against the astrocyte water channel aquaporin-4 (AQP4).MethodsSeveral approaches were tested to develop a robust, passive-transfer mouse model of NMO ON, including NMO-IgG and complement delivery by: (i) retrobulbar infusion; (ii) intravitreal injection; (iii) a single intracranial injection near the optic chiasm; and (iv) 3-days continuous intracranial infusion near the optic chiasm.ResultsLittle ON or retinal pathology was seen using approaches (i) to (iii). Using approach (iv), however, optic nerves showed characteristic NMO pathology, with loss of AQP4 and glial fibrillary acidic protein immunoreactivity, granulocyte and macrophage infiltration, deposition of activated complement, demyelination and axonal injury. Even more extensive pathology was created in mice lacking complement inhibitor protein CD59, or using a genetically modified NMO-IgG with enhanced complement effector function, including significant loss of retinal ganglion cells. In control studies, optic nerve pathology was absent in treated AQP4-deficient mice, or in wild-type mice receiving control (non-NMO) IgG and complement.ConclusionPassive transfer of NMO-IgG and complement by continuous infusion near the optic chiasm in mice is sufficient to produce ON with characteristic NMO pathology. The mouse model of NMO ON should be useful in further studies of NMO pathogenesis mechanisms and therapeutics.

Highlights

Optic neuritis (ON) is a defining feature of neuromyelitis optica (NMO), appropriate animal models of NMO optic neuritis (ON) are lacking
Passive transfer of neuromyelitis optica immunoglobulin G antibody and complement via retrobulbar infusion, intravitreal injection or single perichiasmal injection does not produce optic neuritis Motivated by the success in creating NMO pathology in mouse brain by passive transfer of NMO-IgG and human complement by intracerebral injection [23], several approaches were tried to create ON or retinal cytotoxicity in mice
We first delivered NMO-IgG and complement to the anterior optic nerve by injection approximately 2 mm lateral to the anterior optic nerve following its exposure by lateral canthotomy

Summary

Introduction

Optic neuritis (ON) is a defining feature of neuromyelitis optica (NMO), appropriate animal models of NMO ON are lacking. Neuromyelitis optica (NMO) is an autoimmune inflammatory disease of the central nervous system that causes demyelinating lesions in optic nerve and spinal cord, leading to loss of visual and motor function [1,2,3]. A specific feature of NMO is the presence of serum immunoglobulin G (IgG) autoantibodies (NMO-IgG) against astrocyte water channel aquaporin-4 (AQP4) [4,5]. Disease-relevant animal models of NMO are important for investigating pathogenesis mechanisms, such as the role of inflammatory effector cells [14,15,16] and for testing of potential therapeutics such as antibodies targeting AQP4 [17] or complement [18,19]. Due in part to the limited diffusion of AQP4-IgG and complement from the injection site, pathology in this model was confined to a small region around the injection site, sparing the optic nerves

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