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Characterisation of axonal degeneration during autoimune optic neuritis

Stojic, Aleksandar

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Abstract

The model of experimental autoimmune encephalomyelitis (EAE) is the most common model for studying pathological processes in multiple sclerosis (MS). In a variant of this model, induced by immunisation of Brown Norway rats with myelin oligodendrocyte glycoprotein (MOG), pathological mechanisms reflects many aspects of MS, observed by the activation of adaptive, innate and humoral immune response (Fairless et al., 2012). In addition to “the classical EAE pathology” characterised by inflammatory demyelination of the spinal cord, these animals also develop autoimmune optic neuritis (AON). The dynamics of the pathological events in AON are similar to those observed in acute optic neuritis in patients, a common early manifestation of MS. Taking this into consideration, the aim of this study was to provide a detailed characterisation of the optic nerve pathology during the course of AON in order to gain further insight into mechanisms of axonal injury and visual dysfunction associated with optic neuritis. Testing of visual functions by recording of visual evoked potentials (VEPs) revealed a decrease in visual acuity already during the induction phase of AON. During this phase, major pathological changes (such as inflammatory demyelination and axonal loss) in the optic nerve were still absent. However detailed examination of the optic nerve revealed that the observed visual impairment is timed with disruptions in axonal domains involved in saltatory conduction of action potentials (nodes of Ranvier and paranodes). Further evidence of stress was detected in both compartments of paranodal axon-glia junctions observed by alternation in the axonal neurofilament cytoskeleton and increased production of alpha B-crystallin (cryαB), a heat shock protein involved in oligodendrocyte stress response. Observed signs of stress were more prominent in the optic nerve head (ONH), the area which was also characterised by increased numbers of activated microglia and the deposition of autoantibodies. Following the onset of the clinical disease phase animals were characterised with greater impairments in visual functions and with the presence of inflammatory demyelination and increasing signs of axonal injury in optic nerves. In addition to increased expression of cryαB, a portion of oligodendrocytes associated with inflammatory lesions underwent the process of apoptosis. In order to investigate the origins of observed axonal and oligodendroglial stress and their contribution to disrupted axon-glia paranodal junction in the late induction phase, two different approaches were made. Firstly, the oligodendrocyte compartment was targeted by auto-antibodies through the transfer of sera from MOG-immunised into naïve animals. This led to deposition of auto-antibodies and the presence of oligodendrocyte stress in the ONH, in a similar manner to that observed in the late induction phase. Secondly, a model of primary retinal injury by intravitreal injection of glutamate was performed and successfully mimicked aspects of the retinal pathology characteristic of the early induction phase. This led to the presence of axonal stress in optic nerves in the similar extent to one observed in the late induction phase of AON. In both instances, the observed signs of stress did not translate across the paranodal axon-glia junction to the other compartment. This suggests that axons and oligodendrocytes could be targeted independently during the induction phase of AON by mechanisms involving a primary retinal insult and the actions of the humoral immune response. Collectively, the pathological image observed in the induction phase of AON shares great similarities with the pathology of normal-appearing white matter in MS, in terms of both axonal and oligodendroglial stress, further suggesting that the model of AON is useful for studying early degenerative processes in MS. Observed disruptions of axonal domains in the induction phase of AON could serves as a structural correlate of impairment of visual functions. These findings could be relevant for human studies, particularly in a sub-set of MS patients which are characterised by impaired visual functions in the absence of clinically-defined optic neuritis.

Item Type: Dissertation
Supervisor: Régnier-Vigouroux, Dr. Anne
Date of thesis defense: 10 March 2016
Date Deposited: 16 Mar 2016 12:30
Date: 2016
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 500 Natural sciences and mathematics
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