Dr. Richard Fairless

Neuroinflammatory diseases such as multiple sclerosis (MS) have neurodegenerative burdens that have not been adequately addressed therapeutically, despite an increasing array of effective immunomodulatory therapies being available. Although MS is considered primarily as a demyelinating autoimmune disease, neurodegeneration has been increasingly understood to be the major pathological correlate of irreversible disease progression.

Mechanisms of preclinical neurodegeneration in autoimmune optic neuritis

In a rat model of autoimmune optic neuritis, a commonly reported first presentation of MS, we have demonstrated that degeneration of retinal ganglion cells (RGCs), the retinal neurons whose axons project to the higher visual centres of the brain, begins during the preclinical disease stage. That is, prior to the inflammatory infiltration and demyelination of the optic nerves which define optic neuritis, neurons are already compromised. The relevance of this observation has been strengthened by subsequent reports that in MS patients, the retinal nerve fibre layer consisting of RGC axons can be seen to be reduced independently of whether the patients have clinically defined optic neuritis. In order to correlate this finding with other retinal pathophysiological events, we investigated both the retinal vasculature and microglial activation revealing both an increase in the permeability of the blood-retinal barrier, and increased microglial activation in both the retina and optic nerve head which also occur during this early preclinical stage. Determining the causal relationship between these events is an on-going focus of our group.

Fig1

Figure 1. (A-C) Numbers of activated microglia/macrophages in the retina already begin to increase during the preclinical phase (B, day 5 post immunisation), and continues into the clinical phase (C, day 18 post immunisation). (D-J) An increase in vessel permeability can also be seen to begin during the preclinical phase (E, I) as indicated by increased extravasation of albumin (green) from the blood vessel into the surrounding tissue.


This disease model also elicits a robust auto-antibody response, where the emergence of anti-MOG antibodies correlates with the onset of neurodegeneration. Interestingly, these antibodies are able to extravasate through the semi-permeable blood-brain barrier (BBB) of the optic nerve head, prior to breakdown in the BBB associated with the onset of inflammatory demyelination. We wish to further elucidate whether this early/demyelination-independent degeneration of RGCs reflects antibody-mediated mechanisms which take advantage of the inherent weakness of the BBB at the optic nerve head.

Fig2

Figure 2. Anatomy of the optic nerve head. Light microscopy image of the optic nerve head following Luxol fast blue staining to label myelin, with the retina on the left and the optic nerve on the right.

Role of calcium signalling and glutamate toxicity in progression of neurodegeneration under autoimmune inflammatory conditions


Through a combination of in vitro calcium imaging, and in vivo magnetic resonance imaging with manganese contrast enhancement to reveal calcium entry pathways, we are investigating the influence of calcium accumulation and glutamate-mediated excitotoxicity on RGC degeneration. Calcium has long been known to mediate neuronal toxicity in many diseases, where intracellular calcium can increase to pathological levels in response to a range of insults and injuries. We have also demonstrated that this occurs during the progression of autoimmune optic neuritis, where retinal calcium can be seen to increase during the early phase of the disease, with axonal increases in the optic nerve occurring later. In the retina, both inhibition of calpain, a calcium-activated protease involved in apoptotic signalling, and blockade of the NMDA glutamate receptor, resulted in increased protection of RGCs from degeneration during the preclinical stage of autoimmune optic neuritis. We are now investigating in more detail the contribution of glutamate excitotoxicity to RGC degeneration under autoimmune inflammatory conditions, whether different RGC subsets are more susceptible to this and why, and investigating new therapeutic strategies to achieve neuroprotection.

Fig3

Figure 3. Manganese-enhanced magnetic resonance imaging of the optic system during autoimmune optic neuritis. (A) Identification of the optic nerve (between red lines) and (B) retina (green outline) by MRI imaging. (C-N) Pseudo-colour manganese-enhanced MRI imaging of the optic nerves and retinas. Increased signal intensity can be seen in the optic nerves at clinical time points (L, d1 EAE, AFTER) after systemic manganese injection compared to its pre-manganese signal (K, BEFORE). In contrast, an increased retinal signal could be seen during the preclinical phase (J, d5 p.i., AFTER) compared to before manganese injection (I, BEFORE). This increased signal persisted into the clinical disease stage (N vs M).

 

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Latest Revision: 2022-01-10
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