Current projects in peripheral neuropathy

Disease mechanisms in inflammatory neuropathy

M. David, J. E. Mathey, P.J. Armati, M. Wang, J. Spies, J.D. Pollard

Nerve fibres to some extent resemble electrical cables and like these, are insulated. The insulating material, myelin, surrounds the central nerve fibre (axon) except at regularly occurring regions, the nodes (of Ranvier). At each node, many specialised structures and molecules are arranged, including the ion channels (Sodium & Potassium) which give rise to the current which is transmitted along the nerve. The inflammatory neuropathies G.B.S. & C.I.D.P. are also known as demyelinating neuropathies, since pathologically they are characterised by myelin loss from intact axons. Until recently, research attention focussed on myelin loss as the central problem in these neuropathies, which were all regarded as autoimmune diseases in which myelin was the target of immune attack. Recent studies from our laboratory and others have shown that impaired impulse conduction at the nodes may be a more important mechanism of disease production.

Supported by NH&MRC, The Nerve Research Foundation and the Philip Bushell Foundation.

The role of anti-ganglioside antibodies

M. David, J. Spies, P.J. Armati, K, Sheik, J.D. Pollard

Gangliosides (a form of glycolipid) are an important constituent of neural membranes and are concentrated in nerve in the region of the node. They are known to be the binding site of bacterial neurotoxins such as cholera toxin and antibodies to such toxins have been used to label the nodal region of nerves histologically. Antibodies to certain gangliosides are found in some subtypes of G.B.S. and in MMN. Monique David performed experiments in which the effect antiganglioside antibodies on nerve function and structure was tested. These studies showed certain antibodies, particularly anti GD1a had a very powerful effect on blocking nerve transmission. The effect was reversible and appeared to result from the antibodies’ ability to bind in the nodal region where they may affect the clustering of sodium channels, which are necessary for the generation of the nerve impulse.

Supported by NH&MRC and The Philip Bushell Foundation.

Antibodies to neurofascin

E. Mathey, D. Burke, J.D. Pollard

Neurofascins are other molecules found in the nodal area which play an important role in maintaining the structure of this region, connecting specialised regions of the Schwann cell to the axon. Neurofascins occur in nodes of both central and peripheral nervous system fibres, which share many common features despite the differences between myelinating Schwann cells and oligodendrocytes. Emily Mathey, during her post doctoral studies, made the important finding that antibodies to neurofascin could be demonstrated in some patients with progressive Multiple Sclerosis. When tested in animal models of M.S., antineurofascin antibodies bound to CNS nodes and caused conduction block. The antibodies also bind to Peripheral Nervous System nodes in an animal model of inflammatory neuropathy and in current studies their action on nerve conduction and structure is being studied. The clinical significance of these findings is important for several reasons. First they suggest that myelin is not simply a passive insulator of axons, but that Schwann cells and their specialised regions play an active role in impulse conduction, particularly in their contribution to ion channel arrangements and function at the node. Moreover, they provide an explanation as to why patients with inflammatory neuropathies may improve following therapy over a time course of hours or days. These patients presumably have not remyelinated demyelinated fibres but rather unblocked axonal conduction.

Supported by NH&MRC and The Philip Bushell Foundation.

The mechanism of action of intravenous immunoglobulin

S.S. Lin, J. Spies, M.X. Wang, J.D. Pollard

Dr. Lin, a visiting Taiwanese Neurologist, was awarded her Ph.D for studies on the mechanism of action of intravenous immunoglobulin (IVIg) in Neuropathy. IVIg is the treatment of choice for G.B.S., C.I.D.P. and MMN worldwide and yet its mechanism of action remains unknown. IVIg is very expensive and we have studied its potential mechanisms in an animal model of G.B.S. so that more effective and/or affordable therapy may be developed. Dr. Lin showed that the efficacy of IVIg can be reproduced by the constant region (Fc component) of the immunoglobulin molecule rather than the variable (Fab) component. This finding in itself is important, since it should be possible to manufacture large quantities of this protein by molecular means. Studies by a Canadian group published in the prestigious journal, Nature Medicine, in a bleeding disorder which also responds to IVIg, found that this Fc component reacted with particular receptors on dendritic cells (DCs - the major antigen presenting cell) and that relatively few treated DCs could achieve the same efficacy as large quantities of expensive IVIg. We are now collaborating with this leading Canadian laboratory, to repeat these studies in the neuropathy model.

Supported by The Philip Bushell and Nerve Research Foundations.