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Dr Alexander Davies summarises a departmental seminar by Dr Simon Rinaldi

A myelinated axon (red) with deposition of patient antibody (IgG) at the node of Ranvier (green, centre) and surrounded by unmyelinated axons (blue).
Simon Rinaldi

Using myelinating cultures and other cell-based assays to unravel the inflammatory neuropathies

Dr Simon Rinaldi

2 April 2020, NDCN Seminar

Report by Dr Alexander Davies

In some patients, the development of burning, tingling or numbness in their extremities, or muscle weakness in their arms and legs, could be a sign of the immune system mistakenly attacking the peripheral nerves. Exactly why is the question that vexes Dr Simon Rinaldi, a consultant neurologist and MRC Clinical Scientist at the Nuffield Department of Clinical Neurosciences, and is the subject of his talk – the first seminar to be delivered virtually to the department at the University of Oxford.

Clinically, the inflammatory neuropathies fall into an ‘alphabet soup’ of disease classifications, from acute-onset Guillain-Barré syndrome (GBS), which typically occurs after an infection and in some cases is relatively well defined, to chronic inflammatory demyelinating polyneuropathies (CIDP) in which aetiology is rarely identified. Among these are variants with predominantly sensory, motor, autonomic, focal or widespread symptoms. Current treatments are non-specific and expensive. Intravenous immunoglobulin (IVIg) costs £40,000 per patient per year; in total the UK spends around £200 million per year on IVIg – that’s 0.15% of the entire NHS budget! It is therefore essential to distinguish between the cellular or humoral (antibody) mechanisms of autoimmunity in the peripheral neuropathies.

Simon and his team use a living model of human nerves in the tissue culture lab that recapitulates many of the components of a real nerve: axons, myelin, nodes of Ranvier and their molecular components, all in a dish. These myelinated nerve cultures are being used to test patient serum for the presence of nerve-binding antibodies, as well as the pathogenesis of axon degeneration and demyelination, as demonstrated by anti-disialosyl antibodies from CANOMAD patients (a form of CIDP). The application of complement proteins to nerve cultures treated with another antibody caused a loss of electrical excitability in the nerve cells – likely due to complement pore formation - that correlated remarkably well with clinical findings from nerve conduction studies.

The talk then took a tour via French Polynesia and South America back to the node of Ranvier. This journey charted Simon’s quest for the potential humoural mechanisms behind the spike in GBS cases observed during the recent Zika virus outbreaks in these regions. A small but significant proportion of Zika-GBS patients’ sera reacted with the myelinating cultures. Simon was able to identify antibodies to nodal neurofascin proteins in one fatal case, with efforts ongoing to identify a potentially novel glycolipid antigen recognised by another myelin-reactive antibody.

Thanks to an in-house screening programme pioneered by Simon and now run as part of the NHS diagnostic service, more suspected inflammatory neuropathies are being identified with antibodies to nodal proteins. In patients seropositive for pan-neurofascin antibodies, in which IVIg treatment offers only temporary relief, a more targeted B cell ablation (Rituximab) therapy led to consistently lower antibody titres and improvement in patient mobility and function; indeed early treatment may prove life-saving in this particularly aggressive, rapid-onset neuropathy.

Returning to the clinic Simon concluded with case studies illustrating how knowledge gained from in vitro studies informs us of patients with complex disease presentation, as in the case of coincident neuropathy and nephropathy in contactin-1 antibody patients, and work to define biomarkers for both axonal and demyelinating forms of inflammatory neuropathy.

By building a clearer picture of the diversity and pathogenic mechanisms of seropositive inflammatory neuropathies, Simon’s work continues to help reduce the time to diagnosis and effective treatment, and offer hope to those patients for whom there is currently no cure.