S86 Pathophysiology of myelin and axon in dysimmune neuropathies

Abstract

The dysimmune neuropathies Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), anti-myelin-associated glycoprotein (anti-MAG) neuropathy, and multifocal motor neuropathy (MMN) are usually labeled as demyelinating. These neuropathies, however, may not only affect Schwann cells but also the voltage-gated ion-channels in the axolemma and the signalling between axon and Schwann cell. Damage to these ion-channels may induce conduction block and, indirectly, axonal degeneration. Ion-channels at the node of Ranvier include transient Na-channels for impulse generation, persistent Na-channels that set excitability, and slow K-channels that counteract extreme depolarization. The internode contains fast K-channels counteracting impulse-spreading, channels counteracting extreme hyperpolarization and Na/K-pumps. The non-uniform distribution of ion-channels is maintained by specific adhesion molecules between axolemma and Schwann cell membrane. An example is formed by the paranodal adhesion molecules which separate channel clusters with opposing function: Na-channels at the node and fast K-channels at the juxtaparanode. Immune-mediated damage to nodal and juxtaparanodal ion-channel clusters was demonstrated in animal models of axonal GBS and antibodies against paranodal adhesion molecules in small numbers of patients with GBS or CIDP. Excitability testing in MMN patients showed persistent hyperpolarization of resting membrane potential of which the exact mechanism is unknown. In anti-MAG neuropathy, damage to Schwann cell molecules was shown to induce clustering of intra-axonal neurofilaments which may ultimately lead to axonal degeneration. The main challenge in dysimmune neuropathies is to unravel and modify the mechanisms occurring in human patients that lead to irreversible axonal degeneration.