A significant proportion of patients with Guillain Barré Syndrome (GBS) are left with residual neurological deficits and incomplete recovery. The most important determinant of rate and efficiency of recovery in this setting is the degree of axonal degeneration and successful regeneration. Patients with significant disability almost always have axonal injury and incomplete axonal regeneration. The peripheral nerve axons have an inherent ability to regenerate after injury, but why injured axons do not efficiently regrow and reconnect with their targets to restore function and recovery, in GBS patients with incomplete recovery, has not been systematically examined at immune effector or molecular level. Our laboratory has recently focused on this issue in the context of antiganglioside antibodies.

Anti-ganglioside antibodies are the most commonly recognized autoimmune markers in GBS that are considered to be one set of immune effectors that mediate nerve fiber injury. In GBS, post-infectious molecular mimicry has emerged as the major pathophysiologic mechanism that induces anti-ganglioside antibodies. This is supported by the following key clinical observations: 1) Campylobacter jejuni infection is the most commonly recognized antecedent infection in GBS; 2) the surface of Campylobacter jejuni isolates from patients with GBS carry carbohydrate (sugar) structures similar to gangliosides (carbohydrate-lipid complexes enriched in nerve fibers); and 3) different forms of GBS, are strongly associated with specific antibodies directed against ganglioside molecules. The full spectrum of pathobiologic effects of anti-ganglioside antibodies in GBS remains to be defined. These antibodies are not only implicated in primary nerve fiber injury but antibodies against gangliosides GM1 and GD1 a are also reported to be associated with poor clinical out-come and incomplete functional recovery in some patients with GBS. Based on these observations we hypothesized that antiganglioside antibodies can impair peripheral nerve regeneration and affect recovery in some patients with GBS.

This hypothesis was experimentally tested in a cell culture model of peripheral nerve regeneration. We examined the effects of different experimental antiganglioside antibodies on axon outgrowth in neuronal cell cultures. Our unpublished findings indicate that anti-ganglioside antibodies with GD1a specificity significantly decreased the growth/elongation of the axons in neuronal cultures. We have identified molecules Involved in the antibody-mediated inhibitory signalling to the regenerating axons. The same set of signalling molecules are also involved in the failure of axon regeneration in central nervous system after injury. Pharmacologic inhibitors of the molecules involved in this negative signalling restored axon regeneration in these neuronal cultures. Our studies indicate that inhibition of axon regeneration is part of the spectrum of pathophysiologic ejects of anti-ganglioside antibodies in patients with GBS. Detailed examination of the effects of anti-ganglioside antibodies on axon regeneration may shed light on mechanisms involved in inhibition of axon regeneration and recovery in GBS. Understanding these mechanisms could potentially allow us to promote recovery by developing therapeutic strategies targeting inhibitory factors that prevent successful regeneration in the peripheral nerves.
Acknowledgements. This research was partly funded
by the GBS Foundation.