After the near eradication of polio, Guillain-Barré Syndrome (GBS) is now the commonest cause of acute flaccid paralysis worldwide. GBS comprises a group of related disorders of peripheral nerve, which are characterized by acute onset, usually a single disease phase without recurrence, and autoimmune pathogenesis. Significant progress has been made in our understanding of the pathogenesis of some forms of GBS. Recognition of anti-ganglioside antibodies in some patients with GBS has been a key finding that led to a series of clinical observations, which gave rise to the hypothesis of post-infectious molecular mimicry. That is, that the presence of ganglioside-like antigens on the infectious agents results in induction of anti-ganglioside antibodies. These anti-ganglioside antibodies in turn damage the nerve fibers that are enriched in gangliosides. A substantial amount of experimental evidence now supports the notion that in some patients with GBS anti-ganglioside antibodies are aberrant immune responses that cause nerve fiber dysfunction and injury by both complement independent and dependent mechanisms (reviewed in 1,2) (Complement is a cascade of naturally occurring proteins in blood that in antibody-mediated autoimmune disorders can amplify antibody-mediated tissue injury). The identification of anti-ganglioside anti-bodies as an immune insult in GBS has directed therapeutic research efforts on either eliminating these antibodies or countering their pathologic effects.

Intravenous immunoglobulin (IVIg) has become a standard immunological treatment of GBS because it is widely available and easy to administer. Controlled trials demonstrate that this treatment hastens recovery in GBS patients treated within 2 weeks of on-set of neurological symptoms (reviewed in 3). Although IVIg is known to have several modulatory ejects on the immune systems, the specific mechanisms that facilitate recovery in GBS are not well characterized. Since the primary pathogenic role of antiganglioside antibodies in some patients with GBS is fairly certain, examining the effects of IVIg on these antibodies is likely to provide clues as to how this treatment might work in patients with GBS. Three independent groups, including ours, have examined the effects of IVIg in experimental models of anti-ganglioside antibody- mediated nerve injury that provide new insights into the mechanism(s) of action of IVIg in GBS, which are summarized below.

Buchwald and colleagues have developed a mouse nerve-muscle preparation, in which GBS sera containing antibodies that recognize gangliosides GM1 or GQ1b, block cross talk between nerve and muscle (neuromuscular transmission), thus effusively modeling muscle weakness in a Petri dish. It is suspected that anti-ganglioside antibodies induce similar effects in GBS patients that then cause physiological muscle weakness without destroying nerve fibers. In this experimental model of muscle weakness, IVIg neutralizes the effect of antiganglioside antibodies in sera obtained from untreated patients, whereas sera from patients who were already treated with IVIg did not block neuromuscular transmission, again reflecting neutralization of anti-ganglioside antibodies in IVIg-treated cases. This study demonstrates for the first time that in a physiological model of muscle weakness IVIg protects against anti-ganglioside antibodies by neutralizing their activisms.

Hugh Willison's group in Glasgow has extensively characterized the effects of anti-ganglioside antibodies on neuromuscular transmission. In their experimental model, blocking neuromuscular transmission requires physical disruption of the terminal potion of the nerve fiber, where it connects with the muscle, and depends on both antiganglioside antibodies and complement. This experimental paradigm reproduces some aspects of axon degeneration seen in GBS that is dependent on complement. These investigators showed that in this model IVIg also protects against anti-ganglioside anti- body-mediated nerve injury by antibody neutralization. In this study, for methodological reasons, it could not be directly determined whether protection of motor nerve terminal by IVIg involves inhibition of activation of complement cascaded.

We have developed a neuronal toxicity assay, in which antiganglioside antibodies and complement cause neuronal cell lysis (cell death). This neuron injury is not only produced by GBS sera containing antiganglioside antibodies but also by experimental antiganglioside antibodies. For technical reasons the availability of patient derived and experimental anti-ganglioside antibodies was fortuitous and it allowed us to examine the issue whether complement inhibition forms part of IVIg's protective effects against nerve injury mediated by anti-ganglioside antibodies. Anti-ganglioside antibody dependent complement fixation assays on immobilized gangliosides and peripheral nerve sections showed that IVIg inhibits complement activation, and also neutralizes anti-ganglioside antibodies. These assays allowed us to determine that the inhibition of complement by IVIg was at the level of C3 component of complement activation pathway. Another intriguing finding was that IVIg clearly displaced and captured anti-ganglioside antibodies already bound to immobilized gangliosides, raising the possibility that IVIg can displace and neutralize pathogenic antibodies already bound to the newest. Our study suggests that besides neutralization of circulating anti-ganglioside antibodies, IVIg can also act at the level of nerve either by displacing and capturing anti-ganglioside antibodies already bound to nerves, or inhibiting activation of complement triggered by anti-ganglioside antibody bound to nerves, or both of these actions.

It is clear from the above discussion that IVIg protects nerves from anti-ganglioside antibody-mediated injury in three distinct models. These data suggest that neutralization of autoantibodies and inhibition of complement activation are two major mechanisms whereby IVIg aids recovery in GBS. The advantage of such an approach is that it not only identifies mechanism(s) of anion of an existing drug, but it also provides potential targets for the development of new therapies. The findings from these studies are in the process of bench to bedside translation. Initial efforts in this regard have led to synthesis of soluble oligosaccharides (sugars) that can neutralize and protect nerves from injury by anti-ganglioside antibodies in an experimental model. Although the safety of these soluble oligosaccharides for human use remains to be determined, it is reasonable to conclude that because of basic research efforts, new therapeutic strategies are on the horizon.