GBS is caused by inflammation in the peripheral nervous system (PNS), brought on by an uncontrolled and damaging cascade of pathological events. In recent years, considerable research has centered on antibody responses to peripheral nerve gangliosides as a major initiating event, and the relationship these anti-ganglioside antibodies have to different clinical forms of GBS, including Miller Fisher syndrome. In the past, GBS was believed to be a disorder largely mediated by T lymphocytes - however the current flow or research suggests that the antibody-producing B lymphocytes might be equally, if not more important. This shift in emphasis from T cells to B cells has opened up a new understanding of GBS, and in doing so suggests that some novel therapeutic approaches based on these findings could be developed.

Onset in GBS is generally rapid, and in 20% of cases leads to total paralysis, requiring prolonged intensive therapy with mechanical ventilation. Because of this fast and often severe onset, it is important to halt ongoing damage by initiating treatment early - with this comes an acceptance that the treatment window for GBS is short, and that one cannot undo the damage that has been done, but must wait for natural repair to take place. The current optimal treatment with whole plasma exchange or intravenous immunoglobulin therapy lacks immunological specificity and only halves the severity of the disease. The incentive to understand GBS pathogenesis as a prerequisite to developing and instituting more effective, contemporary immunotherapies thus remains high. By switching conceptual emphasis from a T cell model of GBS to a B cell model, we open up a vista of new therapeutic possibilities, one of which is blocking the complement system of proteins in the blood.

The production of anti-ganglioside antibodies is driven by the infection that precedes the onset of GBS. This is best understood for Campylobacter infection, where the coating on the bacterial surface is the same molecular shape as the coating on the surface of our nerves. As the body makes a protective antibody response against the bacterial coat, it inadvertently fails to realise that the same antibody can also attack the nerve coat. This process, often termed molecular mimicry, lead to immune attack by friendly fire - tragically unwanted for the nerve which takes the brunt of an immune attack that should normally be destined for clearing the bacterial infection.Why only some of us make this immune programming mistake that leads to GBS after infections remains unknown.

Anti-ganglioside antibodies bind to ganglioside-containing cell membranes in different parts of the nerve. After the antibodies bind, they activate a defense system in the body termed the complement cascade. This bunker busting cascade of proteins punches holes in the surface membrane of the nerve cell; water and certain salts flood into the nerve from outside, and the whole area bursts open and disintegrates. As a result of this, not surprisingly the nerve stops working, leading to the loss of nerve function and paralysis that we see in our patients with GBS. Under normal conditions, the complement cascade is present in our bodies to perform this attack mechanism on bacteria that have been coated by antibodies. Thus the consequence of the misdirected anti-ganglioside antibody becomes clear - in addition to tagging the bacteria for attack by complement, the nerves are also tagged, with disastrous consequences.

Complement is not a new subject - many GBS investigators have looked carefully in this direction before, and like all medical science, progress builds gradually on the past discoveries of others and the current work of colleagues in laboratories throughout the world. In recognition of this, my laboratory has recently conducted a detailed series of experiments looking at complement attack pathways brought on by anti-ganglioside antibody binding to nerve. It is very clear that complement activation drives nerve injury in our models of GBS. It is also well established that complement deposits are present in human GBS nerve biopsies. It would thus seem logical that blocking complement activity should prevent tissue injury to nerves where anti-ganglioside antibody is deposited on the membrane. We have therefore looked around for complement blocking drugs (inhibitors) that we could potentially apply to the treatment of GBS. One therapy we have used to investigate this is a complement inhibitor called APT070 (also termed Mirococept), and we published this work in the scientific journal, Annals of Neurology, in 2005. In our model of GBS, alto's therapy is extremely effective, essentially blocking complement activation and thereby completely preventing any nerve damage. We are also now testing other complement blocking drugs that appear to be effective.

Advances in our understanding of the destructive immune pathways underlying GBS has opened up potential new therapies. An important consequence of identifying anti-ganglioside antibodies as a mediator of some forms of GBS is that the knowledge has direct therapeutic approaches towards blockade of antibody-mediated pathways, such as complement inhibition. Therapeutic progress with GBS patients is confounded by the need for large, complex, and expensive clinical trials - this reinforces the need to make rational choices for novel immunotherapy testing, informed by basic studies in model systems that reasonably reflect the pathogenesis of the human disease. Our recent studies on complement blockade represent one such example of this and clearly identify a possible new treatment for GBS that deserves a clinical trial.