Miller Fisher anti-GQ1b antibodies: alpha-latrotoxin-like effects on motorend plates

In the Miller Fisher syndrome (MFS) variant of the Guillain-Barre syndrome, weakness is restricted to extraocular muscles and occasionally other crani obulbar muscles. Most MFS patients have serum antibodies against gangliosid e type GQ1b of which the pathophysiological relevance Is unclear. We examin ed the in vitro effects of MFS sera, MFS IgG, and a human monoclonal anti-G q1b IgM antibody on mouse neuromuscular junctions (NMJs). It was found that anti-Gq1b antibodies bind at NMJs where they induce massive quantal releas e of acetylcholine from nerve terminals and eventually block neuromuscular transmission. This effect closely resembled the effect of the paralytic neu rotoxin alpha-latrotoxin at the mouse NMJs, implying possible involvement o f alpha-latrotoxin receptors or associated downstream pathways. By using co mplement-deficient sera, the effect of anti-GQ1b antibodies on NMJs was sho wn to be entirely dependent on activation of complement components. However , neither classical pathway activation nor the formation of membrane attack complex was required, indicating the effects could be due to involvement o f the alternative pathway and intermediate complement cascade products. Our findings strongly suggest that anti-GQ1b antibodies in conjunction with ac tivated complement components are the principal pathophysiological mediator s of motor symptoms in MFS and that the NMJ is an important site of their a ction.