Miller Fisher anti-GQ1b antibodies: ?-Latrotoxin-like effects on motor end plates

TLDR

Miller Fisher syndrome is a Guillain‑Barré variant causing weakness mainly of extraocular and sometimes other cranial muscles, and most patients possess anti‑GQ1b antibodies whose pathogenic role is uncertain. In vitro studies on mouse neuromuscular junctions showed that MFS sera, IgG, and a monoclonal anti‑GQ1b IgM induce effects that are entirely dependent on complement activation, though the classical pathway and membrane attack complex are not required. Anti‑GQ1b antibodies bind NMJs, trigger massive acetylcholine release and block transmission in a manner resembling α‑latrotoxin, and these effects, mediated by complement, likely underlie the motor symptoms of MFS. Ann Neurol 1999;45:189–199.

Abstract

In the Miller Fisher syndrome (MFS) variant of the Guillain-Barré syndrome, weakness is restricted to extraocular muscles and occasionally other craniobulbar muscles. Most MFS patients have serum antibodies against ganglioside type GQ1b of which the pathophysiological relevance is unclear. We examined the in vitro effects of MFS sera, MFS IgG, and a human monoclonal anti-GQ1b IgM antibody on mouse neuromuscular junctions (NMJs). It was found that anti-GQ1b antibodies bind at NMJs where they induce massive quantal release of acetylcholine from nerve terminals and eventually block neuromuscular transmission. This effect closely resembled the effect of the paralytic neurotoxin α-latrotoxin at the mouse NMJs, implying possible involvement of α-latrotoxin receptors or associated downstream pathways. By using complement-deficient sera, the effect of anti-GQ1b antibodies on NMJs was shown 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 of the alternative pathway and intermediate complement cascade products. Our findings strongly suggest that anti-GQ1b antibodies in conjunction with activated complement components are the principal pathophysiological mediators of motor symptoms in MFS and that the NMJ is an important site of their action. Ann Neurol 1999;45:189–199