Miller Fisher anti-GQ1b antibodies: alpha-latrotoxin-like effects on motor end plates.
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 alpha-latrotoxin at the mouse NMJs, implying possible involvement of alpha-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.
Plomp
J J
JJ
Department of Neurology, Leiden University Medical Centre, The Netherlands.
Molenaar
P C
PC
O'Hanlon
G M
GM
Jacobs
B C
BC
Veitch
J
J
Daha
M R
MR
van Doorn
P A
PA
van der Meché
F G
FG
Vincent
A
A
Morgan
B P
BP
Willison
H J
HJ
D000818:Animals; D000906:Antibodies / Q000276:immunology*; D004594:Electrophysiology; D005732:Gangliosides / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D019846:Miller Fisher Syndrome / Q000276:immunology* / Q000503:physiopathology*; D009045:Motor Endplate / Q000276:immunology* / Q000502:physiology*; D013111:Spider Venoms / Q000276:immunology*