Anti-GQ1b ganglioside antibodies mediate complement-dependent destruction of the motor nerve terminal.
Miller-Fisher syndrome is an autoimmune neuropathy characterized by ataxia, areflexia and ophthalmoplegia, and in the majority of cases the presence of high titres of anti-GQ1b ganglioside antibodies. In an ex vivo model, human and mouse anti-GQ1b antibodies have been shown previously to induce a complement-dependent alpha-latrotoxin-like effect on the murine motor endplate, i.e. they bring about massive quantal release of acetylcholine and eventually block neuromuscular transmission. Using immunofluorescence microscopy with image analysis, we show here that the late stages of this electrophysiological effect temporally coincide with the loss of heavy neurofilament (200 kDa) and type III beta-tubulin immunostaining and structural breakdown of the nerve terminal, as demonstrated by electron microscopy. Ultrastructurally, axon terminals were disorganized, depleted of vesicles, and subdivided by the infiltrating processes of capping Schwann cells. These findings provide clear pathological evidence to support a role for anti-ganglioside antibodies in mediating nerve terminal injury and further advance the view that this site may be of importance as a target in some human neuropathies.
O'Hanlon
G M
GM
University Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow, UK.
Plomp
J J
JJ
Chakrabarti
M
M
Morrison
I
I
Wagner
E R
ER
Goodyear
C S
CS
Yin
X
X
Trapp
B D
BD
Conner
J
J
Molenaar
P C
PC
Stewart
S
S
Rowan
E G
EG
Willison
H J
HJ
D000469:Alkaline Phosphatase / Q000494:pharmacology; D000818:Animals; D001323:Autoantibodies / Q000009:adverse effects*; D003167:Complement Activation / Q000276:immunology*; D004195:Disease Models, Animal; D005732:Gangliosides / Q000037:antagonists & inhibitors / Q000276:immunology*; D007091:Image Processing, Computer-Assisted; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D019846:Miller Fisher Syndrome / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D009046:Motor Neurons / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016900:Neurofilament Proteins / Q000378:metabolism; D009469:Neuromuscular Junction / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D012583:Schwann Cells / Q000473:pathology / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000187:drug effects / Q000276:immunology; D014404:Tubulin / Q000378:metabolism
D001323:Autoantibodies; D005732:Gangliosides; D016900:Neurofilament Proteins; D014404:Tubulin; C051774:neurofilament protein H; C039129:GQ1b ganglioside; D000469:Alkaline Phosphatase