Anti-ganglioside antibody internalization attenuates motor nerve terminal injury in a mouse model of acute motor axonal neuropathy.
In the Guillain-Barré syndrome subform acute motor axonal neuropathy (AMAN), Campylobacter jejuni enteritis triggers the production of anti-ganglioside Abs (AGAbs), leading to immune-mediated injury of distal motor nerves. An important question has been whether injury to the presynaptic neuron at the neuromuscular junction is a major factor in AMAN. Although disease modeling in mice exposed to AGAbs indicates that complement-mediated necrosis occurs extensively in the presynaptic axons, evidence in humans is more limited, in comparison to the extensive injury seen at nodes of Ranvier. We considered that rapid AGAb uptake at the motor nerve terminal membrane might attenuate complement-mediated injury. We found that PC12 rat neuronal cells rapidly internalized AGAb, which were trafficked to recycling endosomes and lysosomes. Consequently, complement-mediated cytotoxicity was attenuated. Importantly, we observed the same AGAb endocytosis and protection from cytotoxicity in live mouse nerve terminals. AGAb uptake was attenuated following membrane cholesterol depletion in vitro and ex vivo, indicating that this process may be dependent upon cholesterol-enriched microdomains. In contrast, we observed minimal AGAb uptake at nodes of Ranvier, and this structure thus remained vulnerable to complement-mediated injury. These results indicate that differential endocytic processing of AGAbs by different neuronal and glial membranes might be an important modulator of site-specific injury in acute AGAb-mediated Guillain-Barré syndrome subforms and their chronic counterparts.
Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.
Simon N
SN
Fewou
Angie
A
Rupp
Lauren E
LE
Nickolay
Kathryn
K
Carrick
Kay N
KN
Greenshields
John
J
Pediani
Jaap J
JJ
Plomp
Hugh J
HJ
Willison
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000737:chemistry; D003167:Complement Activation; D004195:Disease Models, Animal; D004705:Endocytosis; D005260:Female; D005677:G(M1) Ganglioside / Q000737:chemistry; D005732:Gangliosides / Q000276:immunology*; D020275:Guillain-Barre Syndrome / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000473:pathology*; D009469:Neuromuscular Junction / Q000378:metabolism; D016716:PC12 Cells; D011901:Ranvier's Nodes / Q000378:metabolism; D051381:Rats
D000888:Antibodies, Anti-Idiotypic; D005732:Gangliosides; D005677:G(M1) Ganglioside