Anti-ganglioside antibody internalization attenuates motor nerve terminal injury in a mouse model of acute motor axonal neuropathy

Fewou, S. N., Rupp, A., Nickolay, L. E., Carrick, K., Greenshields, K. N., Pediani, J. , Plomp, J. J. and Willison, H. J. (2012) Anti-ganglioside antibody internalization attenuates motor nerve terminal injury in a mouse model of acute motor axonal neuropathy. Journal of Clinical Investigation, 122(3), pp. 1037-1051. (doi:10.1172/JCI59110) (PMID:22307327) (PMCID:PMC3287221)

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Abstract

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Fewou, Dr Simon and Pediani, Dr John and Greenshields, Dr Kay and Willison, Professor Hugh and Carrick, Miss Kathryn and Rupp, Dr Angie
Authors: Fewou, S. N., Rupp, A., Nickolay, L. E., Carrick, K., Greenshields, K. N., Pediani, J., Plomp, J. J., and Willison, H. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
College of Medical Veterinary and Life Sciences > School of Veterinary Medicine
Journal Name:Journal of Clinical Investigation
Journal Abbr.:JCI
ISSN:0021-9738
ISSN (Online):1558-8238
Published Online:06 February 2012

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