Anti-ganglioside antibodies are removed from circulation in mice by neuronal endocytosis

Cunningham, M. , McGonigal, R., Meehan, G. R. , Barrie, J. A., Yao, D., Halstead, S. K. and Willison, H. J. (2016) Anti-ganglioside antibodies are removed from circulation in mice by neuronal endocytosis. Brain, 139(6), pp. 1657-1665. (doi: 10.1093/brain/aww056) (PMID:27017187) (PMCID:PMC4892750)

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Abstract

In axonal forms of Guillain-Barré syndrome, anti-ganglioside antibodies bind gangliosides on nerve surfaces, thereby causing injury through complement activation and immune cell recruitment. Why some nerve regions are more vulnerable than others is unknown. One reason may be that neuronal membranes with high endocytic activity, including nerve terminals involved in neurotransmitter recycling, are able to endocytose anti-ganglioside antibodies from the cell surface so rapidly that antibody-mediated injury is attenuated. Herein we investigated whether endocytic clearance of anti-ganglioside antibodies by nerve terminals might also be of sufficient magnitude to deplete circulating antibody levels. Remarkably, systemically delivered anti-ganglioside antibody in mice was so avidly cleared from the circulation by endocytosis at ganglioside-expressing plasma membranes that it was rapidly rendered undetectable in serum. A major component of the clearance occurred at motor nerve terminals of neuromuscular junctions, from where anti-ganglioside antibody was retrogradely transported to the motor neuron cell body in the spinal cord, recycled to the plasma membrane, and secreted into the surrounding spinal cord. Uptake at the neuromuscular junction represents a major unexpected pathway by which pathogenic anti-ganglioside antibodies, and potentially other ganglioside binding proteins, are cleared from the systemic circulation and also covertly delivered to the central nervous system.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Halstead, Dr Susan and Barrie, Mrs Jennifer and Yao, Dr Denggao and Willison, Professor Hugh and McGonigal, Dr Rhona and Cunningham, Dr Madeleine and Meehan, Dr Gavin
Authors: Cunningham, M., McGonigal, R., Meehan, G. R., Barrie, J. A., Yao, D., Halstead, S. K., and Willison, H. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Brain
Publisher:Oxford University Press
ISSN:0006-8950
ISSN (Online):1460-2156
Published Online:26 March 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Brain 139(6): 1657-1665
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
544031The structural and functional diversity of anti-glycolipid antibody repertoires and their nerve binding domains in human autoimmune neuropathyHugh WillisonWellcome Trust (WELLCOME)092805/Z/10/ZIII -IMMUNOLOGY