Anti-GD1a antibodies activate complement and calpain to injure distal motor nodes of Ranvier in mice

McGonigal, R., Rowan, E.G., Greenshields, K.N., Halstead, S.K., Humphreys, P.D., Rother, R.P., Furukawa, K. and Willison, H.J. (2010) Anti-GD1a antibodies activate complement and calpain to injure distal motor nodes of Ranvier in mice. Brain, 133(7), pp. 1944-1960. (doi:10.1093/brain/awq119)

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Abstract

The motor axonal variant of Guillain-Barre syndrome is associated with anti-GD1a immunoglobulin antibodies, which are believed to be the pathogenic factor. In previous studies we have demonstrated the motor terminal to be a vulnerable site. Here we show both in vivo and ex vivo, that nodes of Ranvier in intramuscular motor nerve bundles are also targeted by anti-GD1a antibody in a gradient-dependent manner, with greatest vulnerability at distal nodes. Complement deposition is associated with prominent nodal injury as monitored with electrophysiological recordings and fluorescence microscopy. Complete loss of nodal protein staining, including voltage-gated sodium channels and ankyrin G, occurs and is completely protected by both complement and calpain inhibition, although the latter provides no protection against electrophysiological dysfunction. In ex vivo motor and sensory nerve trunk preparations, antibody deposits are only observed in experimentally desheathed nerves, which are thereby rendered susceptible to complement-dependent morphological disruption, nodal protein loss and reduced electrical activity of the axon. These studies provide a detailed mechanism by which loss of axonal conduction can occur in a distal dominant pattern as observed in a proportion of patients with motor axonal Guillain-Barre syndrome, and also provide an explanation for the occurrence of rapid recovery from complete paralysis and electrophysiological in-excitability. The study also identifies therapeutic approaches in which nodal architecture can be preserved.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Halstead, Dr Susan and Humphreys, Mr Peter and Willison, Professor Hugh and McGonigal, Dr Rhona and Greenshields, Dr Kay
Authors: McGonigal, R., Rowan, E.G., Greenshields, K.N., Halstead, S.K., Humphreys, P.D., Rother, R.P., Furukawa, K., and Willison, H.J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Brain
ISSN:0006-8950
Published Online:30 May 2010

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