C1q-targeted inhibition of the classical complement pathway prevents injury in a novel mouse model of acute motor axonal neuropathy

McGonigal, R., Cunningham, M. E. , Yao, D., Barrie, J. A., Sankaranarayanan, S., Fewou, S. N., Furukawa, K., Yednock, T. A. and Willison, H. J. (2016) C1q-targeted inhibition of the classical complement pathway prevents injury in a novel mouse model of acute motor axonal neuropathy. Acta Neuropathologica Communications, 4, 23. (doi: 10.1186/s40478-016-0291-x) (PMID:26936605) (PMCID:PMC4776408)

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Abstract

Introduction Guillain-Barré syndrome (GBS) is an autoimmune disease that results in acute paralysis through inflammatory attack on peripheral nerves, and currently has limited, non-specific treatment options. The pathogenesis of the acute motor axonal neuropathy (AMAN) variant is mediated by complement-fixing anti-ganglioside antibodies that directly bind and injure the axon at sites of vulnerability such as nodes of Ranvier and nerve terminals. Consequently, the complement cascade is an attractive target to reduce disease severity. Recently, C5 complement component inhibitors that block the formation of the membrane attack complex and subsequent downstream injury have been shown to be efficacious in an in vivo anti-GQ1b antibody-mediated mouse model of the GBS variant Miller Fisher syndrome (MFS). However, since gangliosides are widely expressed in neurons and glial cells, injury in this model was not targeted exclusively to the axon and there are currently no pure mouse models for AMAN. Additionally, C5 inhibition does not prevent the production of early complement fragments such as C3a and C3b that can be deleterious via their known role in immune cell and macrophage recruitment to sites of neuronal damage. Results and Conclusions In this study, we first developed a new in vivo transgenic mouse model of AMAN using mice that express complex gangliosides exclusively in neurons, thereby enabling specific targeting of axons with anti-ganglioside antibodies. Secondly, we have evaluated the efficacy of a novel anti-C1q antibody (M1) that blocks initiation of the classical complement cascade, in both the newly developed anti-GM1 antibody-mediated AMAN model and our established MFS model in vivo. Anti-C1q monoclonal antibody treatment attenuated complement cascade activation and deposition, reduced immune cell recruitment and axonal injury, in both mouse models of GBS, along with improvement in respiratory function. These results demonstrate that neutralising C1q function attenuates injury with a consequent neuroprotective effect in acute GBS models and promises to be a useful new target for human therapy.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Barrie, Mrs Jennifer and Yao, Dr Denggao and Willison, Professor Hugh and Cunningham, Dr Madeleine and McGonigal, Dr Rhona and Fewou, Dr Simon
Authors: McGonigal, R., Cunningham, M. E., Yao, D., Barrie, J. A., Sankaranarayanan, S., Fewou, S. N., Furukawa, K., Yednock, T. A., and Willison, H. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Acta Neuropathologica Communications
Publisher:BioMed Central
ISSN:2051-5960
ISSN (Online):2051-5960
Copyright Holders:Copyright © 2016 6 McGonigal et al.
First Published:First published in Acta Neuropathologica Communications 4:23
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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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