Complement inhibition prevents glial nodal membrane injury in a GM1 antibody-mediated mouse model

Campbell, C. I., McGonigal, R. , Barrie, J. A., Delaere, J., Bracke, L., Cunningham, M. E. , Yao, D., Delahaye, T., Van de Walle, I. and Willison, H. J. (2022) Complement inhibition prevents glial nodal membrane injury in a GM1 antibody-mediated mouse model. Brain Communications, 4(6), fcac306. (doi: 10.1093/braincomms/fcac306) (PMID:36523267) (PMCID:PMC9746686)

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The involvement of the complement pathway in Guillain–Barré syndrome pathogenesis has been demonstrated in both patient biosamples and animal models. One proposed mechanism is that anti-ganglioside antibodies mediate neural membrane injury through the activation of complement and the formation of membrane attack complex pores, thereby allowing the uncontrolled influx of ions, including calcium, intracellularly. Calcium influx activates the calcium-dependent protease calpain, leading to the cleavage of neural cytoskeletal and transmembrane proteins and contributing to subsequent functional failure. Complement inhibition has been demonstrated to provide effective protection from injury in anti-ganglioside antibody-mediated mouse models of axonal variants of Guillain–Barré syndrome; however, the role of complement in the pathogenesis of demyelinating variants has yet to be established. Thus, it is currently unknown whether complement inhibition would be an effective therapeutic for Guillain–Barré syndrome patients with injuries to the Schwann cell membrane. To address this, we recently developed a mouse model whereby the Schwann cell membrane was selectively targeted with an anti-GM1 antibody resulting in significant disruption to the axo-glial junction and cytoplasmic paranodal loops, presenting as conduction block. Herein, we utilize this Schwann cell nodal membrane injury model to determine the relevance of inhibiting complement activation. We addressed the early complement component C2 as the therapeutic target within the complement cascade by using the anti-C2 humanized monoclonal antibody, ARGX-117. This anti-C2 antibody blocks the formation of C3 convertase, specifically inhibiting the classical and lectin complement pathways and preventing the production of downstream harmful anaphylatoxins (C3a and C5a) and membrane attack complexes. Here, we demonstrate that C2 inhibition significantly attenuates injury to paranodal proteins at the node of Ranvier and improves respiratory function in ex vivo and in vivo Schwann cell nodal membrane injury models. In parallel studies, C2 inhibition also protects axonal integrity in our well-established model of acute motor axonal neuropathy mediated by both mouse and human anti-GM1 antibodies. These data demonstrate that complement inhibition prevents injury in a Schwann cell nodal membrane injury model, which is representative of neuropathies associated with anti-GM1 antibodies, including Guillain–Barré syndrome and multifocal motor neuropathy. This outcome suggests that both the motor axonal and demyelinating variants of Guillain–Barré syndrome should be included in future complement inhibition clinical trials.

Item Type:Articles
Additional Information:Funding: This study was funded by The Wellcome Trust (Grants 092805 and 202789), the University of Glasgow (funded a PhD Scholarship awarded to Clare Campbell), and argenx.
Keywords:Neurology, cellular and molecular neuroscience, biological psychiatry, psychiatry and mental health.
Glasgow Author(s) Enlighten ID:Campbell, Ms Clare and Cunningham, Dr Madeleine and McGonigal, Dr Rhona and Barrie, Mrs Jennifer and Willison, Professor Hugh and Yao, Dr Denggao
Authors: Campbell, C. I., McGonigal, R., Barrie, J. A., Delaere, J., Bracke, L., Cunningham, M. E., Yao, D., Delahaye, T., Van de Walle, I., and Willison, H. J.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Research Centre:College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
Journal Name:Brain Communications
Publisher:Oxford University Press
ISSN (Online):2632-1297
Published Online:23 November 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Brain Communications 4(6): fcac306
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
165079The structural and functional diversity of anti-glycolipid antibody repertoires and their nerve binding domains in human autoimmune neuropathyHugh WillisonWellcome Trust (WELLCOTR)092805/Z/10/ZIII - Immunology
173549Pathophysiological factors in the diagnosis and treatment of the Guillain-Barre syndromesHugh WillisonWellcome Trust (WELLCOTR)202789/Z/16/ZIII - Immunology