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In Guillain-Barré syndrome (GBS), both axonal and demyelinating variants can be mediated by complement-fixing anti-GM1 ganglioside autoantibodies that target peripheral nerve axonal and Schwann cell (SC) membranes, respectively. Critically, the extent of axon degeneration in both variants dictates long-term outcome. The differing pathomechanisms underlying direct axonal injury and the secondary "bystander" axonal degeneration following SC injury are unresolved. To investigate this, we generated glycosyltransferase-disrupted transgenic mice that express GM1 ganglioside either exclusively in neurons (GalNAcT-/--Tg(neuronal)) or glia (GalNAcT-/--Tg(glial)), thereby allowing anti-GM1 antibodies to solely target GM1 in either axonal or SC membranes, respectively. Myelinated axon integrity in distal motor nerves was studied in transgenic mice exposed to anti-GM1 antibody and complement in ex vivo and in vivo injury paradigms. Axonal targeting induced catastrophic acute axonal disruption as expected. When mice with GM1 in SC membranes were targeted, acute disruption of perisynaptic glia, and SC membranes at nodes of Ranvier (NoR) occurred. Following glial injury, axon disruption at nodes also developed sub-acutely, progressing to secondary axon degeneration. These models differentiate the distinctly different axonopathic pathways under in axonal and glial membrane targeting conditions, and provide insights into primary and secondary axon injury, currently a major unsolved area in GBS research.

Original publication

DOI

10.1172/JCI158524

Type

Journal article

Journal

J Clin Invest

Publication Date

07/06/2022

Keywords

Autoimmunity, Demyelinating disorders, Neuroscience