Schwann cell nodal membrane disruption triggers bystander axonal degeneration in a Guillain-Barré syndrome mouse model

Abstract

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 axonal and glial membrane targeting conditions, and provide insights into primary and secondary axon injury, currently a major unsolved area in GBS research.

Case report: Recreational nitrous oxide abuse triggered peripheral neuropathy possibly through the immune-mediated pathogenesis

“…Albuminocytologic dissociation was not found in CSF while we were the first to report positive anti-GM1 IgM antibodies in both CSF and serum. Gangliosides are specifically enriched in nervous system plasma membranes while GM1 is mainly expressed at nodes of Ranvier and motor nerve terminals (13). When GM1 or its mimicry, Campylobacter jejuni strains, .…”

“…Albuminocytologic dissociation was not found in CSF while we were the first to report positive anti-GM1 IgM antibodies in both CSF and serum. Gangliosides are specifically enriched in nervous system plasma membranes while GM1 is mainly expressed at nodes of Ranvier and motor nerve terminals ( 13 ). When GM1 or its mimicry, Campylobacter jejuni strains, are exposed to the autoimmune system, anti-GM1 antibodies are produced and activate the complement cascade, leading to either reversible conduction failure or axonal degeneration in AMAN patients ( 14 ).…”

Glial cells and neurologic autoimmune disorders

“…Therefore, when the myelin sheath of the PNS is damaged in neurologic autoimmune disorders, it ultimately affects the function of Schwann cells and axons. GBS is a rare neurologic autoimmune disease affecting the Schwann cells in the PNS ( McGonigal et al, 2022 ).…”

Development and In Vitro Differentiation of Schwann Cells

“…Therefore, models for exploring the physiology and pathophysiology of Schwann cells in vitro are of profound interest [ 13 ]. At the same time, Schwann cells are highly interesting for tissue engineering, since they play a critical role in nerve regeneration upon injury and are affected in peripheral neuropathies such as Charcot-Marie-Tooth disease and Guillain-Barré syndrome [ 11 , 14 , 15 , 16 ]. Therefore, the potential of Schwann cells regarding regenerative cell transplantation has been intensely explored in rodent models, with encouraging results.…”