Anti-GM1 Antibodies Cause Complement-Mediated Disruption of Sodium Channel Clusters in Peripheral Motor Nerve Fibers

Abstract

Voltage-gated Naϩ (Na v ) channels are highly concentrated at nodes of Ranvier in myelinated axons and facilitate rapid action potential conduction. Autoantibodies to gangliosides such as GM1 have been proposed to disrupt nodal Nav channels and lead to Guillain-Barré syndrome, an autoimmune neuropathy characterized by acute limb weakness. To test this hypothesis, we examined the molecular organization of nodes in a disease model caused by immunization with gangliosides. At the acute phase with progressing limb weakness, Na v channel clusters were disrupted or disappeared at abnormally lengthened nodes concomitant with deposition of IgG and complement products. Paranodal axoglial junctions, the nodal cytoskeleton, and Schwann cell microvilli, all of which stabilize Na v channel clusters, were also disrupted. The nodal molecules disappeared in lesions with complement deposition but no localization of macrophages. During recovery, complement deposition at nodes decreased, and Na v channels redistributed on both sides of affected nodes. These results suggest that Na v channel alterations occur as a consequence of complement-mediated disruption of interactions between axons and Schwann cells. Our findings support the idea that acute motor axonal neuropathy is a disease that specifically disrupts the nodes of Ranvier.

Guillain–Barré syndrome: a century of progress

“…In summary, many collaborative efforts have demonstrated that anti-GM1 and anti-GQ1b antibodies bind to peripheral nerve and neuromuscular junctions 64,65 , and anti-GD1a antibodies bind to the nodes of Ranvier, paranodal myelin and neuromuscular junction 66,67,68 . Upon binding, the antibodies activate the complement cascade, resulting in formation of the membrane attack complex, disruption of sodium channel clusters at the node of Ranvier with disruption of nodal architecture 69 , and calcium influx and calpain-dependent neuronal and glial injury at the neuromuscular junction 70,71 .This injury can be ameliorated with complement inhibitors 72,73 .…”

Cutting Edge: Guillain-Barré Syndrome-Associated IgG Responses to Gangliosides Are Generated Independently of CD1 Function in Mice

“…This "molecular mimicry" theory has been further substantiated by establishing animal models of human GBS. Rabbits sensitized with GM1-like LOS from C. jejuni (CF90-26) generate IgG anti-GM1 Abs that induce complement-mediated disruption of sodium channel clusters in the peripheral nerves, leading to the development of flaccid limb weakness (7). It is noteworthy that, whereas most IgG Abs against bacterial polysaccharides are of the IgG2 isotype, the cross-reactive IgG Abs to gangliosides and LOS that develop during C. jejuni enteritis-associated GBS comprise primarily IgG1 and IgG3 subclasses (8).…”

Simultaneous immunohistochemical detection of gangliosides and neuronal markers in paraformaldehyde-fixed nervous tissues by acetone etching

“…A comparison of ganglioside location between normal mice and ganglioside synthase knockout mice by co-staining for neuronal markers may be also useful for analyzing the function of affected gangliosides. Furthermore, this approach can detect the localization of gangliosides suspected as target antigens that might be expressed by a certain subpopulation of DRG neurons (Gong et al, 2002) and a subregion at the nodes of Ranvier (Susuki et al, 2007) in autoimmune neuropathies. Co-staining for type IV collagen readily outlines the tissue framework (Matsuno et al, 1996), including the nerve cell body, myelin sheath, and blood vessels, enabling us to locate gangliosides easily.…”