Anti-GM1 antibodies cause complement-mediated disruption of sodium channel clusters in peripheral motor nerve fibers.
Voltage-gated Na+ (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.
Susuki
Keiichiro
K
Department of Neurology and Research Institute for Neuroimmunological Diseases, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan. ksusuki@uchc.edu
Rasband
Matthew N
MN
Tohyama
Koujiro
K
Koibuchi
Katsura
K
Okamoto
Saori
S
Funakoshi
Kei
K
Hirata
Koichi
K
Baba
Hiroko
H
Yuki
Nobuhiro
N
D000818:Animals; D001323:Autoantibodies / Q000502:physiology*; D003165:Complement System Proteins / Q000502:physiology*; D005677:G(M1) Ganglioside / Q000276:immunology*; D008297:Male; D009412:Nerve Fibers / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010525:Peripheral Nerves / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011817:Rabbits; D011901:Ranvier's Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D015222:Sodium Channels / Q000378:metabolism*
D001323:Autoantibodies; D015222:Sodium Channels; D005677:G(M1) Ganglioside; D003165:Complement System Proteins