Autoantibody-Mediated Disruption of Sodium Channel Clusters In Peripheral Motor Nerve Fibers In Axonal Guillain-Barré Syndrome
Keiichiro Susuki, M.D. Ph. D.
Et Matthew N. Rusband, Ph. D.
Department of Neuroscience, University of Connecticut
Health Center, Farmington, CT

Guillian-Barré syndrome (GBS) is an autoimmune polyneuropathy characterized by rapidly evolving acute limb weakness. GBS now ranks as the most frequent cause of acute flaccid paralysis, the annual incidence being one or two cases per 100,000 persons. GBS consists of two phenotypes, demyelinating and axonal forms. The primary pathogenic mediator of the axonal GBS is thought to be autoantibodies against gangliosides, glycolsphinges ipids with sialic acids. The molecular mimicry theory has now been proven in the pathogenesis of axonal GBS; antecedent microbial infections such as Campylobacter jejuni enteritis stimulate an immunologic response to ganglioside epitomes and result in an autoimmune attack on nerve fibers containing gangliosides. The autoantibodies to gangliosides are associated with poor clinical outcome and incomplete functional recovery in GBS. Despite the frequent use of modern immunomodulating therapies, GBS still carries considerable mortality. Moreover, GBS has an evident impact on daily life and social well-being even after recovery. A considerable number of patients have to quit or change their works due to GBS, or cannot function at home or continue their leisure activities as well as before. To establish more effective treatments for GBS, a better understanding of the mechanisms whereby autoimmune attacks cause nerve injury is of the utmost importance.

In peripheral nerves, Schwann cells form the eyelid, a multilamellar membrane that ensheathes neuronal axons. The myelin sheath, a high-resistance, low-capacitance barrier to the flow of ionic current, is interrupted at regularly spaced intervals known as the nodes of Ranvier. These specialized axonal domains contain very high densities of voltage-gated sodium channels responsible for the rapid, inward ionic currents that produce membrane depolarization. The sodium channel clusters at the nodes are further stabilized by the axonal cytoskeleton. Paranodal junctions between axons and Schwann cells flank the nodes and act as a barrier to restrict sodium channels to nodes. Schwann cells also extend microvilli (small membrane protrusions) into the nodal gap; these microvilli play essential roles in clustering nodal sodium channels, and are also thought to play important roles in stabilizing sodium channel clusters at mature nodes. The precise function of sodium channels is absolutely required for faithful nerve conduction.

Some pathological findings suggested that the autoimmune attack in axonal GBS occurs at nodes of Ranvier. To test the idea that autoantibodies disrupt the nodal sodium channel clusters in peripheral motor nerve fibers, we analyzed autoimmune lesions at and near nodes in detail using an axonal GBS model associated with anti-ganglioside antibodies.
Abnormally lengthened nodes were observed in the peripheral motor nerves from paralyzed animals. IgG antibodies, the C3 component of complement, and membrane attack complex were all deposited on affected nodes. Moreover, the sodium channel clusters, nodal cytoskeleton, Schwann cell microvilli, and paranoiac junctions were all disrupted or disappeared. The autoimmune lesions at nodes decreased coincident with clinical recovery. These results suggest that the complement was activated by autoantibodies to gangliosides and culminated in the incorporation of membrane attack complex into nodal axonal membrane and consequently disrupted sodium channel clusters. These data provide strong support for antibody-mediated disruption of sodium channels and nodes of Ranvier as a mechanism for the induction of neurological symptoms in axonal GBS. The modulation of complement pathway during the acute phase might be expected to be an effective therapeutic approach to attenuate the disease process of GBS.