Anti-ganglioside antibodies can bind peripheral nerve nodes of Ranvier and activate the complement cascade without inducing acute conduction block in vitro

Abstract

The neurophysiological effects of nine neuropathy-associated human anti-ganglioside antisera, three monoclonal antibodies to ganglioside GM1 (GM1) and of the cholera toxin B subunit (a GM1 ligand) were studied on mouse sciatic nerve in vitro. GM1 antisera and monoclonal antibodies from patients with chronic motor neuropathies and Guillain-Barre syndrome, and GQ1b/ disialosyl antisera and monoclonal antibodies from patients with chronic ataxic neuropathies and Miller Fisher syndrome were studied. In vitro recording, for up to 6 h, of compound nerve action potentials, latencies, rise times and stimulus thresholds from isolated desheathed sciatic nerve was performed in the presence of antiganglioside antibodies and fresh human serum as an additional source of complement. No changes were observed over this time course, with 4-6 h values for all electrophysiological parameters being within 15% of the starting values for both normal and antibody containing sera and for the cholera toxin B subunit. Parallel experiments on identically prepared desheathed nerves performed with 0.5 nM saxitoxin led to complete conduction block within 10 min of application. Under identical conditions to those used for electrophysiological recordings, quantitative immunohistological evaluation revealed a significant increase in IgM (immunoglobulin M) deposition at nodes of Ranvier from 5.3+/-3.1% to 28.7+/-8.4% (mean+/-SEM) of desheathed nerves exposed to three normal and three antibody containing sera, respectively (P < 0.03). Complement activation was seen at 100% of normal and 79% of disease-associated IgM positive nodes of Ranvier. These data indicate that anti-ganglioside antibodies can diffuse into a desheathed nerve, bind to nodes of Ranvier and fix complement in vitro without resulting in any overt physiological deterioration of the nerve over 4-6 h. This suggests that the node of Ranvier is relatively resistant to acute antiganglioside antibody mediated injury over this time scale and that anti-ganglioside antibodies and the cholera toxin B subunit are unlikely to have major direct pharmacological effects on nodal function, at least in comparison with the effect of saxitoxin. This in vitro sciatic nerve model appears of limited use for analysing electrophysiologically the effects of anti-ganglioside antibodies on nerve function, possibly because its short-term viability and isolation from circulating systemic factors do not permit the evolution of an inflammatory lesion of sufficient magnitude to induce overt electrophysiological abnormalities. In vivo models may be more suitable for identifying the effects of these antibodies on nerve conduction.

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

“…action potential conduction (Paparounas et al, 1999). A reduction of functioning Na v channels results in reduced inward Na ϩ currents and increased threshold for generation of action potentials.…”

Anti-ganglioside antibody internalization attenuates motor nerve terminal injury in a mouse model of acute motor axonal neuropathy

“…In the acute motor axonal neuropathy (AMAN) variant of GBS, the lipopolysaccharide of C. jejuni initiates the production of Abs against the gangliosides GM1 and GD1a via molecular mimicry (1). Human autopsy (2) and experimental animal (3)(4)(5) evidence suggests that anti-ganglioside Abs (AGAbs) bind to the axolemmal membrane at the node of Ranvier, where they fix complement, resulting in nodal dysfunction and, in severe cases, axonal degeneration.…”

The neuropathic potential of anti-GM1 autoantibodies is regulated by the local glycolipid environment in mice

“…With respect to the antibody induction phase of the illness, it is clearly established that anti-GM1 antibodies can arise through molecular mimicry with structurally homologous Campylobacter jejuni lipooligosaccharides (LOS) (15)(16)(17)(18). In contrast, examination of the effector pathways through which anti-GM1 antibodies selectively bind to and induce injury in motor nerve membranes, while avoiding damage to other neural and non-neural plasma membranes containing abundant GM1, is confounded by inconsistent and often counterintuitive data (9,(19)(20)(21)(22). In particular, the sensitivity or resistance of the membrane toward undergoing anti-GM1 antibody-mediated injury cannot be fully explained by the presence and density of plasma membrane GM1.…”