Immunoglobulins inhibit pathophysiological effects of anti-GQ1b-positive sera at motor nerve terminals through inhibition of antibody binding

Abstract

High-dose intravenous immunoglobulin is an effective treatment for many antibody-mediated neuromuscular diseases, suggesting that intravenous immunoglobulin directly interferes with the pathways through which the pathogenic antibodies exert their effects. However, the precise mechanisms of action are unclear. Serum anti-GQ1b antibodies are strongly associated with ophthalmoplegia in patients with Miller Fisher syndrome and Guillain-Barre syndrome. They induce complement-mediated alpha-latrotoxin-like effects on mouse neuromuscular junctions ex vivo, comprising transient muscle fiber twitching, due to a dramatic increase in the frequency of miniature end-plate potentials (spontaneous quantal acetylcholine release), followed by transmission block. To clarify the mechanisms by which intravenous immunoglobulin may act in Miller Fisher syndrome and Guillain-Barre syndrome, the authors investigated its effects on the interaction of anti-GQ1b antibodies with GQ1b in vitro and on anti-GQ1b antibody-mediated neuromuscular junction injury ex vivo, using anti-GQ1b-positive serum samples from Miller Fisher syndrome and Guillain-Barre syndrome patients. They showed that intravenous immunoglobulin inhibits the binding of anti-GQ1b antibodies to GQ1b, thereby preventing complement activation and subsequent pathophysiological effects in their ex vivo mouse neuromuscular junction model. These results provide further support for the hypothesis that anti-ganglioside antibodies are the pathogenic factors in Miller Fisher syndrome and Guillain-Barre syndrome and show that this neuromuscular junction model provides a suitable system for investigating the therapeutic effects of intravenous immunoglobulin in antibody-mediated neuromuscular diseases. Valerie Biousse