Neuropathophysiological potential of Guillain-Barré syndrome anti-ganglioside-complex antibodies at mouse motor nerve terminals
Clinical and Experimental Neuroimmunology , Volume 2 - Issue 3 p. 59- 67
Objectives: Anti-ganglioside antibodies are present in approximately half of Guillain-Barré syndrome (GBS) patients. Recently, it has been shown that a considerable proportion of these patients has serum antibodies against antigenic epitopes formed by a complex of two different gangliosides. However, direct experimental evidence for neuropathogenicity of this special category of antibodies is currently lacking. Here, we explored a series of GBS and GBS-variant sera with anti-ganglioside-complex antibodies for their ability to induce complement-dependent deleterious effects at the living neuronal membrane. Methods: The neuropathophysiological potential of 31 GBS sera containing either anti-GM1/GD1a- or anti-GM1/GQ1b-ganglioside-complex antibodies was studied at motor nerve terminal presynaptic membranes in the mouse phrenic nerve/diaphragm muscle ex vivo experimental model. With electrophysiological measurements and confocal fluorescence microscopy, we assessed and quantified the damaging effect on neuronal membranes by anti-ganglioside-complex antibodies. Results: We show that anti-GM1/GD1a- and anti-GM1/GQ1b-ganglioside-complex positive sera can induce complement-mediated functional and morphological injury at mouse motor nerve terminals ex vivo. Of the 31 investigated anti-ganglioside-complex patient sera, 17 sera induced increases in miniature end-plate potential frequency in this experimental model, mostly associated with muscle fibre twitches. Variability in potency was observed, with the anti-GM1/GD1a-complex sera inducing the most outspoken effects. Conclusions: The present study shows the presence of ganglioside-complexes as available antigens in living neuronal membranes and supplies proof-of-principle that anti-ganglioside-complex antibodies in sera from GBS patients can induce complement-mediated damage. This strongly supports the hypothesis that autoimmune targeting of ganglioside-complexes is of pathogenic relevance in a proportion of GBS patients.
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|Clinical and Experimental Neuroimmunology
|Erasmus MC: University Medical Center Rotterdam
Zitman, F., Greenshields, K., Kuijf, M., Ueda, M., Kaida, K. I., Broos, L., … Plomp, J. (2011). Neuropathophysiological potential of Guillain-Barré syndrome anti-ganglioside-complex antibodies at mouse motor nerve terminals. Clinical and Experimental Neuroimmunology, 2(3), 59–67. doi:10.1111/j.1759-1961.2011.00022.x