-Novel molecular mechanisms associated with impaired peripheral nerve repair mediated by antiganglioside antibodies

CRISTIAN ROMAN BACAGLIO; ANDRES BERARDO; BARBARA BEATRIZ BAEZ; ANA LAURA VIVINETTO; MATTALLONI M.S; CLARA CASTAÑARES; KAZIM SHEIKH; PABLO H H LOPEZ

Congreso; SOCIEDAD ARGENTINA DE INVESTIGACION EN NEUROCIENCIAS; 2019

Guillain Barré Syndrome (GBS) is an acute monophasic polyneuropathy characterized by the presence of ascending muscular paralysis and arreflexia. In a subgroup of patients, paralysis is related to the presence of high titers of antibodies targeting gangliosides (anti-Gg). Passive transfer studies with a mAb anti-Gg (anti GD1a-GT1b, clone 1b7) in a murine model of axon regeneration confirmed that these antibodies are able to inhibit nerve repair by negative modulation of actin and tubulin cytoskeleton in growth cones. In vitro studies demonstrated that this effect is mediated through the activation of RhoA/ROCK/CRMP-2 dependent and independent signaling pathways. However, recent findings in this model show that nerves from animals exposed to anti-Gg display a significant failure in the clearance of tissue debris, suggesting a possible effect on non-neural cells. Chronic administration of a pharmacological inhibitor of the RhoA/ROCK pathway, Y-27632; was able to reverse this effect. Experiments display that mice treated with mAb 1B7 show a reduced number of macrophage extravasation/migration in sciatic nerves respect to control IgG-treated nerves. Furthermore, in vivo experiments highlight the role of anti-Gg in the modulation of macrophage phenotype. Circulating and sciatic nerve extravasated macrophages showed a M2-like phenotype in mice treated with anti-Gg compared to IgG control. In conclusion, these results suggest an inhibitory effect of anti-Gg on nerve repair by targeting non-neural cells.