Anti-ganglioside antibody internalization attenuates motor nerve terminal injury in a mouse model of acute motor axonal neuropathy
Simon N. Fewou, … , Jaap J. Plomp, Hugh J. Willison
Simon N. Fewou, … , Jaap J. Plomp, Hugh J. Willison
Published February 6, 2012
Citation Information: J Clin Invest. 2012;122(3):1037-1051. https://doi.org/10.1172/JCI59110.
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Anti-ganglioside antibody internalization attenuates motor nerve terminal injury in a mouse model of acute motor axonal neuropathy

Abstract

In the Guillain-Barré syndrome subform acute motor axonal neuropathy (AMAN), Campylobacter jejuni enteritis triggers the production of anti-ganglioside Abs (AGAbs), leading to immune-mediated injury of distal motor nerves. An important question has been whether injury to the presynaptic neuron at the neuromuscular junction is a major factor in AMAN. Although disease modeling in mice exposed to AGAbs indicates that complement-mediated necrosis occurs extensively in the presynaptic axons, evidence in humans is more limited, in comparison to the extensive injury seen at nodes of Ranvier. We considered that rapid AGAb uptake at the motor nerve terminal membrane might attenuate complement-mediated injury. We found that PC12 rat neuronal cells rapidly internalized AGAb, which were trafficked to recycling endosomes and lysosomes. Consequently, complement-mediated cytotoxicity was attenuated. Importantly, we observed the same AGAb endocytosis and protection from cytotoxicity in live mouse nerve terminals. AGAb uptake was attenuated following membrane cholesterol depletion in vitro and ex vivo, indicating that this process may be dependent upon cholesterol-enriched microdomains. In contrast, we observed minimal AGAb uptake at nodes of Ranvier, and this structure thus remained vulnerable to complement-mediated injury. These results indicate that differential endocytic processing of AGAbs by different neuronal and glial membranes might be an important modulator of site-specific injury in acute AGAb-mediated Guillain-Barré syndrome subforms and their chronic counterparts.

Authors

Simon N. Fewou, Angie Rupp, Lauren E. Nickolay, Kathryn Carrick, Kay N. Greenshields, John Pediani, Jaap J. Plomp, Hugh J. Willison

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Figure 6

Anti-GD1a Ab uptake protects NMJs from injury in vivo.

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Anti-GD1a Ab uptake protects NMJs from injury in vivo. (A) Sternomastoid...
(A) Sternomastoid muscles from live anesthetized mice were labeled with anti-GD1a together with NHS (0 minutes) or anti-GD1a alone for 30 minutes, followed by 60 minutes with Ringer’s before exposure to NHS. Control mice received Ringer’s alone. NMJs were visually assessed for the loss of CFP overlying the acetylcholine receptor staining, and the percentage of NMJs that retained the CFP (healthy NMJs) was calculated. There is an increase in healthy NMJs in tissue incubated at 37°C. NMJs incubated in Ringer’s for 60 minutes (to allow Ab uptake) before exposure to NHS are protected from injury. Scale bar: 50 μm. (B) Quantitative analysis of NMJ integrity showing significant preservation of the endplate structure (arrows in A) in tissues subjected to a gap of 60 minutes incubation with Ringer’s prior to exposure to NHS. n = 3; **P < 0.001.