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Glycine receptor autoantibodies disrupt inhibitory neurotransmission

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Crisp, Sarah J 


Chloride-permeable glycine receptors have an important role in fast inhibitory neurotransmission in the spinal cord and brainstem. Human immunoglobulin G (IgG) autoantibodies to glycine receptors are found in a substantial proportion of patients with progressive encephalomyelitis with rigidity and myoclonus, and less frequently in other variants of stiff person syndrome. Demonstrating a pathogenic role of glycine receptor autoantibodies would help justify the use of immunomodulatory therapies and provide insight into the mechanisms involved. Here purified IgGs from four patients with progressive encephalomyelitis with rigidity and myoclonus or stiff person syndrome and glycine receptor autoantibodies were observed to profoundly disrupt glycinergic neurotransmission. In whole cell patch clamp recordings from cultured rat spinal motoneurons, glycinergic synaptic currents were almost completely abolished following incubation in patient IgGs. Most human autoantibodies targeting other CNS neurotransmitter receptors, such as N-methyl-D-aspartate (NMDA) receptors, affect whole cell currents only after several hours’ incubation and this effect has been shown to be the result of antibody-mediated crosslinking and internalisation of receptors. By contrast, we observed substantial reductions in glycinergic currents with all four patient IgG preparations with 15 minutes of exposure to patient IgGs. Moreover, monovalent Fab fragments generated from the purified IgG of three of the four patients also profoundly reduced glycinergic currents compared with control Fab-IgG. We conclude that human glycine receptor autoantibodies disrupt glycinergic neurotransmission, and also suggest that the pathogenic mechanisms include direct antagonistic actions on glycine receptors.



autoantibody, glycine receptor, progressive encephalomyelitis with rigidity and myoclonus (PERM), stiff person syndrome (SPS), Aged, Animals, Autoantibodies, Cells, Cultured, Excitatory Postsynaptic Potentials, Female, Humans, Immunoglobulin Fab Fragments, Immunoglobulin G, Male, Middle Aged, Motor Neurons, Neural Inhibition, Patch-Clamp Techniques, Pregnancy, Rats, Rats, Sprague-Dawley, Receptors, Glycine, Spinal Cord, Stiff-Person Syndrome, Synapses, Synaptic Transmission

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Brain: a journal of neurology

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Oxford University Press
SJC is supported by from the Wellcome Trust (101696/Z/13/Z), the National Institute for Health Research (NIHR), BMA Foundation for Medical Research (Vera Down Award 2017) and the National Organisation for Rare Disorders (16006). CLD is supported by the Wellcome Trust. SRI is supported by the Wellcome Trust (104079/Z/14/Z), BMA Research Grants- Vera Down grant (2013) and Margaret Temple (2017), and by Epilepsy Research UK (P1201). The research was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC; The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health). LJ, MIL and AV received support from the Nuffield Department of Clinical Neurosciences. DMK is supported by the Wellcome Trust, Medical Research Council and Epilepsy Research UK.