Abstract
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 disrupt profoundly glycinergic neurotransmission. In whole-cell patch clamp recordings from cultured rat spinal motor neurons, 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 internalization of receptors. By contrast, we observed substantial reductions in glycinergic currents with all four patient IgG preparations with 15 min of exposure to patient IgGs. Moreover, monovalent Fab fragments generated from the purified IgG of three of 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.
Highlights
Over the past 15 years autoantibodies to extracellular epitopes of neuronal surface proteins have been described in patients with a spectrum of acquired neuropsychiatric diseases (Crisp et al, 2016)
While specific autoantibodies to exposed epitopes in the CNS are identified in an increasing proportion of patients presenting with neurological disorders, it is sometimes unclear whether the autoantibodies are pathogenic or whether they occur as an epiphenomenon, for example as a result of neuronal damage due to degenerative processes or seizures (Crisp et al, 2016; Dalmau et al, 2017)
While laboratory studies support a pathogenic role of autoantibodies to N-methyl-D-aspartate (NMDA) receptors (Hughes et al, 2010; Planaguma et al, 2015), -amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (Peng et al, 2015; Haselmann et al, 2018), gammaaminobutyric acid (GABA) B receptors (Nibber et al, 2017), and potassium-channel associated proteins such as leucine rich glioma inactivated 1 (LGI1) (Petit-Pedrol et al, 2018), whether autoantibodies to glycine receptors interfere with normal neuronal signalling remains under-explored
Summary
Over the past 15 years autoantibodies to extracellular epitopes of neuronal surface proteins have been described in patients with a spectrum of acquired neuropsychiatric diseases (Crisp et al, 2016). The discovery of such autoantibodies has revolutionized neurological practice since, in contrast to autoantibodies against intracellular epitopes, these autoantibodies have the potential to be directly pathogenic and the associated diseases correspondingly often respond to immunomodulatory therapies. Knowledge that an autoantibody to a neuronal surface protein is pathogenic facilitates the prompt clinical recognition of patients likely to respond to early immunotherapy aimed at reducing the levels of the antibodies (e.g. plasmapheresis) and suppressing the pathogenic immune response. While laboratory studies support a pathogenic role of autoantibodies to N-methyl-D-aspartate (NMDA) receptors (Hughes et al, 2010; Planaguma et al, 2015), -amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (Peng et al, 2015; Haselmann et al, 2018), gammaaminobutyric acid (GABA) B receptors (Nibber et al, 2017), and potassium-channel associated proteins such as leucine rich glioma inactivated 1 (LGI1) (Petit-Pedrol et al, 2018), whether autoantibodies to glycine receptors interfere with normal neuronal signalling remains under-explored
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