Glycine Receptor β-Targeting Autoantibodies Contribute to the Pathology of Autoimmune Diseases

Background and ObjectivesStiff-person syndrome (SPS) and progressive encephalomyelitis with rigidity and myoclonus (PERM) are rare neurologic disorders of the CNS. Until now, exclusive GlyR alpha subunit-binding autoantibodies with subsequent changes in function and surface numbers were reported. GlyR autoantibodies have also been described in patients with focal epilepsy. Autoimmune reactivity against the GlyR beta subunits has not yet been shown. Autoantibodies against GlyR alpha 1 target the large extracellular N-terminal domain. This domain shares a high degree of sequence homology with GlyR beta making it not unlikely that GlyR beta-specific autoantibody (aAb) exist and contribute to the disease pathology.MethodsIn this study, we investigated serum samples from 58 patients for aAb specifically detecting GlyR beta. Studies in microarray format, cell-based assays, and primary spinal cord neurons and spinal cord tissue immunohistochemistry were performed to determine specific GlyR beta binding and define aAb binding to distinct protein regions. Preadsorption approaches of aAbs using living cells and the purified extracellular receptor domain were further used. Finally, functional consequences for inhibitory neurotransmission upon GlyR beta aAb binding were resolved by whole-cell patch-clamp recordings.ResultsAmong 58 samples investigated, cell-based assays, tissue analysis, and preadsorption approaches revealed 2 patients with high specificity for GlyR beta aAb. Quantitative protein cluster analysis demonstrated aAb binding to synaptic GlyR beta colocalized with the scaffold protein gephyrin independent of the presence of GlyR alpha 1. At the functional level, binding of GlyR beta aAb from both patients to its target impair glycine efficacy.DiscussionOur study establishes GlyR beta as novel target of aAb in patients with SPS/PERM. In contrast to exclusively GlyR alpha 1-positive sera, which alter glycine potency, aAbs against GlyR beta impair receptor efficacy for the neurotransmitter glycine. Imaging and functional analyses showed that GlyR beta aAbs antagonize inhibitory neurotransmission by affecting receptor function rather than localization.