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

• Published in: Neurology : neuroimmunology & neuroinflammation Vol. 11; no. 2; p. e200187
• Main Authors: Wiessler, Anna-Lena, Talucci, Ivan, Piro, Inken, Seefried, Sabine, Hörlin, Verena, Baykan, Betül B, Tüzün, Erdem, Schaefer, Natascha, Maric, Hans M, Sommer, Claudia, Villmann, Carmen
• Format: Journal Article
• Language: English
• Published: United States 01.03.2024
• Subjects: Autoantibodies; Autoimmune Diseases; Carrier Proteins - metabolism; Glycine; Humans; Receptors, Glycine - chemistry; Receptors, Glycine - metabolism; Stiff-Person Syndrome
• DOI: 10.1212/NXI.0000000000200187
• ISSN: 2332-7812

Stiff-person syndrome (SPS) and progressive encephalomyelitis with rigidity and myoclonus (PERM) are rare neurologic disorders of the CNS. Until now, exclusive GlyRα 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 GlyRβ subunits has not yet been shown. Autoantibodies against GlyRα1 target the large extracellular N-terminal domain. This domain shares a high degree of sequence homology with GlyRβ making it not unlikely that GlyRβ-specific autoantibody (aAb) exist and contribute to the disease pathology. In this study, we investigated serum samples from 58 patients for aAb specifically detecting GlyRβ. Studies in microarray format, cell-based assays, and primary spinal cord neurons and spinal cord tissue immunohistochemistry were performed to determine specific GlyRβ 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 GlyRβ aAb binding were resolved by whole-cell patch-clamp recordings. Among 58 samples investigated, cell-based assays, tissue analysis, and preadsorption approaches revealed 2 patients with high specificity for GlyRβ aAb. Quantitative protein cluster analysis demonstrated aAb binding to synaptic GlyRβ colocalized with the scaffold protein gephyrin independent of the presence of GlyRα1. At the functional level, binding of GlyRβ aAb from both patients to its target impair glycine efficacy. Our study establishes GlyRβ as novel target of aAb in patients with SPS/PERM. In contrast to exclusively GlyRα1-positive sera, which alter glycine potency, aAbs against GlyRβ impair receptor efficacy for the neurotransmitter glycine. Imaging and functional analyses showed that GlyRβ aAbs antagonize inhibitory neurotransmission by affecting receptor function rather than localization.