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Glycine Receptor ß-Targeting Autoantibodies Contribute to the Pathology of Autoimmune Diseases.
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.
Affiliation
  • Wiessler AL; From the Institute for Clinical Neurobiology (A.-L.W., V.H., N.S., C.V.), University of Wuerzburg; Department of Neurology (I.T., I.P., S.S., C.S.), University Hospital Wuerzburg; Rudolf Virchow Center for Integrative and Translational Bioimaging (I.T., H.M.M.), University of Wuerzburg, Germany; Dep
  • Talucci I; From the Institute for Clinical Neurobiology (A.-L.W., V.H., N.S., C.V.), University of Wuerzburg; Department of Neurology (I.T., I.P., S.S., C.S.), University Hospital Wuerzburg; Rudolf Virchow Center for Integrative and Translational Bioimaging (I.T., H.M.M.), University of Wuerzburg, Germany; Dep
  • Piro I; From the Institute for Clinical Neurobiology (A.-L.W., V.H., N.S., C.V.), University of Wuerzburg; Department of Neurology (I.T., I.P., S.S., C.S.), University Hospital Wuerzburg; Rudolf Virchow Center for Integrative and Translational Bioimaging (I.T., H.M.M.), University of Wuerzburg, Germany; Dep
  • Seefried S; From the Institute for Clinical Neurobiology (A.-L.W., V.H., N.S., C.V.), University of Wuerzburg; Department of Neurology (I.T., I.P., S.S., C.S.), University Hospital Wuerzburg; Rudolf Virchow Center for Integrative and Translational Bioimaging (I.T., H.M.M.), University of Wuerzburg, Germany; Dep
  • Hörlin V; From the Institute for Clinical Neurobiology (A.-L.W., V.H., N.S., C.V.), University of Wuerzburg; Department of Neurology (I.T., I.P., S.S., C.S.), University Hospital Wuerzburg; Rudolf Virchow Center for Integrative and Translational Bioimaging (I.T., H.M.M.), University of Wuerzburg, Germany; Dep
  • Baykan BB; From the Institute for Clinical Neurobiology (A.-L.W., V.H., N.S., C.V.), University of Wuerzburg; Department of Neurology (I.T., I.P., S.S., C.S.), University Hospital Wuerzburg; Rudolf Virchow Center for Integrative and Translational Bioimaging (I.T., H.M.M.), University of Wuerzburg, Germany; Dep
  • Tüzün E; From the Institute for Clinical Neurobiology (A.-L.W., V.H., N.S., C.V.), University of Wuerzburg; Department of Neurology (I.T., I.P., S.S., C.S.), University Hospital Wuerzburg; Rudolf Virchow Center for Integrative and Translational Bioimaging (I.T., H.M.M.), University of Wuerzburg, Germany; Dep
  • Schaefer N; From the Institute for Clinical Neurobiology (A.-L.W., V.H., N.S., C.V.), University of Wuerzburg; Department of Neurology (I.T., I.P., S.S., C.S.), University Hospital Wuerzburg; Rudolf Virchow Center for Integrative and Translational Bioimaging (I.T., H.M.M.), University of Wuerzburg, Germany; Dep
  • Maric HM; From the Institute for Clinical Neurobiology (A.-L.W., V.H., N.S., C.V.), University of Wuerzburg; Department of Neurology (I.T., I.P., S.S., C.S.), University Hospital Wuerzburg; Rudolf Virchow Center for Integrative and Translational Bioimaging (I.T., H.M.M.), University of Wuerzburg, Germany; Dep
  • Sommer C; From the Institute for Clinical Neurobiology (A.-L.W., V.H., N.S., C.V.), University of Wuerzburg; Department of Neurology (I.T., I.P., S.S., C.S.), University Hospital Wuerzburg; Rudolf Virchow Center for Integrative and Translational Bioimaging (I.T., H.M.M.), University of Wuerzburg, Germany; Dep
  • Villmann C; From the Institute for Clinical Neurobiology (A.-L.W., V.H., N.S., C.V.), University of Wuerzburg; Department of Neurology (I.T., I.P., S.S., C.S.), University Hospital Wuerzburg; Rudolf Virchow Center for Integrative and Translational Bioimaging (I.T., H.M.M.), University of Wuerzburg, Germany; Dep
Neurol Neuroimmunol Neuroinflamm ; 11(2): e200187, 2024 Mar.
Article in En | MEDLINE | ID: mdl-38215349
ABSTRACT
BACKGROUND AND

OBJECTIVES:

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 GlyRß 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 GlyRß making it not unlikely that GlyRß-specific autoantibody (aAb) exist and contribute to the disease pathology.

METHODS:

In this study, we investigated serum samples from 58 patients for aAb specifically detecting GlyRß. Studies in microarray format, cell-based assays, and primary spinal cord neurons and spinal cord tissue immunohistochemistry were performed to determine specific GlyRß 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 GlyRß aAb binding were resolved by whole-cell patch-clamp recordings.

RESULTS:

Among 58 samples investigated, cell-based assays, tissue analysis, and preadsorption approaches revealed 2 patients with high specificity for GlyRß aAb. Quantitative protein cluster analysis demonstrated aAb binding to synaptic GlyRß colocalized with the scaffold protein gephyrin independent of the presence of GlyRα1. At the functional level, binding of GlyRß aAb from both patients to its target impair glycine efficacy.

DISCUSSION:

Our study establishes GlyRß as novel target of aAb in patients with SPS/PERM. In contrast to exclusively GlyRα1-positive sera, which alter glycine potency, aAbs against GlyRß impair receptor efficacy for the neurotransmitter glycine. Imaging and functional analyses showed that GlyRß aAbs antagonize inhibitory neurotransmission by affecting receptor function rather than localization.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Autoimmune Diseases / Stiff-Person Syndrome / Receptors, Glycine Limits: Humans Language: En Journal: Neurol Neuroimmunol Neuroinflamm Year: 2024 Document type: Article Country of publication:
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Autoimmune Diseases / Stiff-Person Syndrome / Receptors, Glycine Limits: Humans Language: En Journal: Neurol Neuroimmunol Neuroinflamm Year: 2024 Document type: Article Country of publication: