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

Journal

Neurology(R) neuroimmunology & neuroinflammation
ISSN: 2332-7812
Titre abrégé: Neurol Neuroimmunol Neuroinflamm
Pays: United States
ID NLM: 101636388

Informations de publication

Date de publication:
Mar 2024
Historique:
medline: 12 1 2024
pubmed: 12 1 2024
entrez: 12 1 2024
Statut: ppublish

Résumé

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.

Sections du résumé

BACKGROUND AND OBJECTIVES OBJECTIVE
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.
METHODS METHODS
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.
RESULTS RESULTS
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.
DISCUSSION CONCLUSIONS
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.

Identifiants

DOI: 10.1212/NXI.0000000000200187 PMID: 38215349
pubmed: 38215349
doi: 10.1212/NXI.0000000000200187
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

e200187

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Auteurs

Anna-Lena 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; Department of Neurology (B.B.B.), Istanbul Faculty of Medicine; and Institute of Experimental Medical Research (E.T.), Istanbul University, Turkey.

Ivan 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; Department of Neurology (B.B.B.), Istanbul Faculty of Medicine; and Institute of Experimental Medical Research (E.T.), Istanbul University, Turkey.
ORCID: 0000-0001-5617-8869

Inken 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; Department of Neurology (B.B.B.), Istanbul Faculty of Medicine; and Institute of Experimental Medical Research (E.T.), Istanbul University, Turkey.

Sabine 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; Department of Neurology (B.B.B.), Istanbul Faculty of Medicine; and Institute of Experimental Medical Research (E.T.), Istanbul University, Turkey.

Verena 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; Department of Neurology (B.B.B.), Istanbul Faculty of Medicine; and Institute of Experimental Medical Research (E.T.), Istanbul University, Turkey.

Betül B 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; Department of Neurology (B.B.B.), Istanbul Faculty of Medicine; and Institute of Experimental Medical Research (E.T.), Istanbul University, Turkey.

Erdem 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; Department of Neurology (B.B.B.), Istanbul Faculty of Medicine; and Institute of Experimental Medical Research (E.T.), Istanbul University, Turkey.
ORCID: 0000-0002-4483-0394

Natascha 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; Department of Neurology (B.B.B.), Istanbul Faculty of Medicine; and Institute of Experimental Medical Research (E.T.), Istanbul University, Turkey.

Hans M 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; Department of Neurology (B.B.B.), Istanbul Faculty of Medicine; and Institute of Experimental Medical Research (E.T.), Istanbul University, Turkey.

Claudia 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; Department of Neurology (B.B.B.), Istanbul Faculty of Medicine; and Institute of Experimental Medical Research (E.T.), Istanbul University, Turkey.
ORCID: 0000-0002-7064-5002

Carmen 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; Department of Neurology (B.B.B.), Istanbul Faculty of Medicine; and Institute of Experimental Medical Research (E.T.), Istanbul University, Turkey.
ORCID: 0000-0003-1498-6950

Classifications MeSH