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Glutamate receptor δ2 serum antibodies in pediatric opsoclonus myoclonus ataxia syndrome

Glutamate receptor δ2 serum antibodies in pediatric opsoclonus myoclonus ataxia syndrome
Glutamate receptor δ2 serum antibodies in pediatric opsoclonus myoclonus ataxia syndrome
Objective To identify neuronal surface antibodies in opsoclonus myoclonus ataxia syndrome (OMAS) using contemporary antigen discovery methodology.Methods OMAS patient serum immunoglobulin G immunohistochemistry using age-equivalent rat cerebellar tissue was followed by immunoprecipitation, gel electrophoresis, and mass spectrometry. Data are available via ProteomeXchange (identifier PXD009578). This generated a list of potential neuronal surface cerebellar autoantigens. Live cell-based assays were used to confirm membrane-surface antigens and adsorb antigen-specific immunoglobulin Gs. The serologic results were compared to the clinical data.Results Four of the 6 OMAS sera tested bound rat cerebellar sections. Two of these sera with similar immunoreactivities were used in immunoprecipitation experiments using cerebellum from postnatal rat pups (P18). Mass spectrometry identified 12 cell-surface proteins, of which glutamate receptor δ2 (GluD2), a predominately cerebellar-expressed protein, was found at a 3-fold-higher concentration than the other 11 proteins. Antibodies to GluD2 were identified in 14/16 (87%) OMAS samples, compared with 5/139 (5%) pediatric and 1/38 (2.6%) adult serum controls (p < 0.0001), and in 2/4 sera from patients with neuroblastoma without neurologic features. Adsorption of positive OMAS sera against GluD2-transfected cells substantially reduced but did not eliminate reactivity toward cerebellar sections.Conclusion Autoantibodies to GluD2 are common in patients with OMAS, bind to surface determinants, and are potentially pathogenic.
0028-3878
e1-e10
Berridge, Georgina
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Menassa, David A.
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Moloney, Teresa
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Waters, Patrick J.
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Welding, Imogen
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Thomsen, Selina
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Zuberi, Sameer
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Fischer, Roman
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Aricescu, Radu
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Pike, Michael
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Dale, Russell C.
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Kessler, Benedikt
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Vincent, Angela
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Lim, Ming
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Irani, Sarosh
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Lang, Bethan
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Berridge, Georgina
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Menassa, David A.
eeb394a6-c72b-49d7-a820-95b0256c22d5
Moloney, Teresa
e213675f-d2e8-4db3-9db6-4c4c11a0e285
Waters, Patrick J.
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Welding, Imogen
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Thomsen, Selina
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Zuberi, Sameer
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Fischer, Roman
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Aricescu, Radu
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Pike, Michael
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Dale, Russell C.
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Kessler, Benedikt
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Vincent, Angela
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Lim, Ming
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Irani, Sarosh
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Lang, Bethan
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Berridge, Georgina, Menassa, David A., Moloney, Teresa, Waters, Patrick J., Welding, Imogen, Thomsen, Selina, Zuberi, Sameer, Fischer, Roman, Aricescu, Radu, Pike, Michael, Dale, Russell C., Kessler, Benedikt, Vincent, Angela, Lim, Ming, Irani, Sarosh and Lang, Bethan (2018) Glutamate receptor δ2 serum antibodies in pediatric opsoclonus myoclonus ataxia syndrome. Neurology, e1-e10. (doi:10.1212/WNL.0000000000006035).

Record type: Article

Abstract

Objective To identify neuronal surface antibodies in opsoclonus myoclonus ataxia syndrome (OMAS) using contemporary antigen discovery methodology.Methods OMAS patient serum immunoglobulin G immunohistochemistry using age-equivalent rat cerebellar tissue was followed by immunoprecipitation, gel electrophoresis, and mass spectrometry. Data are available via ProteomeXchange (identifier PXD009578). This generated a list of potential neuronal surface cerebellar autoantigens. Live cell-based assays were used to confirm membrane-surface antigens and adsorb antigen-specific immunoglobulin Gs. The serologic results were compared to the clinical data.Results Four of the 6 OMAS sera tested bound rat cerebellar sections. Two of these sera with similar immunoreactivities were used in immunoprecipitation experiments using cerebellum from postnatal rat pups (P18). Mass spectrometry identified 12 cell-surface proteins, of which glutamate receptor δ2 (GluD2), a predominately cerebellar-expressed protein, was found at a 3-fold-higher concentration than the other 11 proteins. Antibodies to GluD2 were identified in 14/16 (87%) OMAS samples, compared with 5/139 (5%) pediatric and 1/38 (2.6%) adult serum controls (p < 0.0001), and in 2/4 sera from patients with neuroblastoma without neurologic features. Adsorption of positive OMAS sera against GluD2-transfected cells substantially reduced but did not eliminate reactivity toward cerebellar sections.Conclusion Autoantibodies to GluD2 are common in patients with OMAS, bind to surface determinants, and are potentially pathogenic.

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Accepted/In Press date: 18 May 2018
e-pub ahead of print date: 25 July 2018

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Local EPrints ID: 422674
URI: https://eprints.soton.ac.uk/id/eprint/422674
ISSN: 0028-3878
PURE UUID: f9a1ffd6-3f64-4a91-9811-51d714afd79f

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Date deposited: 30 Jul 2018 16:30
Last modified: 13 Mar 2019 18:13

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Contributors

Author: Georgina Berridge
Author: Teresa Moloney
Author: Patrick J. Waters
Author: Imogen Welding
Author: Selina Thomsen
Author: Sameer Zuberi
Author: Roman Fischer
Author: Radu Aricescu
Author: Michael Pike
Author: Russell C. Dale
Author: Benedikt Kessler
Author: Angela Vincent
Author: Ming Lim
Author: Sarosh Irani
Author: Bethan Lang

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