Naturally occurring antibodies isolated from PD patients inhibit synuclein seeding in vitro and recognize Lewy pathology

Xinyi Li, Wouter Koudstaal, Lauren Fletcher, Martha Costa, Margot van Winsen, Berdien Siregar, Hanna Inganäs, Julie Kim, Elissa Keogh, Jeremy Macedo, Trevin Holland, Stuart Perry, Frederique Bard, Jeroen J. Hoozemans, Jaap Goudsmit, Adrian Apetri, Gabriel Pascual

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Deposition of α-synuclein into Lewy bodies and Lewy neurites is the hallmark of Parkinson’s disease (PD). It is hypothesized that α-synuclein pathology spreads by a “prion-like” mechanism (i.e., by seeded aggregation or templated misfolding). Therefore, various extracellular α-synuclein conformers and/or posttranslational modifications may serve as biomarkers of disease or potential targets for novel interventions. To explore whether the antibody repertoires of PD patients contain anti-α-synuclein antibodies that can potentially be used as markers or immunotherapy, we interrogated peripheral IgG + memory B cells from PD patients for reactivity to α-synuclein. In total, ten somatically mutated antibodies were recovered, suggesting the presence of an ongoing antigen-driven immune response. The three antibodies that had the highest affinity to recombinant full-length α-synuclein, aSyn-323.1, aSyn-336.1 and aSyn-338.1, were characterized further and shown to recognize epitopes in the C terminus of α-synuclein with binding affinities between 0.3 and 2.8 μM. Furthermore, all three antibodies were able to neutralize the “seeding” of intracellular synuclein aggregates in an in vitro α-synuclein seeding assay. Finally, differential reactivities were observed for all three human anti-α-synuclein antibodies across tissue treatment conditions by immunohistochemistry. Our results suggest that the memory B-cell repertoire of PD patients might represent a potential source of biomarkers and therapies.
LanguageEnglish
JournalActa Neuropathologica
DOIs
Publication statusPublished - 2019

Cite this

Li, Xinyi ; Koudstaal, Wouter ; Fletcher, Lauren ; Costa, Martha ; van Winsen, Margot ; Siregar, Berdien ; Inganäs, Hanna ; Kim, Julie ; Keogh, Elissa ; Macedo, Jeremy ; Holland, Trevin ; Perry, Stuart ; Bard, Frederique ; Hoozemans, Jeroen J. ; Goudsmit, Jaap ; Apetri, Adrian ; Pascual, Gabriel. / Naturally occurring antibodies isolated from PD patients inhibit synuclein seeding in vitro and recognize Lewy pathology. In: Acta Neuropathologica. 2019.
@article{29c62774183b4f2f9648e5d12035134f,
title = "Naturally occurring antibodies isolated from PD patients inhibit synuclein seeding in vitro and recognize Lewy pathology",
abstract = "Deposition of α-synuclein into Lewy bodies and Lewy neurites is the hallmark of Parkinson’s disease (PD). It is hypothesized that α-synuclein pathology spreads by a “prion-like” mechanism (i.e., by seeded aggregation or templated misfolding). Therefore, various extracellular α-synuclein conformers and/or posttranslational modifications may serve as biomarkers of disease or potential targets for novel interventions. To explore whether the antibody repertoires of PD patients contain anti-α-synuclein antibodies that can potentially be used as markers or immunotherapy, we interrogated peripheral IgG + memory B cells from PD patients for reactivity to α-synuclein. In total, ten somatically mutated antibodies were recovered, suggesting the presence of an ongoing antigen-driven immune response. The three antibodies that had the highest affinity to recombinant full-length α-synuclein, aSyn-323.1, aSyn-336.1 and aSyn-338.1, were characterized further and shown to recognize epitopes in the C terminus of α-synuclein with binding affinities between 0.3 and 2.8 μM. Furthermore, all three antibodies were able to neutralize the “seeding” of intracellular synuclein aggregates in an in vitro α-synuclein seeding assay. Finally, differential reactivities were observed for all three human anti-α-synuclein antibodies across tissue treatment conditions by immunohistochemistry. Our results suggest that the memory B-cell repertoire of PD patients might represent a potential source of biomarkers and therapies.",
author = "Xinyi Li and Wouter Koudstaal and Lauren Fletcher and Martha Costa and {van Winsen}, Margot and Berdien Siregar and Hanna Ingan{\"a}s and Julie Kim and Elissa Keogh and Jeremy Macedo and Trevin Holland and Stuart Perry and Frederique Bard and Hoozemans, {Jeroen J.} and Jaap Goudsmit and Adrian Apetri and Gabriel Pascual",
year = "2019",
doi = "10.1007/s00401-019-01974-5",
language = "English",
journal = "Acta Neuropathologica",
issn = "0001-6322",
publisher = "Springer Verlag",

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Li, X, Koudstaal, W, Fletcher, L, Costa, M, van Winsen, M, Siregar, B, Inganäs, H, Kim, J, Keogh, E, Macedo, J, Holland, T, Perry, S, Bard, F, Hoozemans, JJ, Goudsmit, J, Apetri, A & Pascual, G 2019, 'Naturally occurring antibodies isolated from PD patients inhibit synuclein seeding in vitro and recognize Lewy pathology', Acta Neuropathologica. https://doi.org/10.1007/s00401-019-01974-5

Naturally occurring antibodies isolated from PD patients inhibit synuclein seeding in vitro and recognize Lewy pathology. / Li, Xinyi; Koudstaal, Wouter; Fletcher, Lauren; Costa, Martha; van Winsen, Margot; Siregar, Berdien; Inganäs, Hanna; Kim, Julie; Keogh, Elissa; Macedo, Jeremy; Holland, Trevin; Perry, Stuart; Bard, Frederique; Hoozemans, Jeroen J.; Goudsmit, Jaap; Apetri, Adrian; Pascual, Gabriel.

In: Acta Neuropathologica, 2019.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Naturally occurring antibodies isolated from PD patients inhibit synuclein seeding in vitro and recognize Lewy pathology

AU - Li, Xinyi

AU - Koudstaal, Wouter

AU - Fletcher, Lauren

AU - Costa, Martha

AU - van Winsen, Margot

AU - Siregar, Berdien

AU - Inganäs, Hanna

AU - Kim, Julie

AU - Keogh, Elissa

AU - Macedo, Jeremy

AU - Holland, Trevin

AU - Perry, Stuart

AU - Bard, Frederique

AU - Hoozemans, Jeroen J.

AU - Goudsmit, Jaap

AU - Apetri, Adrian

AU - Pascual, Gabriel

PY - 2019

Y1 - 2019

N2 - Deposition of α-synuclein into Lewy bodies and Lewy neurites is the hallmark of Parkinson’s disease (PD). It is hypothesized that α-synuclein pathology spreads by a “prion-like” mechanism (i.e., by seeded aggregation or templated misfolding). Therefore, various extracellular α-synuclein conformers and/or posttranslational modifications may serve as biomarkers of disease or potential targets for novel interventions. To explore whether the antibody repertoires of PD patients contain anti-α-synuclein antibodies that can potentially be used as markers or immunotherapy, we interrogated peripheral IgG + memory B cells from PD patients for reactivity to α-synuclein. In total, ten somatically mutated antibodies were recovered, suggesting the presence of an ongoing antigen-driven immune response. The three antibodies that had the highest affinity to recombinant full-length α-synuclein, aSyn-323.1, aSyn-336.1 and aSyn-338.1, were characterized further and shown to recognize epitopes in the C terminus of α-synuclein with binding affinities between 0.3 and 2.8 μM. Furthermore, all three antibodies were able to neutralize the “seeding” of intracellular synuclein aggregates in an in vitro α-synuclein seeding assay. Finally, differential reactivities were observed for all three human anti-α-synuclein antibodies across tissue treatment conditions by immunohistochemistry. Our results suggest that the memory B-cell repertoire of PD patients might represent a potential source of biomarkers and therapies.

AB - Deposition of α-synuclein into Lewy bodies and Lewy neurites is the hallmark of Parkinson’s disease (PD). It is hypothesized that α-synuclein pathology spreads by a “prion-like” mechanism (i.e., by seeded aggregation or templated misfolding). Therefore, various extracellular α-synuclein conformers and/or posttranslational modifications may serve as biomarkers of disease or potential targets for novel interventions. To explore whether the antibody repertoires of PD patients contain anti-α-synuclein antibodies that can potentially be used as markers or immunotherapy, we interrogated peripheral IgG + memory B cells from PD patients for reactivity to α-synuclein. In total, ten somatically mutated antibodies were recovered, suggesting the presence of an ongoing antigen-driven immune response. The three antibodies that had the highest affinity to recombinant full-length α-synuclein, aSyn-323.1, aSyn-336.1 and aSyn-338.1, were characterized further and shown to recognize epitopes in the C terminus of α-synuclein with binding affinities between 0.3 and 2.8 μM. Furthermore, all three antibodies were able to neutralize the “seeding” of intracellular synuclein aggregates in an in vitro α-synuclein seeding assay. Finally, differential reactivities were observed for all three human anti-α-synuclein antibodies across tissue treatment conditions by immunohistochemistry. Our results suggest that the memory B-cell repertoire of PD patients might represent a potential source of biomarkers and therapies.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/30805666

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