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Protective anti‐prion antibodies in human immunoglobulin repertoires

Prion immunotherapy may hold great potential, but antibodies against certain PrP epitopes can be neurotoxic. Here, we identified > 6,000 PrP‐binding antibodies in a synthetic human Fab phage display library, 49 of which we characterized in detail. Antibodies directed against the flexible tail of...

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Autores principales: Senatore, Assunta, Frontzek, Karl, Emmenegger, Marc, Chincisan, Andra, Losa, Marco, Reimann, Regina, Horny, Geraldine, Guo, Jingjing, Fels, Sylvie, Sorce, Silvia, Zhu, Caihong, George, Nathalie, Ewert, Stefan, Pietzonka, Thomas, Hornemann, Simone, Aguzzi, Adriano
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506995/
https://www.ncbi.nlm.nih.gov/pubmed/32776637
http://dx.doi.org/10.15252/emmm.202012739
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author Senatore, Assunta
Frontzek, Karl
Emmenegger, Marc
Chincisan, Andra
Losa, Marco
Reimann, Regina
Horny, Geraldine
Guo, Jingjing
Fels, Sylvie
Sorce, Silvia
Zhu, Caihong
George, Nathalie
Ewert, Stefan
Pietzonka, Thomas
Hornemann, Simone
Aguzzi, Adriano
author_facet Senatore, Assunta
Frontzek, Karl
Emmenegger, Marc
Chincisan, Andra
Losa, Marco
Reimann, Regina
Horny, Geraldine
Guo, Jingjing
Fels, Sylvie
Sorce, Silvia
Zhu, Caihong
George, Nathalie
Ewert, Stefan
Pietzonka, Thomas
Hornemann, Simone
Aguzzi, Adriano
author_sort Senatore, Assunta
collection PubMed
description Prion immunotherapy may hold great potential, but antibodies against certain PrP epitopes can be neurotoxic. Here, we identified > 6,000 PrP‐binding antibodies in a synthetic human Fab phage display library, 49 of which we characterized in detail. Antibodies directed against the flexible tail of PrP conferred neuroprotection against infectious prions. We then mined published repertoires of circulating B cells from healthy humans and found antibodies similar to the protective phage‐derived antibodies. When expressed recombinantly, these antibodies exhibited anti‐PrP reactivity. Furthermore, we surveyed 48,718 samples from 37,894 hospital patients for the presence of anti‐PrP IgGs and found 21 high‐titer individuals. The clinical files of these individuals did not reveal any enrichment of specific pathologies, suggesting that anti‐PrP autoimmunity is innocuous. The existence of anti‐prion antibodies in unbiased human immunological repertoires suggests that they might clear nascent prions early in life. Combined with the reported lack of such antibodies in carriers of disease‐associated PRNP mutations, this suggests a link to the low incidence of spontaneous prion diseases in human populations.
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spelling pubmed-75069952020-09-28 Protective anti‐prion antibodies in human immunoglobulin repertoires Senatore, Assunta Frontzek, Karl Emmenegger, Marc Chincisan, Andra Losa, Marco Reimann, Regina Horny, Geraldine Guo, Jingjing Fels, Sylvie Sorce, Silvia Zhu, Caihong George, Nathalie Ewert, Stefan Pietzonka, Thomas Hornemann, Simone Aguzzi, Adriano EMBO Mol Med Articles Prion immunotherapy may hold great potential, but antibodies against certain PrP epitopes can be neurotoxic. Here, we identified > 6,000 PrP‐binding antibodies in a synthetic human Fab phage display library, 49 of which we characterized in detail. Antibodies directed against the flexible tail of PrP conferred neuroprotection against infectious prions. We then mined published repertoires of circulating B cells from healthy humans and found antibodies similar to the protective phage‐derived antibodies. When expressed recombinantly, these antibodies exhibited anti‐PrP reactivity. Furthermore, we surveyed 48,718 samples from 37,894 hospital patients for the presence of anti‐PrP IgGs and found 21 high‐titer individuals. The clinical files of these individuals did not reveal any enrichment of specific pathologies, suggesting that anti‐PrP autoimmunity is innocuous. The existence of anti‐prion antibodies in unbiased human immunological repertoires suggests that they might clear nascent prions early in life. Combined with the reported lack of such antibodies in carriers of disease‐associated PRNP mutations, this suggests a link to the low incidence of spontaneous prion diseases in human populations. John Wiley and Sons Inc. 2020-08-10 2020-09-07 /pmc/articles/PMC7506995/ /pubmed/32776637 http://dx.doi.org/10.15252/emmm.202012739 Text en © 2020 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Senatore, Assunta
Frontzek, Karl
Emmenegger, Marc
Chincisan, Andra
Losa, Marco
Reimann, Regina
Horny, Geraldine
Guo, Jingjing
Fels, Sylvie
Sorce, Silvia
Zhu, Caihong
George, Nathalie
Ewert, Stefan
Pietzonka, Thomas
Hornemann, Simone
Aguzzi, Adriano
Protective anti‐prion antibodies in human immunoglobulin repertoires
title Protective anti‐prion antibodies in human immunoglobulin repertoires
title_full Protective anti‐prion antibodies in human immunoglobulin repertoires
title_fullStr Protective anti‐prion antibodies in human immunoglobulin repertoires
title_full_unstemmed Protective anti‐prion antibodies in human immunoglobulin repertoires
title_short Protective anti‐prion antibodies in human immunoglobulin repertoires
title_sort protective anti‐prion antibodies in human immunoglobulin repertoires
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506995/
https://www.ncbi.nlm.nih.gov/pubmed/32776637
http://dx.doi.org/10.15252/emmm.202012739
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