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Immunological memory to hyperphosphorylated tau in asymptomatic individuals

Several reports have described the presence of antibodies against Alzheimer’s disease-associated hyperphosphorylated forms of tau in serum of healthy individuals. To characterize the specificities that can be found, we interrogated peripheral IgG(+) memory B cells from asymptomatic blood donors for...

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Autores principales: Pascual, Gabriel, Wadia, Jehangir S., Zhu, Xueyong, Keogh, Elissa, Kükrer, Başak, van Ameijde, Jeroen, Inganäs, Hanna, Siregar, Berdien, Perdok, Gerrard, Diefenbach, Otto, Nahar, Tariq, Sprengers, Imke, Koldijk, Martin H., der Linden, Els C. Brinkman-van, Peferoen, Laura A., Zhang, Heng, Yu, Wenli, Li, Xinyi, Wagner, Michelle, Moreno, Veronica, Kim, Julie, Costa, Martha, West, Kiana, Fulton, Zara, Chammas, Lucy, Luckashenak, Nancy, Fletcher, Lauren, Holland, Trevin, Arnold, Carrie, Anthony Williamson, R., Hoozemans, Jeroen J., Apetri, Adrian, Bard, Frederique, Wilson, Ian A., Koudstaal, Wouter, Goudsmit, Jaap
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5390017/
https://www.ncbi.nlm.nih.gov/pubmed/28341999
http://dx.doi.org/10.1007/s00401-017-1705-y
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author Pascual, Gabriel
Wadia, Jehangir S.
Zhu, Xueyong
Keogh, Elissa
Kükrer, Başak
van Ameijde, Jeroen
Inganäs, Hanna
Siregar, Berdien
Perdok, Gerrard
Diefenbach, Otto
Nahar, Tariq
Sprengers, Imke
Koldijk, Martin H.
der Linden, Els C. Brinkman-van
Peferoen, Laura A.
Zhang, Heng
Yu, Wenli
Li, Xinyi
Wagner, Michelle
Moreno, Veronica
Kim, Julie
Costa, Martha
West, Kiana
Fulton, Zara
Chammas, Lucy
Luckashenak, Nancy
Fletcher, Lauren
Holland, Trevin
Arnold, Carrie
Anthony Williamson, R.
Hoozemans, Jeroen J.
Apetri, Adrian
Bard, Frederique
Wilson, Ian A.
Koudstaal, Wouter
Goudsmit, Jaap
author_facet Pascual, Gabriel
Wadia, Jehangir S.
Zhu, Xueyong
Keogh, Elissa
Kükrer, Başak
van Ameijde, Jeroen
Inganäs, Hanna
Siregar, Berdien
Perdok, Gerrard
Diefenbach, Otto
Nahar, Tariq
Sprengers, Imke
Koldijk, Martin H.
der Linden, Els C. Brinkman-van
Peferoen, Laura A.
Zhang, Heng
Yu, Wenli
Li, Xinyi
Wagner, Michelle
Moreno, Veronica
Kim, Julie
Costa, Martha
West, Kiana
Fulton, Zara
Chammas, Lucy
Luckashenak, Nancy
Fletcher, Lauren
Holland, Trevin
Arnold, Carrie
Anthony Williamson, R.
Hoozemans, Jeroen J.
Apetri, Adrian
Bard, Frederique
Wilson, Ian A.
Koudstaal, Wouter
Goudsmit, Jaap
author_sort Pascual, Gabriel
collection PubMed
description Several reports have described the presence of antibodies against Alzheimer’s disease-associated hyperphosphorylated forms of tau in serum of healthy individuals. To characterize the specificities that can be found, we interrogated peripheral IgG(+) memory B cells from asymptomatic blood donors for reactivity to a panel of phosphorylated tau peptides using a single-cell screening assay. Antibody sequences were recovered, cloned, and expressed as full-length IgGs. In total, 52 somatically mutated tau-binding antibodies were identified, corresponding to 35 unique clonal families. Forty-one of these antibodies recognize epitopes in the proline-rich and C-terminal domains, and binding of 26 of these antibodies is strictly phosphorylation dependent. Thirteen antibodies showed inhibitory activity in a P301S lysate seeded in vitro tau aggregation assay. Two such antibodies, CBTAU-7.1 and CBTAU-22.1, which bind to the proline-rich and C-terminal regions of tau, respectively, were characterized in more detail. CBTAU-7.1 recognizes an epitope that is similar to that of murine anti-PHF antibody AT8, but has different phospho requirements. Both CBTAU-7.1 and CBTAU-22.1 detect pathological tau deposits in post-mortem brain tissue. CBTAU-7.1 reveals a similar IHC distribution pattern as AT8, immunostaining (pre)tangles, threads, and neuritic plaques. CBTAU-22.1 shows selective detection of neurofibrillary changes by IHC. Taken together, these results suggest the presence of an ongoing antigen-driven immune response against tau in healthy individuals. The wide range of specificities to tau suggests that the human immune repertoire may contain antibodies that can serve as biomarkers or be exploited for therapy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00401-017-1705-y) contains supplementary material, which is available to authorized users.
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spelling pubmed-53900172017-04-27 Immunological memory to hyperphosphorylated tau in asymptomatic individuals Pascual, Gabriel Wadia, Jehangir S. Zhu, Xueyong Keogh, Elissa Kükrer, Başak van Ameijde, Jeroen Inganäs, Hanna Siregar, Berdien Perdok, Gerrard Diefenbach, Otto Nahar, Tariq Sprengers, Imke Koldijk, Martin H. der Linden, Els C. Brinkman-van Peferoen, Laura A. Zhang, Heng Yu, Wenli Li, Xinyi Wagner, Michelle Moreno, Veronica Kim, Julie Costa, Martha West, Kiana Fulton, Zara Chammas, Lucy Luckashenak, Nancy Fletcher, Lauren Holland, Trevin Arnold, Carrie Anthony Williamson, R. Hoozemans, Jeroen J. Apetri, Adrian Bard, Frederique Wilson, Ian A. Koudstaal, Wouter Goudsmit, Jaap Acta Neuropathol Original Paper Several reports have described the presence of antibodies against Alzheimer’s disease-associated hyperphosphorylated forms of tau in serum of healthy individuals. To characterize the specificities that can be found, we interrogated peripheral IgG(+) memory B cells from asymptomatic blood donors for reactivity to a panel of phosphorylated tau peptides using a single-cell screening assay. Antibody sequences were recovered, cloned, and expressed as full-length IgGs. In total, 52 somatically mutated tau-binding antibodies were identified, corresponding to 35 unique clonal families. Forty-one of these antibodies recognize epitopes in the proline-rich and C-terminal domains, and binding of 26 of these antibodies is strictly phosphorylation dependent. Thirteen antibodies showed inhibitory activity in a P301S lysate seeded in vitro tau aggregation assay. Two such antibodies, CBTAU-7.1 and CBTAU-22.1, which bind to the proline-rich and C-terminal regions of tau, respectively, were characterized in more detail. CBTAU-7.1 recognizes an epitope that is similar to that of murine anti-PHF antibody AT8, but has different phospho requirements. Both CBTAU-7.1 and CBTAU-22.1 detect pathological tau deposits in post-mortem brain tissue. CBTAU-7.1 reveals a similar IHC distribution pattern as AT8, immunostaining (pre)tangles, threads, and neuritic plaques. CBTAU-22.1 shows selective detection of neurofibrillary changes by IHC. Taken together, these results suggest the presence of an ongoing antigen-driven immune response against tau in healthy individuals. The wide range of specificities to tau suggests that the human immune repertoire may contain antibodies that can serve as biomarkers or be exploited for therapy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00401-017-1705-y) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2017-03-24 2017 /pmc/articles/PMC5390017/ /pubmed/28341999 http://dx.doi.org/10.1007/s00401-017-1705-y Text en © The Author(s) 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Paper
Pascual, Gabriel
Wadia, Jehangir S.
Zhu, Xueyong
Keogh, Elissa
Kükrer, Başak
van Ameijde, Jeroen
Inganäs, Hanna
Siregar, Berdien
Perdok, Gerrard
Diefenbach, Otto
Nahar, Tariq
Sprengers, Imke
Koldijk, Martin H.
der Linden, Els C. Brinkman-van
Peferoen, Laura A.
Zhang, Heng
Yu, Wenli
Li, Xinyi
Wagner, Michelle
Moreno, Veronica
Kim, Julie
Costa, Martha
West, Kiana
Fulton, Zara
Chammas, Lucy
Luckashenak, Nancy
Fletcher, Lauren
Holland, Trevin
Arnold, Carrie
Anthony Williamson, R.
Hoozemans, Jeroen J.
Apetri, Adrian
Bard, Frederique
Wilson, Ian A.
Koudstaal, Wouter
Goudsmit, Jaap
Immunological memory to hyperphosphorylated tau in asymptomatic individuals
title Immunological memory to hyperphosphorylated tau in asymptomatic individuals
title_full Immunological memory to hyperphosphorylated tau in asymptomatic individuals
title_fullStr Immunological memory to hyperphosphorylated tau in asymptomatic individuals
title_full_unstemmed Immunological memory to hyperphosphorylated tau in asymptomatic individuals
title_short Immunological memory to hyperphosphorylated tau in asymptomatic individuals
title_sort immunological memory to hyperphosphorylated tau in asymptomatic individuals
topic Original Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5390017/
https://www.ncbi.nlm.nih.gov/pubmed/28341999
http://dx.doi.org/10.1007/s00401-017-1705-y
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