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The process of somatic hypermutation increases polyreactivity for central nervous system antigens in primary central nervous system lymphoma

The immunoglobulin (Ig) heavy and light chain variable gene mutational pattern of the B-cell receptor (BCR) in primary central nervous system lymphoma (PCNSL) cells suggests antigenic selection to drive pathogenesis and confinement to the central nervous system (CNS). This hypothesis is supported by...

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Autores principales: Montesinos-Rongen, Manuel, Terrao, Monica, May, Caroline, Marcus, Katrin, Blümcke, Ingmar, Hellmich, Martin, Küppers, Ralf, Brunn, Anna, Deckert, Martina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Fondazione Ferrata Storti 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927892/
https://www.ncbi.nlm.nih.gov/pubmed/32193251
http://dx.doi.org/10.3324/haematol.2019.242701
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author Montesinos-Rongen, Manuel
Terrao, Monica
May, Caroline
Marcus, Katrin
Blümcke, Ingmar
Hellmich, Martin
Küppers, Ralf
Brunn, Anna
Deckert, Martina
author_facet Montesinos-Rongen, Manuel
Terrao, Monica
May, Caroline
Marcus, Katrin
Blümcke, Ingmar
Hellmich, Martin
Küppers, Ralf
Brunn, Anna
Deckert, Martina
author_sort Montesinos-Rongen, Manuel
collection PubMed
description The immunoglobulin (Ig) heavy and light chain variable gene mutational pattern of the B-cell receptor (BCR) in primary central nervous system lymphoma (PCNSL) cells suggests antigenic selection to drive pathogenesis and confinement to the central nervous system (CNS). This hypothesis is supported by the observation that the tumor B-cell receptor (tBCR) of PCNSL is polyreactive and may be stimulated by CNS proteins. To obtain further insight into the role of the germinal center (GC) reaction on BCR reactivity, we constructed recombinant antibodies (recAb) with Ig heavy and light chain sequences of the corresponding naïve BCR (nBCR) by reverting tBCR somatic mutations in ten PCNSL. Analysis of nBCR-derived recAb reactivity by a protein microarray and immunoprecipitation demonstrated auto- and polyreactivity in all cases. Self- /polyreactivity was not lost during the GC reaction; surprisingly, tBCR significantly increased self-/polyreactivity. In addition to proteins recognized by both the nBCR and tBCR, tBCR gained self-/polyreactivity particularly for proteins expressed in the CNS including proteins of oligodendrocytes/ myelin, the S100 protein family, and splicing factors. Thus, in PCNSL pathogenesis, a faulty GC reaction may increase self-/polyreactivity, hereby facilitating BCR signaling via multiple CNS antigens, and may ultimately foster tumor cell survival in the CNS.
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spelling pubmed-79278922021-03-05 The process of somatic hypermutation increases polyreactivity for central nervous system antigens in primary central nervous system lymphoma Montesinos-Rongen, Manuel Terrao, Monica May, Caroline Marcus, Katrin Blümcke, Ingmar Hellmich, Martin Küppers, Ralf Brunn, Anna Deckert, Martina Haematologica Article The immunoglobulin (Ig) heavy and light chain variable gene mutational pattern of the B-cell receptor (BCR) in primary central nervous system lymphoma (PCNSL) cells suggests antigenic selection to drive pathogenesis and confinement to the central nervous system (CNS). This hypothesis is supported by the observation that the tumor B-cell receptor (tBCR) of PCNSL is polyreactive and may be stimulated by CNS proteins. To obtain further insight into the role of the germinal center (GC) reaction on BCR reactivity, we constructed recombinant antibodies (recAb) with Ig heavy and light chain sequences of the corresponding naïve BCR (nBCR) by reverting tBCR somatic mutations in ten PCNSL. Analysis of nBCR-derived recAb reactivity by a protein microarray and immunoprecipitation demonstrated auto- and polyreactivity in all cases. Self- /polyreactivity was not lost during the GC reaction; surprisingly, tBCR significantly increased self-/polyreactivity. In addition to proteins recognized by both the nBCR and tBCR, tBCR gained self-/polyreactivity particularly for proteins expressed in the CNS including proteins of oligodendrocytes/ myelin, the S100 protein family, and splicing factors. Thus, in PCNSL pathogenesis, a faulty GC reaction may increase self-/polyreactivity, hereby facilitating BCR signaling via multiple CNS antigens, and may ultimately foster tumor cell survival in the CNS. Fondazione Ferrata Storti 2020-03-19 /pmc/articles/PMC7927892/ /pubmed/32193251 http://dx.doi.org/10.3324/haematol.2019.242701 Text en Copyright© 2021 Ferrata Storti Foundation http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
spellingShingle Article
Montesinos-Rongen, Manuel
Terrao, Monica
May, Caroline
Marcus, Katrin
Blümcke, Ingmar
Hellmich, Martin
Küppers, Ralf
Brunn, Anna
Deckert, Martina
The process of somatic hypermutation increases polyreactivity for central nervous system antigens in primary central nervous system lymphoma
title The process of somatic hypermutation increases polyreactivity for central nervous system antigens in primary central nervous system lymphoma
title_full The process of somatic hypermutation increases polyreactivity for central nervous system antigens in primary central nervous system lymphoma
title_fullStr The process of somatic hypermutation increases polyreactivity for central nervous system antigens in primary central nervous system lymphoma
title_full_unstemmed The process of somatic hypermutation increases polyreactivity for central nervous system antigens in primary central nervous system lymphoma
title_short The process of somatic hypermutation increases polyreactivity for central nervous system antigens in primary central nervous system lymphoma
title_sort process of somatic hypermutation increases polyreactivity for central nervous system antigens in primary central nervous system lymphoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927892/
https://www.ncbi.nlm.nih.gov/pubmed/32193251
http://dx.doi.org/10.3324/haematol.2019.242701
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