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Ferrata Storti Foundation
Haematologica 2021 Volume 106(3):708-717
Non-Hodgkin Lymphoma
The process of somatic hypermutation increases polyreactivity for central nervous system antigens in primary central nervous system lymphoma
Manuel Montesinos-Rongen,1 Monica Terrao,1 Caroline May,2 Katrin Marcus,2 Ingmar Blümcke,3 Martin Hellmich,4 Ralf Küppers,5 Anna Brunn1
and Martina Deckert1
1Institute of Neuropathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne; 2Medizinisches Proteom-Center, Ruhr-University Bochum, Bochum; 3Department of Neuropathology, University Hospital Erlangen, Erlangen, Germany; 4Institute of Medical Statistics and Computational Biology (IMSB), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne and 5Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Medical School, Essen, Germany, and German Cancer Consortium (DKTK), Essen/Düsseldorf, Germany
ABSTRACT
The immunoglobulin (Ig) heavy and light chain variable gene muta- tional 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 immuno- precipitation demonstrated auto- and polyreactivity in all cases. Self- /polyreactivity was not lost during the GC reaction; surprisingly, tBCR sig- nificantly 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 oligodendro- cytes/myelin, the S100 protein family, and splicing factors. Thus, in PCNSL pathogenesis, a faulty GC reaction may increase self-/polyreactivity, here- by facilitating BCR signaling via multiple CNS antigens, and may ultimate- ly foster tumor cell survival in the CNS.
Introduction
Primary lymphoma of the central nervous system (PCNSL) is a distinct diffuse large B-cell lymphoma (DLBCL) entity confined to the central nervous system (CNS).1
PCNSL tumor cells carry somatically mutated rearranged immunoglobulin (Ig) heavy and light chain variable genes,2,3 revealing a germinal center (GC) experience of the lymphoma cells.4 A prerequisite for the GC reaction is a unique micromilieu in which follicular dendritic cells present cognate antigen to B cells and helper T cells mediate B-cell selection, aiming to increase B-cell receptor (BCR) affinity for the antigen. Considering confinement to the CNS, the observation of ongoing somatic hypermutation (SHM),2 a GC B-cell-specific process, raises the intriguing question as to the impact of the target organ, particularly of CNS antigens, on this organ-specific DLBCL entity. While T-helper cells and antigen presenting cells are present in the PCNSL-infiltrated CNS, their in vivo characteristics and function have not yet been elucidated. Thus, it is still unknown whether a GC reaction indeed occurs in the CNS. Despite the observation of follicle-like structures in the lep- tomeninges, but not the brain parenchyma, in some patients with late multiple scle-
Correspondence:
MARTINA DECKERT
martina.deckert@uni-koeln.de
Received: November 8, 2019. Accepted: March 18, 2020. Pre-published: March 19, 2020.
https://doi.org/10.3324/haematol.2019.242701
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