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

Haematologica. 2021 Mar 1;106(3):708-717. doi: 10.3324/haematol.2019.242701.

Abstract

The immunoglobulin (Ig) heavy and light chain variable gene mutational pattern of the B cell receptor (BCR) in primary central nervous system (CNS) lymphoma (PCNSL) cells suggests antigenic selection to drive pathogenesis and confinement to the 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 naive BCR (nBCR) by reverting tBCR somatic mutations in 10 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Central Nervous System
  • Central Nervous System Neoplasms* / genetics
  • Germinal Center
  • Humans
  • Immunoglobulin Heavy Chains*
  • Receptors, Antigen, B-Cell / genetics

Substances

  • Immunoglobulin Heavy Chains
  • Receptors, Antigen, B-Cell

Grant support

Funding: This work was supported by a grant from the Wilhelm Sander- Stiftung (Grant 2011.092.2) (to MD and MMR) and the Deutsche Krebshilfe (Grant 70112052) (to MD), the Köln Fortune Program (Grant 2680138201) (to MMR), the Medical Faculty at RUB (FoRUM) (CM), the HUPO Brain Proteome Project (to HBPP) (to CM), PURE and OsteoSys (EFRE 080041) (to CM), de.NBI, (FKZ 031 A 534A) (to CM) as well as Eranet Neuron Silence (FS 4108270133) (to CM).