Somatic Hypermutation and B Cell Receptor Selection in Normal and Transformed Human B Cells

Abstract

From the beginning to the end, the life of B cells is dominated by selection of the cells for expression of an appropriate antigen receptor. However, recent studies revealed that there are several diseases in the human where B cells lost their dependence on a B cell receptor (BCR). In classic Hodgkin's lymphoma, the lymphoma cells presumably derive from "crippled" germinal center (GC) B cells that acquired unfavorable somatic Ig gene mutations, which often render originally functional immunoglobulin (Ig) genes nonfunctional. A peculiar situation is observed among Epstein-Barr virus (EBV)-infected B cells in angioimmunoblastic lymphadenopathy with dysproteinaemia (AILD)-type T cell lymphoma, where somatic hypermutation uncoupled from any selection for functionality of the BCR is observed in expanding clones. Clones of EBV-harboring B cells that show ongoing hypermutation during proliferation and are Ig-deficient in at least a fraction of cases were recently also identified in post-transplant lymphoproliferative disorders. Hence, transformed B cells may, in particular settings, escape the normal selectional forces to express a BCR, and EBV may cause dramatic changes in B cell differentiation programs. Somatic hypermutation may be involved in lymphomagenesis by several means. Some chromosomal translocations into Ig loci likely involve DNA-strand breaks associated with hypermutation. Moreover, by aberrant targeting of the CD95 gene, GC B cells and lymphomas developing from them may become resistant to elimination by CD95 ligand-expressing T cells. Finally, aberrant hypermutation of multiple proto-oncogenes appears to be a major factor in diffuse large cell lymphoma pathogenesis.

Epstein-Barr virus–associated lymphoproliferative disorders

“…These crippling mutations are almost restricted to the EBVinfected cells and not detected in EBV-negative cells, which assumes a potential influence of EBV on these proliferating cells [93]. Although crippling mutations are also seen in classic Hodgkin lymphoma, HRS cells lack the intraclonal diversity because of the shutdown of the ongoing somatic mutations, in contrast to the EBV-infected B cells in AILT that continue to undergo somatic mutations even with the presence of crippling mutations [94]. The reasons for the sustained somatic hypermutation status are largely unknown, although it has been speculated by some that the rich FDRC meshwork and the increased number of CD4-positive helper T cells in AILT cases may stimulate the proliferating B cells to undergo somatic mutations and probably escape apoptosis [8].…”

Autologous lymphoma vaccines induce human T cell responses against multiple, unique epitopes

“…Furthermore, we have analyzed T cell lines generated from FL patients who had been actively immunized with the unique Id protein expressed by their tumors to The main goal of this study was to elucidate the precise nature of the antigenic epitopes recognized by human Id-specific T cells. The intrinsic variability in nucleotide sequence generated by VDJ recombination, nontemplated addition of nucleotides in the CDR segments of Ig V H , and somatic point mutations can all produce potentially unique antigenic epitopes (7)(8)(9)(10)(11)(12). In all eight independently derived T cell lines from the four patients studied, the functional T cell epitopes localized to the hypervariable regions (CDR2 and CDR3) of corresponding tumor Ig V H .…”

“…It is well documented that somatic mutations in variable heavy chain and variable light chain genes of Ig result in clonotypic expression of unique surface Ig receptor in normal and malignant B cells (7)(8)(9)(10)(11)(12). Therefore, it is possible that the T cell epitope(s) identified above may have been generated by somatic mutation of Ig V H genes.…”

“…In B cell malignancies, the clonotypic surface Ig expressed by malignant B cells, idiotype (Id), is a tumor-specific antigen (4-6) and, therefore, provides a unique opportunity to target the antitumor immune responses. Gene rearrangements that occur during variable, diversity, and joining region (VDJ) and variable and joining region (VJ) recombination of Ig heavy and light chains and during the somatic hypermutation that is prevalent in mature normal and malignant B cells, including follicular lymphoma (FL), further increased the probability of the generation of unique epitopes that can provide tumor-specific target antigens (7)(8)(9)(10)(11)(12).…”

Epstein-Barr Virus-Associated Classical Hodgkin Lymphoma and Its Therapeutic Strategies

“…Although the origin of the HRS cells had been an issue of intense debate due to no obvious normal cellular counterpart to the phenotype of HRS cells, the presence of non-functional somatic mutations in rearranged immunoglobulin genes of HRS cells confi rmed that they originate from preapoptotic B cells that lost the capacity to express a high-affi nity B-cell receptor, which were then rescued from apoptosis by transforming events (Kuppers et al, 1994;Kuppers, 2003). To date, many cases of aberrant activation of signaling pathways and transcription factors involved in the rescue of HRS cells from apoptosis have been identifi ed, knowledge from which has been applied to the development of novel therapeutic agents for relapsed HL after primary treatment.…”