Three Blood articles show that Epstein-Barr virus (EBV) can rescue B-cell receptor–deficient (BCR-) germinal center (GC) B cells from apoptosis by giving rise to lymphoblastoid cell lines.
Epstein-Barr virus (EBV) has been associated with several germinal center (GC)–derived B-cell lymphomas, such as endemic and sporadic Burkitt lymphoma, classical Hodgkin lymphoma (cHL), and posttransplantation lymphoproliferative disease (PTLD), inducing a typical latency I, II, and III gene expression program in these entities, respectively. As malignant cells in cHL and PTLD are B-cell receptor–deficient (BCR-), 3 studies in Blood asked whether EBV can rescue BCR-deficient GC B cells from apoptosis.
Bechtel and colleagues isolated CD77+ GC B cells from human tonsils and established 28 BCR- lymphoblastoid cell lines displaying a latency type III gene expression program. Two of these BCR- cell lines harbored destructive somatic mutations in originally functional immunoglobulin (Ig) variable region genes that prevent the expression of a functional BCR at the cell surface. As no transcriptional silencing of heavy chain Ig genes was detected, it was postulated that other genetic and epigenetic mechanisms were responsible for the absence of BCR expression in the remaining cases.
Similarly, Chaganti and colleagues established 106 BCR- clones from human tonsilar CD10+ GC B cells. Six of these clones harbored destructive crippling somatic mutations within their Ig genes. In contrast to GC B cells, down-regulation of surface Ig or sequence-inactivating mutations were not detected in lymphoblastoid cell lines derived from naive or memory B cells.
Mancao and colleagues used a different approach, selecting for BCR- CD77+ cells from human adenoids. A total of 5 BCR- latency type III clones showed “crippled” Ig genes. Of note, all of the EBV-infected B-cell lines entered S-phase independently of their surface BCR status.
Several questions have to be addressed in the future. First, why does EBV induce different latency gene expression programs in different GC-derived entities such as cHL and PTLD, while the newly established GC cell lines uniformly display a type III latency? One explanation might be that under in vitro conditions type III cells have a proliferative advantage over type II cells. Alternatively, additional genetic and epigenetic changes in malignant disease could alter EBV-induced gene expression programs. Second, which of the EBV-encoded genes is responsible for the transformation of BCR- GC B cells? In this context, latent membrane protein 2A (LMP2A) is of special interest, as Caldwell et al1 have shown that it can substitute for a functional BCR receptor and that its expression is correlated with crippling mutations in cHL. Finally, how does EBV change the phenotype of a BCR- GC B cell? As shown by Bechtel et al, CD77 and BCL6 are down-regulated in lymphoblastoid GC B-cell lines, indicating that EBV infection is not compatible with a full GC B-cell phenotype as postulated before,2 but further analyses are necessary to clarify the relationship between EBV and BCR- GC B cells.
In summary, these newly generated BCR- GC B-cell lines will help to further elucidate the role of EBV in the pathogenesis of BCR- lymphomas such as cHL and PTLD. ▪
