Somatic hypermutation and B cell receptor selection in normal and transformed human B cells.

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.