Somatic hypermutation in normal and transformed human B cells

Abstract

Summary: In the human, most IgM+IgD+ as well as CD5* peripheral blood B cells express unmutated V genes and thus can be assigned to a pre‐germinal centre (GC) stage of development. The memory B‐cell compartment generated in die GC reaction and characterized by cells bearing somatically mutated V‐region genes consists not only of class‐switched cells, but also of lgM‐only B cells and perhaps a subset of IgM+IgD+ B cells expressing the CD27 antigen. Comparison of the rearranged V‐region genes of human B‐cell lymphomas with those of the normal B‐cell subsets allows the identification of the progenitor cells of these tumours in terms of their stage of maturation. On this basis, most B‐cell on‐Hodgkin lymphomas, and in addition Hodgkin and Reed‐Stern berg (HRS) cells in Hodgkin's disease (HD). are derived from B cells ac a GC or post‐GC stage of development. The mutation pattern indicates that the precursors of the tumour clones have been stringently selected for expression of a functional antigen receptor with one notable exception: HRS cells in classical (but: not lymphocyte‐predominant) HD appear to be derived from “crippled” GC B cells. Sequence analysis of rearranged V genes amplified from single tonsillar GC B cells revealed that the somatic hypermutation process introduces deletions and/or insertions into V‐region genes more frequently that indicated by previous investigations. Presumably, this feature of the hypermutation mechanism is often responsible for the generation of heavy chain disease, and also several types of chromosomal translocations of oncogenes into immunoglobulin loci in human B‐cell lymphomas.