Immunoglobulin (Ig)M⁺IgD⁺ B cells are generally assumed to represent antigen-inexperienced, naive B cells expressing variable (V) region genes without somatic mutations. We report here that human IgM⁺IgD⁺ peripheral blood (PB) B cells expressing the CD27 cell surface antigen carry mutated V genes, in contrast to CD27-negative IgM⁺IgD⁺ B cells. IgM⁺IgD⁺CD27⁺ B cells resemble class-switched and IgM-only memory cells in terms of cell phenotype, and comprise ∼15% of PB B lymphocytes in healthy adults. Moreover, a very small population (<1% of PB B cells) of highly mutated IgD-only B cells was detected, which likely represent the PB counterpart of IgD-only tonsillar germinal center and plasma cells. Overall, the B cell pool in the PB of adults consists of ∼40% mutated memory B cells and 60% unmutated, naive IgD⁺CD27⁻ B cells (including CD5⁺ B cells). In the somatically mutated B cells, V_H region genes carry a two- to threefold higher load of somatic mutation than rearranged V_κ genes. This might be due to an intrinsically lower mutation rate in κ light chain genes compared with heavy chain genes and/or result from κ light chain gene rearrangements in GC B cells. A common feature of the somatically mutated B cell subsets is the expression of the CD27 cell surface antigen which therefore may represent a general marker for memory B cells in humans.

In Hodgkin's disease (HD), the Hodgkin and Reed-Sternberg (HRS) cells represent only a minute population in the diseased tissue. The investigation of lineage derivation and clonal origin of these cells has yielded conflicting results. We have analyzed HRS cells micromanipulated from infiltrated tissue sections of 10 primary HD patients for rearranged V genes, extending a previous study. Clonally related rearrangements were found in nine cases, indicating that HRS cells represent a dominant clone of B lineage-derived cells in at least a large fraction of cases of HD. Rearranged VH genes from HRS cells carried a high load of somatic mutation, indicating that HRS cells are derived from germinal center (GC) cells or their progeny. Stop codons in some in-frame V gene rearrangements suggest that the HRS cell precursors reside inside GCs, have acquired crippling mutations that prevent antigenic selection, but escape apoptosis through some transforming event.

The origin of human lymphomas has been studied by various approaches, including histology and immunophenotyping. In some types of lymphoma these studies suggested the cellular origin, but in many instances the origin could not be identified. When somatic mutations of the genes for the variable region of the B-lymphocyte antigen receptor proved to be a hallmark of germinal-center B cells and their descendants, sequence analysis of the variable-region genes of B-cell lymphomas offered a molecular approach to studying the origin of the tumors. Before discussing the results of these studies, we outline the human peripheral B-cell repertoire and its generation. . . .