Identifying the precursors of Hodgkin and Reed-Sternberg cells in Hodgkin's disease: role of the germinal center in B-cell lymphomagenesis.

In the course of T-cell-dependent immune responses, germinal centers (GCs) are established within secondary lymphoid organs. In these structures, B lymphocytes clonally expand and modify their immunoglobulin (Ig) V genes by somatic hypermutation. In a process called affinity maturation, GC B cells expressing antigen receptor with increased affinity to the cognate antigen are selected, whereas B cells acquiring unfavorable mutations die by apoptosis. By molecular single cell analysis of Hodgkin and Reed-Sternberg (HRS) cells in Hodgkin's disease (HD), it could be shown that the HRS cells in classical as well as lymphocyte predominant (LP) HD represent clonal populations of mature B cells. Whereas HRS cells in classical HD appear to derive from crippled GC B cells that lost the capacity to express antigen receptor, the precursors of the HRS cells in LP HD are mutating, antigen-selected GC B cells. It is likely that chromosomal translocations resulting from mistakes in class switch recombination or somatic hypermutation (and potentially V gene editing) play an important role in the pathogenesis of GC B-cell-derived lymphomas.