Normal and malignant B-cell development with special reference to Hodgkin's disease.
During their development, B lymphocytes are repeatedly selected for the expression of an appropriate surface receptor: the pre-B-cell receptor at the pre-B-cell stage and surface immunoglobulin (Ig) at the transition from a pre-B cell to a mature B cell. Furthermore, stringent selection for B cells expressing high affinity antibodies operates when antigen-activated B cells proliferate within germinal centers (GC). Here, somatic point mutations are introduced into rearranged V region genes at a high rate, and B cells acquiring favorable mutations are selected to differentiate into memory B cells or plasma cells. In the frame of this developmental scheme, extending a recent analysis, we investigated 10 primary cases of Hodgkin's disease (HD) for B-lineage origin and clonality [1]. Single Hodgkin and Reed-Sternberg (H-RS) cells were micromanipulated from frozen tissue sections and analyzed by PCR for rearranged V genes. Clonal VH and/or V kappa/ V delta gene rearrangements were obtained from 9 of the cases. This shows that H-RS cells represent a clonal, B-lineage-derived population of tumor cells. Somatic mutations were found in all clonal VH gene rearrangements. Interestingly, mutations leading to stop codons in in-frame V gene rearrangements were detected in four cases. Since GC B cells acquiring such crippling mutations are usually efficiently eliminated within the GC, the finding of those mutations indicates that H-RS cells are derived from precursors within the GC that escaped apoptosis by a transforming event.
Rajewsky
K
K
Institute for Genetics, University of Cologne, Germany.
Kanzler
H
H
Hansmann
M L
ML
Küppers
R
R
D000818:Animals; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology*; D002470:Cell Survival / Q000276:immunology; D018858:Germinal Center / Q000276:immunology*; D006689:Hodgkin Disease / Q000276:immunology*; D006801:Humans; D016539:Reed-Sternberg Cells / Q000276:immunology; D012016:Reference Values; D014410:Tumor Stem Cell Assay