1. Somatic mutation of the CD95 gene in human B cells as a side-effect of the germinal center reaction.
- Author
-
Müschen, M, Re, D, Jungnickel, B, Diehl, V, Rajewsky, K, and Küppers, R
- Subjects
Germinal Center ,B-Lymphocytes ,Humans ,Flow Cytometry ,Cloning ,Molecular ,Polymerase Chain Reaction ,Sequence Analysis ,DNA Mutational Analysis ,Signal Transduction ,Apoptosis ,Immunologic Memory ,Mutagenesis ,Protein Structure ,Tertiary ,Genes ,Tumor Suppressor ,Exons ,fas Receptor ,Cloning ,Molecular ,Genes ,Tumor Suppressor ,Protein Structure ,Tertiary ,Medical and Health Sciences ,Immunology - Abstract
Somatic hypermutation specifically modifies rearranged immunoglobulin (Ig) genes in germinal center (GC) B cells. However, the bcl-6 gene can also acquire somatic mutations during the GC reaction, indicating that certain non-Ig genes can be targeted by the somatic hypermutation machinery. The CD95 gene, implicated in negative selection of B lymphocytes in GCs, is specifically expressed by GC B cells and was recently identified as a tumor suppressor gene being frequently mutated in (post) GC B cell lymphomas. In this study, the 5' region (5'R) and/or the last exon coding for the death domain (DD) of the CD95 gene were investigated in naive, GC, and memory B cells from seven healthy donors. About 15% of GC and memory, but not naive, B cells carried mutations within the 5'R (mutation frequency 2.5 x 10(-4) per basepair). Mutations within the DD were very rare but could be efficiently selected by inducing CD95-mediated apoptosis: in 22 apoptosis-resistant cells, 12 DD mutations were found. These results indicate that human B cells can acquire somatic mutations of the CD95 gene during the GC reaction, which potentially confers apoptosis resistance and may counteract negative selection through the CD95 pathway.
- Published
- 2000