Somatic mutation of the CD95 gene in human B cells as a side-effect of the germinal center reaction.
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.
Müschen
M
M
Institute for Genetics, Department of Immunology, University of Cologne, Köln, Germany.
Re
D
D
Jungnickel
B
B
Diehl
V
V
Rajewsky
K
K
Küppers
R
R
D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005434:Flow Cytometry; D016147:Genes, Tumor Suppressor / Q000235:genetics; D018858:Germinal Center / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics / Q000276:immunology; D016296:Mutagenesis / Q000235:genetics*; D016133:Polymerase Chain Reaction; D017434:Protein Structure, Tertiary; D017421:Sequence Analysis; D015398:Signal Transduction; D019014:fas Receptor / Q000737:chemistry / Q000235:genetics* / Q000276:immunology
D019014:fas Receptor