The Journal of Experimental Medicine
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Published online 18 December 2000.
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© The Rockefeller University Press, 0022-1007/2000/12/1833/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 12, December 18, 2000 1833-1840

Brief Definitive Report

Somatic Mutation of the CD95 Gene in Human B Cells as a Side-Effect of the Germinal Center Reaction

Markus Müschena,b, Daniel Reb, Berit Jungnickela, Volker Diehlb, Klaus Rajewskya, and Ralf Küppersa,b
a Institute for Genetics, Department of Immunology,
b Department for Internal Medicine I, University of Cologne, 50931 Köln, Germany

Correspondence to: Ralf Küppers, University of Cologne, Dept. of Internal Medicine I, LFI E4 R706, Joseph-Stelzmann-Straße 9, 50931 Köln, Germany. Tel:49-221-478-4490 Fax:49-221-478-6383 E-mail:rkuppers{at}mac.genetik.uni-koeln.de.

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.

Key Words: CD95 (Apo-1/Fas), germinal center, B lymphocytes, somatic hypermutation, apoptosis


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