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Immunol. 167, 1877–1881 TRENDS in Immunology Vol.23 No.2 February 2002 http://immunology.trends.com 1471-4906/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S1471-4906(01)02115-9 75 Opinion The CD95 (Apo-1/Fas) molecule belongs to the tumor necrosis factor receptor (TNFR) family [1] and is an almost ubiquitously expressed transmembrane death receptor [2]. Usually, the induction of apoptosis by CD95 requires crosslinking of CD95 by CD95 ligand (CD95L), which is expressed only in a few anatomically well-defined structures, including germinal centers (GCs) [3]. Crosslinking of CD95 by CD95L leads to the assembly of a death-inducing signaling complex (DISC), which includes trimerized CD95, CD95/Fas-associated death- domain-containing protein (FADD) and procaspase-8 (Fig. 1). The DISC is assembled around the cytoplasmic death domain (DD) of CD95, which thus, plays a pivotal role in the transduction of the death signal [2]. CD95 mediates negative selection of B cells within the germinal center In the B-cell lineage, expression levels of CD95 peak at the GC stage of differentiation [4], which contributes to the susceptibility of GC B cells to apoptosis [3,4] (Fig. 1). Indeed, human GC B cells carry a preformed DISC that is maintained in an inactive configuration by FADD-like interleukin-1β-converting-enzyme-inhibitory protein (c-FLIP) (Fig. 1) [5]. CD40 stimulation and Ig crosslinking – mimicking the T-cell–B-cell interaction – prevent the degradation of c-FLIP, suggesting that inhibition of the CD95 pathway is involved in positive selection and affinity maturation within the GC [3,5]. This idea is supported by the analysis of The origin of CD95-gene mutations in B-cell lymphoma Markus Müschen, Klaus Rajewsky, Martin Krönke and Ralf Küppers CD95 (Apo-1/Fas) is crucial for the negative selection of B cells within the germinal center (GC).Impairment of CD95-mediated apoptosis results in defective affinity maturation and the persistence of autoreactive B-cell clones. CD95 was defined recently as a tumor-suppressor gene and is silenced in many tumor entities. In contrast to other malignancies, in GC-derived B-cell lymphomas, inactivation of the CD95 gene is often a result of deleterious mutations. Such mutations occur also at a low frequency in normal GC, but not naive, B cells. We propose that CD95 mutations in B-cell lymphomas originate from the GC reaction and are introduced most probably as targeting errors of the somatic hypermutation machinery,which bears – besides its physiological role – an inherent risk of malignant transformation and the persistence of autoreactive B-cell specificities. ‘…the somatic-hypermutation machinery can act occasionally outside of the Ig loci.’