A Novel Cytidine Deaminase Affects Antibody Diversity

University of Chicago switch-specific endonuclease then cleaves the doubleChicago, Illinois 60637 strand DNA at random sites within or near Sm and the downstream S region involved in the particular switch. As the switch region repeats are varied, the endonucleAntibody molecules are encoded by immunoglobulin (Ig) ase(s) would not recognize a particular sequence but genes and are produced exclusively in B lymphocytes. rather a particular structure. Other mechanisms for proSite-specific recombination events (V(D)J recombinaducing the double-strand breaks are also possible, as tion) occurring in precursor cells (preB) lead to the exnothing is known about the process. pression in each B cell of a single heavy chain and a Somatic Hypermutation single light chain gene, each with a specific variable (V) The somatic hypermutation process also takes place in region. An initial repertoire of millions of different B cells, germinal centers in lymph nodes and spleen and, as each with a different antigen binding site, is generated discussed above, is also initiated when a B cell encounfrom about 100 V genes, their combinatorial joining with ters an antigen that can react with its specific Ig molea small set of different J (and D) genes, and small delecules. SHM is coupled with a very high rate of B cell tions and insertions of nucleotides at the V(D)J joining divisions (about once every 6 hr). As the mutation prosites. The Ig genes created by V(D)J recombination are cess continues for about ten or more cell generations, further diversified by two processes; class switch reit generates a clone of related B cells expressing a varicombination (CSR) alters the constant region and soety of differently modified derivatives of the Ig heavy matic hypermutation (SHM) alters the variable region. and light chain variable genes expressed by the founder When a mature B cell encounters an antigen that can cell. B cells that produce mutated Igs with a high affinity bind to the Ig molecules expressed on its surface, both for the immunizing antigen are selected for survival and of these processes are induced. Two papers in this issue can become long lived memory cells. of Cell report a significant step in understanding the SHM is limited to the variable region of the Ig gene mechanisms involved in generating antibody diversity, and its proximate flanks, covering a mutable stretch of by showing that a novel cytidine deaminase (AID) plays 1 to 2 kb from the 59 end of the transcribed region a crucial role in both CSR and SHM (Muramatsu et al., (Figure 2) (reviewed in Storb, 1996). SHM results in point 2000; Revy et al., 2000). mutations at a frequency of up to 20% of the nucleotides Class Switch Recombination within this region of the Ig gene. There is clear evidence Class switch recombination and SHM both take place that SHM is linked to transcription (Storb et al., 1998a). in lymphoid germinal centers, but not necessarily in the Placing an Ig promoter 59 of the constant region of an same cell at the same time. The germinal centers repreIg gene causes mutation of the normally unmutated consent organized assemblies of B cells, as well as T cells stant region (Peters and Storb, 1996). Removal of the and dendritic cells (Liu et al., 1991a). CSR alters the Ig enhancers inhibits SHM (Betz et al., 1994). The mechaconstant (C) region of the heavy chain gene by switching nism of creating the mutations is not understood, but it from the original Cm to one of five or six other C regions is proposed that a mutator factor is delivered to the (in the mouse, these are in 59 to 39 order in the heavy mutable target during transcription and, in collaboration chain locus, Cg3, g1, g2b, g2a, e, and a, and in man they with certain DNA polymerases, induces somatic point are g3, g1, a1, g2, g4, e, and a2). Switch recombination mutations, rare deletions and insertions (Figure 3). DNA results in the deletion of DNA sequences located in the mismatch repair appears to correct certain mutations, germline between the “switch” (S) region upstream of especially those derived from G or C nucleotides. Cm, and one of the S regions located upstream of each Activation-Induced Cytidine Deaminase (AID) of the downstream constant region genes (Figure 1). Germinal center B cells, the cells in which CSR and SHM Each S region is composed of tandem short repetitive are active, produce a novel cytidine deaminase (AID) sequences that are similar, but not identical to each that is expressed only in these cells (Muramatsu et al., other. 1999). Its expression is induced when mature B cells The molecular basis of class switch recombination is are activated to undergo CSR and/or SHM. Its sequence not understood (Stavnezer, 1996). The choice of the is homologous to the mammalian RNA editing deamidownstream switch region is determined by cytokines; nase, APOBEC-1, which changes a single ribo-cytidine for example, IL4 induces switching to Ce. The direct to uridine in the intestinal apolipoprotein-B mRNA. The effect of cytokine action appears to be transcriptional amino acid homology of mouse AID with the mouse activation of a promoter (named I region promoter) locatalytic APOBEC-1 subunit is 34%. AID has deaminase cated upstream of each switch region and production activity when tested for deamination of deoxycytidine. of germline transcripts that extend from the I region The homology of mouse AID with the mouse or human through the associated C region (Figure 1). Im-Cm and editing APOBEC-1 is greater than that with general mouse or human cytidine deaminases, or with human CMP deaminase. It appears therefore that AID may be * To whom correspondence should be addressed (e-mail: stor@