*2.1.2. Class switch recombination*

Class switch recombination (CSR) is a process that replaces the default Cμ exons with exons from a downstream constant chain (Cα, Cϵ, or Cγ), resulting in a change from IgM expressed by naïve B cells to expression of one of the downstream isotypes IgA, IgG, IgE.

CSR occurs by intrachromosomal deletion and recombination events between two different switch (S) regions localized upstream of each constant region in the IgH locus. S regions are GC-rich with a high frequency of the WGCW (A/T-G-G-A/T) motif, which is a target of activation-induced deaminase (AID) activity. CSR has two phases: (1) the break at the donor and acceptor S regions, and (2) the ligation process between distal breaks [12].

The recombination is initiated by AID, an enzyme that deaminates cytosines into uracil at the donor and acceptor S regions. Subsequently, the base excision repair (BER) pathway creates a single strand break (SSB) that is processed to double strand breaks (DSB) by mismatch repair (MMR). After the formation of DSBs in the S regions (donor and acceptor), these S regions are recombined by non-homologous end joining (NHEJ) [13].

Four recurrent translocations, t(1;14)(p22;q32), t(3;14)(p14.1;q32), t(11;18)(q21;q21), and t(14;18)(q32;q21), have been described in marginal zone B-cell lymphomas of MALT type. The two latter translocations involve the MALT1 gene. These translocations seem to occur as

The Antigen Receptor as a Driver of B-Cell Lymphoma Development and Evolution

http://dx.doi.org/10.5772/intechopen.72122

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Somatic hypermutation (SHM) is the biological underlying mechanism for the generation of the secondary antibody repertoire. AID is the single enzyme that is responsible for the initia-

SHM is a post-rearrangement diversification process that introduces point mutations in the variable regions of the Ig loci, which can alter the antibody binding to its cognate antigen. AID acts enzymatically as a cytosine deaminase that converts cytosine to uracil. Uracil is mutagenic when paired with guanosine, this U:G mismatch triggers error-prone DNA repair in B cells. SHM results in a mutation rate of circa 1 mutation/1000 bp per cell generation. This mutation frequency is a million-fold higher than spontaneous mutation rate in somatic cells [26]. Highly selected antibodies with neutralizing activity against influenza virus can accumulate 30–40 mutations, and broadly neutralizing antibodies against HIV more than 100

AID acts on a single strand, thus its activity is probably generated during at transcription bubbles (**Figure 1**). Once AID produced deamination of dC to dU the error-prone processing begins. First AID-catalyzed uracils in the DNA are recognized by either the uracil-DNA glycosylase (UNG)—triggering the base excision repair (BER) pathway—or by the mismatch recognition heterodimer MutSα—initiating the mismatch repair (MMR) pathway. In BER, UNG binds to the U:G mispair and produces an abasic site, then this site is cleaved by the apurinic/apyrimidinic endonuclease (APE1), which removes the abasic site nucleotide and the DNA polymerase Polβ resynthesizes the DNA strand [29]. In the MMR pathway, the proteins MSH2 and MSH6 bind to the U:G mismatch and recruit DNA Polη, a low fidelity polymerase,

The processing of uracils by BER and MMR may result in different outcomes. The introduced uracils may (1) be replaced by another nucleotide, (2) expose DNA to further mutations in its vicinity like mutations at A:T pairs or (3) can be converted into DNA DSBs. The latter seems

Because of its mutagenic potential, SHM has multiple layers of regulation and competition between alternative pathways that define the level of SHM [31]. There is also increasing evidence that epigenetic factors, such as DNA methylation and post-translational histone modifications play major roles in regulating SHM [32]. Its implications in lymphoma development

When SHM affect off-target genes, it is referred to as aberrant SHM. Aberrant SHM can be mainly detected in FL, BL, DLBCL, and CLL [33–35]. This topic has been extensively reviewed

a result of illegitimate V(D)J-mediated recombination [22, 24].

that introduces error during nucleotide synthesis [30].

*2.1.4. Somatic hypermutation (SHM)*

tion of this process [25].

mutations [27, 28].

to be necessary for CSR.

remain elusive.

elsewhere [36–39].

During normal B-cell development, the DNA repair pathways (BER and MMR) reduce the effect of off-target AID activity. However, several external factors like cellular stress, hypoxia, and viral infections; or intrinsic factors such as alterations in repair pathways may change the outcome of AID-induced lesions [14].
