Maturation of the antibody repertoire results in the production of efficient antibodies of various isotypes, via a two-step process. The first step is stochastic recombination, resulting in the expression of rearranged IgH (m) and L genes by mature B cells (Tonegawa, 1983). The second is driven by antigen encounter and involves two processes: immunoglobulin class switch recombination (CSR) and the generation of somatic hypermutations (SHM), which precedes the selection of B cells expressing a B cell receptor (BCR) with a high affinity for antigen.

A. Generation of the Primary Antibody Repertoire Generation of the primary repertoire is antigen and T cell independent and occurs in the primary lymphoid organs: the fetal liver and bone marrow. B cell precursors are engaged in the B cell differentiation pathway once they have produced the transcription factor Pax5 and express CD19 molecules on their membrane (Souabni et al., 2002). They undergo sequential rearrangements of the V (D) J regions of the immunoglobulin (Ig) genes. Rearrangement begins in the D to J segments, then extends to the V to DJ segments of the heavy chain, followed by the V to J regions of the k or l light chain (Bassing et al., 2002b; Ghia et al., 1996). V (D) J rearrangements are site specific and are mediated by the recognition of recombination signal sequences (RSS), which consist of conserved heptamers and nonamers separated by 12-and 23-bp spacers, respectively. V (D) J recombination is initiated by the Rag1–Rag2 complex, which is lymphoid specific and tightly regulated (Gellert, 2002; Mombaerts et al., 1992; Shinkai et al., 1992). The Rag proteins recognize and bind to RSS regions, introducing a DNA double-strand break (DNA DSB) at the junction between the heptamer and the coding sequence, leaving hairpinsealed coding ends on the chromosome and phosphorylated, blunt signal ends excised from the chromosome. The resulting DNA damage is repaired by the general DNA repair machinery of the cell, including, in particular, the nonhomologous end-joining (NHEJ) pathway (Haber, 2000). In this pathway, DSB are recognized by the DNA-dependent protein kinase (DNA–PK)