Related Mechanisms of Antibody Somatic Hypermutation and Class Switch Recombination

Abstract

The primary antibody repertoire is generated by mechanisms involving the assembly of the exons that encode the antigen-binding variable regions of immunoglobulin heavy (IgH) and light (IgL) chains during the early development of B lymphocytes. After antigen-dependent activation, mature B lymphocytes can further alter their IgH and IgL variable region exons by the process of somatic hypermutation (SHM), which allows the selection of B cells in which SHMs resulted in the production of antibodies with increased antigen affinity. In addition, during antigen-dependent activation, B cells can also change the constant region of their IgH chain through a DNA double-strand-break (DSB) dependent process referred to as IgH class switch recombination (CSR), which generates B cell progeny that produce antibodies with different IgH constant region effector functions that are best suited for a elimination of a particular pathogen or in a particular setting. Both the mutations that underlie SHM and the DSBs that underlie CSR are initiated in target genes by activation-induced cytidine deaminase (AID). This review describes in depth the processes of SHM and CSR with a focus on mechanisms that direct AID cytidine deamination in activated B cells and mechanisms that promote the differential outcomes of such cytidine deamination.

B Cell Responses: Cell Interaction Dynamics and Decisions

“…multiple inputs (including the BCR, CD40, TLRs, and cytokines) to determine the isotype to which they will ''switch.'' CSR depends on expression of activation-induced cytidine deaminase (AID) and induction of mutations and double strand breaks in switch regions (Hwang et al, 2015). When CSR occurs, the intervening DNA regions are excised, such that subsequent CSR events can only occur to downstream genes.…”

“…AID deaminates cytidine residues in transcribed VDJ and VJ regions. Base excision repair (BER) and mismatch repair (MMR) mechanisms convert AID cytidine deamination lesions to point mutations and a small frequency of insertions and deletions (Hwang et al, 2015). The precise mechanisms acting to target AID to VDJ and VJ regions in GC B cells are not yet defined, but the higher activity of AID in complementarity determining regions (CDRs) is partially explained by the enrichment of a consensus AID motif in these regions.…”

The Bayesian optimist's guide to adaptive immune receptor repertoire analysis

“…Isotype can change through class-switch recombination, which arises due to double-stranded breaks resulting from AID deamination (116,200). High-throughput sequencing including isotype information is now available, and is shining light on this process.…”

The Memories of NK Cells: Innate-Adaptive Immune Intrinsic Crosstalk

“…The first mechanism is called somatic hyper mutation process (SHM) and consists in a modulation of the antigen receptor affinity by inserting random point mutations in the sequences coding for the variable regions of the receptorial immunoglobulin. Such editing, which takes place in the germinal center, is followed by the positive selection of the cells which display an improved antigen recognition [7]. The second mechanism, also carried out in the germinal center, is called isotype-switching or class-switch recombination (CSR).…”

“…According to CSR, postgerminative B cells and related plasma cells mount and produce immunoglobulins characterized by a new constant region. When secreted, these isotype-switched immunoglobulins are able to perform different biological activities, aimed at a more rapid clearance of pathogens in the different contexts in which they are released [7]. Irrespective of the different strategies put in place to ensure the presence of long-lived populations, or to improve their response, there is no doubt that the effectiveness of the immunologic answer relies on the gene rearrangement able to amplify the repertoire of receptors.…”