IgH chain class switch recombination: mechanism and regulation

Abstract

IgH class switching occurs rapidly after activation of mature naive B cells, resulting in a switch from expression of IgM and IgD to expression of IgG, IgE, or IgA; this switch improves the ability of Abs to remove the pathogen that induces the humoral immune response. Class switching occurs by a deletional recombination between two switch regions, each of which is associated with a H chain constant region gene. Class switch recombination (CSR) is instigated by activation-induced cytidine deaminase, which converts cytosines in switch regions to uracils. The uracils are subsequently removed by two DNA-repair pathways, resulting in mutations, single-strand DNA breaks, and the double-strand breaks required for CSR. We discuss several aspects of CSR, including how CSR is induced, CSR in B cell progenitors, the roles of transcription and chromosomal looping in CSR, and the roles of certain DNA-repair enzymes in CSR.

Figure 1. Diagram of the mouse IgH genes in naïve mature B cells expressing IgM and IgD, and CSR to IgG2b

During CSR to IgG2b, AID deaminates the Sμ and Sγ2b regions, instigating DSB formation. The Sμ and Sγ2b regions recombine by an intrachromosomal deletional recombination, which causes the expressed VDJ segment to become associated with the Cγ2b gene. Splicing diagrams of the μ and δ mRNAs, the γ2b germline transcripts (GLTs), and γ2b mRNA are indicated beneath the genes. Eμ and 3′Eα are the two major enhancers that regulate expression of Ig heavy chains and CSR.

Figure 2. Models for the generation of DNA DSBs during CSR

(A) Diagram of how the base excision repair (BER) pathway converts AID-induced dUs to DNA breaks. (B) Diagram of a model for how the mismatch repair pathway converts SSBs produced by UNG and APE activity to DSBs appropriate for NHEJ. See text for more information.

Figure 3. Diagrams of models of chromosome looping within the C_H gene locus obtained from chromosome conformation capture (3C) assays

(A) In mature naïve B cells the Eμ and 3′Eα enhancers are interacting. (B) A model for the interactions predicted from 3C assays for splenic B cells induced to switch to IgG1, showing interactions between the two enhancers, and the Em-Sm-Cμ, and Sg1-Cγ1 loci. The S regions are not diagrammed, and the sites of interaction are not precisely known, so the diagram only indicates approximate locations. See text for more explanation.