FIGURE 1

IgA structure and class switch recombination (CSR). (a) The intron–exon structure of the constant heavy-chain (CH) gene. Each exon encodes a separate domain (C1, C2, C3). The hinge (H) region is encoded at the 5' end of the C2 exon and the 18-amino-acid extension at the C-terminal end of secreted IgA is encoded at the 3' end of the C3 exon (tail piece available for J-chain combination). The transmembrane and cytoplasmic tail sequences are encoded by the M exon located 3' of the C3 exon. The shaded box represents 3'-untranslated RNA. (b) Three-dimensional model of monomeric human IgA2 showing wide separation of antigen-binding sites at the top (reproduced with permission from ref. ¹²⁸). (c) Following V(D)J recombination, synthesis of the heavy chain and subsequent association with a light chain, an IgM molecule is expressed on the surface of the B cell. CSR to IgA (shown for the mouse) is preceded by the production of an germline transcript (not shown), which is formed following transcription through the initiation (I) exon, the intronic switch (S) region, and the C exons. Transcription is initiated from cytokine-inducible promoters upstream of the I exon. Processing of this primary transcript generates the germline transcript and a spliced out S-region transcript. The spliced out S-region stably associates with the template DNA strand of the S-region, forming a stable RNA–DNA hybrid. The displaced G-rich single-stranded DNA is thought to be the substrate for the enzyme activation-induced cytidine deaminase (AID). DNA double-strand breaks at the S-region and DNA repair result in joining of the S and S regions yielding the rearranged IgA heavy chain constant region and the excised intervening DNA, depicted as a DNA switch circle, which represents a short-lasting sign of local CSR. E upstream of the S region indicates the intronic enhancer. Gene elements depicted are not to scale.