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After functional V(D)J recombination, bone mar-row immature B cells express a BCR made up of surface IgM. In secondary lymphoid organs, ma-ture B cells simultaneously express surface IgD of the same specificity as surface IgM through alternative splicing of a pre-mRNA composed of V(D)J and both C and C heavy chain con-stant exons (Moore et al., 1981; Preud’homme et al., 2000; Chen and Cerutti, 2010). After en-countering antigen, in adequate lymphoid tissue structures providing accessory signals (direct in-teractions with T cells and follicular dendritic cells and binding of cytokines secreted by such cells), activated B cells undergo classical class-switch recombination (cCSR) and substitute the C gene with C, C, or C, thereby generat-ing secondary IgG, IgA, and IgE BCR and anti-body classes with the same antigenic specificity but new effector functions. This recombina-tion targets specific stretches of repetitive DNA (S regions) preceding C and all C, C, and C genes and requires the DNA-editing en-zyme activation-induced deaminase (AID; Pavri and Nussenzweig, 2011). Transcription and, to an even higher extent, accessibility of the IgH locus S regions to cCSR is under the control of the IgH 3 regulatory region (3RR), located downstream of C, and encompassing the four transcriptional enhancers hs3a, hs1,2, hs3b, and hs4 (Vincent-Fabert et al., 2010a; Pinaud et al., 2011). Genomic disruption or complete dele-tion of the 3RR in the mouse abrogates cCSR to all IgG, IgA, and IgE classes (Vincent-Fabert et al., 2010a,b; Pinaud et al., 2011). Recently the 3RR was also reported to be transcribed and itself undergo AID-mediated mutation and recombination around phylogenetically con-served switch-like DNA repeats, highlighting its close functional partnership with AID (Péron et al., 2012). Despite the absence of a repetitive S region upstream of C and similar to class switching from IgM to IgG, IgA, and IgE, some CD38+ human B cells from tonsils carry an IgH locus switched to IgD expression after an AID-mediated deletio