Elucidation of the enigmatic IgD class-switch recombination via germline deletion of the IgH 3' regulatory region

J Exp Med. 2014 May 5;211(5):975-85. doi: 10.1084/jem.20131385. Epub 2014 Apr 21.


Classical class-switch recombination (cCSR) substitutes the Cμ gene with Cγ, Cε, or Cα, thereby generating IgG, IgE, or IgA classes, respectively. This activation-induced deaminase (AID)-driven process is controlled by the IgH 3' regulatory region (3'RR). Regulation of rare IgD CSR events has been enigmatic. We show that μδCSR occurs in mouse mesenteric lymph node (MLN) B cells and is AID-dependent. AID attacks differ from those in cCSR because they are not accompanied by extensive somatic hypermutation (SHM) of targeted regions and because repaired junctions exhibit features of the alternative end-joining (A-EJ) pathway. In contrast to cCSR and SHM, μδCSR is 3'RR-independent, as its absence affects neither breakpoint locations in Sμ- and Sδ-like (σ(δ)) nor mutation patterns at Sμ-σ(δ) junctions. Although mutations occur in the immediate proximity of the μδ junctions, SHM is absent distal to the junctions within both Sμ and rearranged VDJ regions. In conclusion, μδCSR is active in MLNs, occurs independently of 3'RR-driven assembly, and is even dramatically increased in 3'RR-deficient mice, further showing that its regulation differs from cCSR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology
  • Base Sequence
  • Blotting, Southern
  • Cloning, Molecular
  • Cytidine Deaminase / immunology
  • Cytidine Deaminase / metabolism
  • DNA Primers / genetics
  • Germ-Line Mutation / genetics*
  • Immunoglobulin Class Switching / genetics
  • Immunoglobulin Class Switching / immunology*
  • Immunoglobulin D / genetics
  • Immunoglobulin D / immunology*
  • Immunoglobulin Heavy Chains / genetics*
  • Immunohistochemistry
  • Lymph Nodes / cytology
  • Lymph Nodes / immunology
  • Mice
  • Molecular Sequence Data
  • Real-Time Polymerase Chain Reaction
  • Regulatory Sequences, Nucleic Acid / genetics*
  • Sequence Analysis, DNA


  • DNA Primers
  • Immunoglobulin D
  • Immunoglobulin Heavy Chains
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase