Downstream class switching leads to IgE antibody production by B lymphocytes lacking IgM switch regions
- 16 February 2010
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 107 (7), 3040-3045
- https://doi.org/10.1073/pnas.0915072107
Abstract
Ig heavy chain (IgH) class-switch recombination (CSR) replaces the IgH C mu constant region exons with one of several sets of downstream IgH constant region exons (e.g., C gamma, C epsilon, or C alpha), which affects switching from IgM to another IgH class (e.g., IgG, IgE, or IgA). Activation-induced cytidine deaminase (AID) initiates CSR by promoting DNA double-strand breaks (DSBs) within switch (S) regions flanking the donor C mu (S mu) and a downstream acceptor C(H) (e.g., S gamma, S epsilon, S alpha) that are then joined to complete CSR. DSBs generated in S mu frequently are joined within S mu to form internal switch region deletions (ISD). AID-induced ISD and mutations have been considered rare in downstream S regions, suggesting that AID targeting to these S regions requires its prior recruitment to S mu. We have now assayed for CSR and ISD in B cells lacking S mu (S mu(-/-) B cells). In S mu(-/-) B cells activated for CSR to IgG1 and IgE, CSR to IgG1 was greatly reduced; but, surprisingly, CSR to IgE occurred at nearly normal levels. Moreover, normal B cells had substantial S gamma1 ISD and increased mutations in and near S gamma1, and levels of both were greatly increased in S mu(-/-) B cells. Finally, S mu(-/-) B cells underwent downstream CSR between S gamma1 and S epsilon on alleles that lacked S mu CSR to these sequences. Our findings show that AID targets downstream S regions independently of CSR with Smu and implicate an alternative pathway for IgE class switching that involves generation and joining of DSBs within two different downstream S regions before S mu joining.Keywords
This publication has 42 references indexed in Scilit:
- Alternative end-joining catalyzes robust IgH locus deletions and translocations in the combined absence of ligase 4 and Ku70Proceedings of the National Academy of Sciences, 2010
- Competition between the RNA Transcript and the Nontemplate DNA Strand during R-Loop Formation In Vitro: a Nick Can Serve as a Strong R-Loop Initiation SiteMolecular and Cellular Biology, 2010
- G Clustering Is Important for the Initiation of Transcription-Induced R-Loops In Vitro, whereas High G Density without Clustering Is Sufficient ThereafterMolecular and Cellular Biology, 2009
- Balancing AID and DNA repair during somatic hypermutationTrends in Immunology, 2009
- Integrity of the AID serine-38 phosphorylation site is critical for class switch recombination and somatic hypermutation in miceProceedings of the National Academy of Sciences of the United States of America, 2009
- Involvement of Artemis in nonhomologous end-joining during immunoglobulin class switch recombinationThe Journal of Experimental Medicine, 2008
- Sequence Dependence of Chromosomal R-Loops at the Immunoglobulin Heavy-Chain Sμ Class Switch RegionMolecular and Cellular Biology, 2007
- The in vivo pattern of AID targeting to immunoglobulin switch regions deduced from mutation spectra in msh2−/− ung−/− miceThe Journal of Experimental Medicine, 2006
- Immunoglobulin class-switch recombination in mice devoid of any Sμ tandem repeatBlood, 2004
- R-loops at immunoglobulin class switch regions in the chromosomes of stimulated B cellsNature Immunology, 2003