Zhang, TingtingFranklin, AndrewBoboila, CristianMcQuay, AmyGallagher, MichaelManis, JohnKhamlichi, Ahmed AmineAlt, Frederick2019-10-052010Zhang, T., A. Franklin, C. Boboila, A. McQuay, M. P. Gallagher, J. P. Manis, A. A. Khamlichi, and F. W. Alt. 2010. “Downstream Class Switching Leads to IgE Antibody Production by B Lymphocytes Lacking IgM Switch Regions.” Proceedings of the National Academy of Sciences 107 (7): 3040–45. https://doi.org/10.1073/pnas.0915072107.0027-84240744-28311091-6490http://nrs.harvard.edu/urn-3:HUL.InstRepos:41483346Ig 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 CH (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 gamma 1 ISD and increased mutations in and near S gamma 1, and levels of both were greatly increased in S mu(-/-) B cells. Finally, S mu(-/-) B cells underwent downstream CSR between S gamma 1 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 S mu 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.en-USJournal Article2019-10-0510.1073/pnas.0915072107