摘要：

Ig heavy chain (IgH) class-switch recombination (CSR) replaces the IgH Cp constant region exons with one of several sets of downstream IgH constant region exons (e.g., Cγ, Cϵ, or Cα). which affects switching from 1gM to another igH class (e.g., lgG, IgE. or IgA). Activationinduced cytidine deaminase (AID) initiates (SR by promoting DNA double-strand breaks (DSBs) within switch (S) regions flanking the donor Cμ (Sμ) and a downstream acceptor C_H (e.g., Sγ, Sϵ, Sα) that are then joined to complete CSR. DSBs generated in Sp frequently are joined within Sμ to form internal switch region deletions (ISD). AIDinduced ISD and mutations have been considered rare in downstream S regions, suggesting that AID targeting to these S regions requires its prior recruitment to Sμ We have now assayed for CSR and ISD in B cells lacking Sit (Sμ^-/- B cells). In Sμ^-/- B cells activated for (SR to IgGi and IgE, CSR to IgGi was greatly reduced; but surprisingly, (SR to IgE occurred at nearly normal levels. Moreover, normal B cells had substantial Sμ 1SD and increased mutations in and near Sμ, and levels of both were greatly increased in Sμ ^-/-B cells. Finally, Sμ^-/- B cells underwent downstream (SR between Sγ1 and Sϵ on alleles that lacked Sμ CSR to these sequences. Our findings show that AID targets downstream S regions independently of (SR with Sμ and implicate an alternative pathway for IgE class switching that involves generation and joining of DSBs within two different downstream S regions before Sμ joining.

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