Abstract
The induction of allergen-specific IgE synthesis requires the cognate interactions between B and T helper (Th) 2 cells. The B cell-activating signal for IgE synthesis is delivered through interleukin (IL)-4 or IL-13 and CD40 ligand, which are provided by activated Th2 cells. Signaling through the IL-4 receptor α chain (IL-4Rα) triggers IL-4- or IL-13-dependent germline Cε transcription by activating signal transducer and activator of transcription (STAT)-6 through members of the Janus kinase (JAK) family. In addition to the known JAK-STAT pathway, two adaptor molecules associated with the IL-4Rα, which include Src homologous and collagen (Shc ) and a product of the fes proto-oncogene family, are involved in the induction of germline Cε transcription. These adaptor molecules transmit the downstream signaling, leading to activation of PU.1, a product of the ets proto-oncogene family, which co-operates functionally with STAT-6 for germline Cε transcription. Ligation of CD40 in the presence of IL-4 or IL-13 leads to expression of activation-induced cytidine deaminase (AID). This novel RNA-editing enzyme plays a role upstream of the putative switch recom-binase, activation of which results in IgE isotype switching, mature Cε transcription and IgE synthesis. Although CD40 signaling activates multiple pathways that are critical for the activation of the switch recom-bination machinery, none of the known second messengers and transcription factors generated by CD40 ligation is involved in AID expression and isotype switching. Elucidation of the merging point of IL-4Rα and CD40 signaling pathways required for IgE switching will provide potential new strategies for the isotype-specific regulation of IgE synthesis.
