Regulatory Mechanisms of Human Ige Synthesis

ABSTRACTThe 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-1 3-dependent germline Ce 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 Ce transcription. These adaptor molecules transmit the downstream signaling, leading to activation of PU.1, a product of the ets proto-oncogene family, which cooperates 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 recombinase, 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 recombination 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