AID is specifically expressed in germinal center B cells (Muramatsu et al., 1999). A number of activation stimuli promote AID expression in splenic B cells, such as LPS alone or in combination with interleukin-4 (IL-4) or TGFp (Muramatsu et al, 1999) and CD40 ligation (Dedeoglu et al., 2004). Therefore, under physiological conditions, expression of AID is linked to the B-cell activation program taking place in germinal centers. JAK/STAT and NF-kB pathways have been shown to be involved in IL-4-induced AID expression in B cells (Dedeoglu et al., 2004; Zhou et al., 2003).
E-proteins are helix-loop-helix (HLH) transcription factors that bind E boxes at DNA. E-proteins can also form heterodimers with antagonist HLH proteins that lack the DNA-binding domain preventing transcription, known as inhibitors of differentiation (Id1-4). It has been shown that the E47 E-protein can induce the expression of AID in B cells through the activation of an intronic enhancer in the Aicda gene. This activation seems negatively regulated by Id3. Accordingly, E47 deficiency and Id3 overexpression result in a decrease in CSR (Sayegh et al., 2003). Another Id protein, Id2, has been reported to repress AID expression by antagonizing the activity of the Pax5 transcription factor (Gonda et al., 2003). Further, Blimp1, a master transcription factor involved in plasma cell differentiation, represses the expression of Pax5 (Lin et al., 2002) and AID (Shaffer et al., 2002) and in the absence of the Blimp1 regulator interferon regulatory factor-4 (IRF-4) CSR and AID expression are severely impaired (Klein et al., 2006; Sciammas et al., 2006). These results provide evidence that regulation of AID expression is intertwined in the B-cell activation and developmental programs to ensure a tight restriction.
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