FIGURE 1.

Induction of aicda expression by activated B cell surface molecules. From left to right: (i) the TLR4-MD2-CD14 complex is the receptor for LPS or other bacterial glycoproteins; TLR9 is located in endosomes and recognizes CpG DNA from microbial pathogens. TLR4 and TLR9 associate with adaptor protein MyD88 or Trif through the Tir domain, depicted in yellow; (ii) the BCR complex containing BCR, Igα and Igβ is crosslinked by physically-linked antigens. The CD19/CD21/CD81 co-receptor is activated by the C3d(g) complement cleavage product and modulates the BCR signaling threshold. CD81 is a co-receptor for HCV E2 envelope protein; (iii) cytokine receptors IL-4R and TGF-βR mediate aicda induction and CSR. IL-4R-triggered signaling can be inhibited by activated CD45; and (iv) among the TNF receptor family of B cell surface molecules, CD40 is engaged by CD154 expressed on CD4⁺ T cell surface and exists as a trimer at B cell surface. CD30, when engaged by CD153 expressed CD40⁺ T_H cell surface, negatively regulates CD40 signaling. TACI, BAFF-R and BCMA are receptors for BAFF and/or APRIL secreted by dentritic cells and can mediate CSR in B cells of mucosal areas. Activated intracellular signal transduction pathways likely converge to assemble an enhanceosome, which would include NF-κB, Stat6, Pax5, E47, the Irf8/SpiB complex and the HoxC4/Oct1/2/OcaB complex, at the aicda locus to induce efficient aicda expression. The arrows depict the transcription initiation of aicda or other germinal center B cell-specific genes.