Xu Zhenming, Pone Egest J, Al-Qahtani Ahmed, Park Seok-Rae, Zan Hong, Casali Paolo
Center for Immunology, School of Medicine and School of Biological Sciences, University of California, Irvine, CA 92697-4120, USA.
Crit Rev Immunol. 2007;27(4):367-97. doi: 10.1615/critrevimmunol.v27.i4.60.
Expression and activity of activation-induced cytidine deaminase (AID) encoded by the aicda gene are essential for immunoglobulin (Ig) gene somatic hypermutation (SHM) and class switch DNA recombination (CSR). SHM and CSR unfold, in general, in germinal centers and/are central to the maturation of effective antibody responses. AID expression is induced by activated B-cell CD40 signaling, which is critical for the germinal center reaction, and is further enhanced by other stimuli, including interleukin-4 (IL-4) secreted from CD4+ T cells or Toll-like receptor (TLR)-activating bacterial and/or viral molecules. Integration of different intracellular signal transduction pathways, as activated by these stimuli, leads to a dynamic aicda-regulating program, which involves both positively acting trans-factors, such as Pax5, HoxC4, E47, and Irf8, and negative modulators, such as Blimp1 and Id2, to restrict aicda expression primarily to germinal center B cells. The phosphatidylinositol 3-kinase (PI 3-K), which functions downstream of activated B-cell receptor (BCR) signaling, likely plays an important role in triggering the downregulation of aicda expression in postgerminal center B cells and throughout plasmacytoid differentiation. In B cells undergoing SHM and CSR, AID activity, and, possibly, AID targeting to the Ig locus are regulated at a posttranslational level, including AID dimerization/oligomerization, nuclear/cytoplasmic AID translocation, and phosphorylation of the AID Ser38 residue by protein kinase A (PKA). Here, we discuss the role of B-cell activation signals, transcription regulation programs, and posttranslational modifications in controlling aicda expression and AID activity, thereby delineating an integrated model of modulation of SHM and CSR in the germinal center reaction.
由aicda基因编码的激活诱导胞苷脱氨酶（AID）的表达和活性对于免疫球蛋白（Ig）基因的体细胞超突变（SHM）和类别转换DNA重组（CSR）至关重要。一般而言，SHM和CSR在生发中心发生，并且是有效抗体反应成熟的核心。AID表达由活化的B细胞CD40信号诱导，这对生发中心反应至关重要，并且会被其他刺激进一步增强，包括CD4 + T细胞分泌的白细胞介素-4（IL-4）或Toll样受体（TLR）激活的细菌和/或病毒分子。这些刺激激活的不同细胞内信号转导途径的整合导致了一个动态的aicda调节程序，该程序涉及正向作用的转录因子，如Pax5、HoxC4、E47和Irf8，以及负向调节剂，如Blimp1和Id2，从而将aicda表达主要限制在生发中心B细胞。磷脂酰肌醇3激酶（PI 3-K）在活化的B细胞受体（BCR）信号下游起作用，可能在触发生发中心后B细胞和整个浆细胞样分化过程中aicda表达的下调中起重要作用。在经历SHM和CSR的B细胞中，AID活性以及可能的AID靶向Ig基因座在翻译后水平受到调节，包括AID二聚化/寡聚化、AID在细胞核/细胞质中的转运以及蛋白激酶A（PKA）对AID Ser38残基的磷酸化。在此，我们讨论B细胞激活信号、转录调控程序和翻译后修饰在控制aicda表达和AID活性中的作用，从而勾勒出生发中心反应中SHM和CSR调节的整合模型。
