B cells undergoing physiologically programmed or aberrant genomic alterations provide an opportune system to study the causes and consequences of genome mutagenesis. Activated B cells in germinal centers express activation-induced cytidine deaminase (AID) to accomplish physiological somatic hypermutation (SHM) of their antibody-encoding genes. In attempting to diversify their immunoglobulin (Ig) heavy- and light-chain genes, several B-cell clones successfully optimize their antigen-binding affinities. However, SHM can sometimes occur at non-Ig loci, causing genetic alternations that lay the foundation for lymphomagenesis, particularly diffuse large B-cell lymphoma. Thus, SHM acts as a double-edged sword, bestowing superb humoral immunity at the potential risk of initiating disease. We refer to off-target, non-Ig AID mutations — that are often but not always associated with disease — as aberrant SHM (aSHM). A key challenge in understanding SHM and aSHM is determining how AID targets and mutates specific DNA sequences in the Ig loci to generate antibody diversity and non-Ig genes to initiate lymphomagenesis. Herein, we discuss some current advances regarding the regulation of AID’s DNA mutagenesis activity in B cells.

中文翻译：

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淋巴瘤发生和转化过程中的体细胞超突变机制

经历生理编程或异常基因组改变的 B 细胞为研究基因组突变的原因和后果提供了一个合适的系统。生发中心激活的 B 细胞表达激活诱导的胞苷脱氨酶 (AID)，以实现其抗体编码基因的生理体细胞超突变 (SHM)。在尝试使其免疫球蛋白 (Ig) 重链和轻链基因多样化时，一些 B 细胞克隆成功优化了其抗原结合亲和力。然而，SHM 有时可能发生在非 Ig 位点，导致基因改变，为淋巴瘤的发生奠定基础，特别是弥漫性大 B 细胞淋巴瘤。因此，SHM就像一把双刃剑，在引发疾病的潜在风险下赋予极强的体液免疫能力。我们将脱靶、非 Ig AID 突变（通常但并不总是与疾病相关）称为异常 SHM (aSHM)。了解 SHM 和 aSHM 的一个关键挑战是确定 AID 如何靶向并突变 Ig 位点中的特定 DNA 序列以产生抗体多样性和非 Ig 基因以启动淋巴瘤发生。在此，我们讨论有关 B 细胞中 AID DNA 诱变活性调节的一些最新进展。