Department of Physiological Chemistry, Genentech, San Francisco, CA 94080, USA.
J Immunol. 2010 Jul 1;185(1):166-73. doi: 10.4049/jimmunol.1000515. Epub 2010 May 28.
Ab class switch recombination involves a recombination between two repetitive DNA sequences known as switch (S) regions that vary in length, content, and density of the repeats. Abs expressed by B cells are diversified by somatic hypermutation and class switch recombination. Both class switch recombination and somatic hypermutation are initiated by activation-induced cytidine deaminase (AID), which preferentially recognizes certain hot spots that are far more enriched in the S regions. We found that removal of the largest S region, Sgamma1 (10 kb), in mice can result in the accumulation of mutations and short-range intra-S recombination in the donor Smu region. Furthermore, elevated levels of IgE were detected in trinitrophenol-OVA-immunized mice and in anti-CD40 plus IL-4-stimulated B cells in vitro. We propose that AID availability and targeting in part might be regulated by its DNA substrate. Thus, prominently transcribed S regions, such as Sgamma1, might provide a sufficient sink for AID protein to titrate away AID from other accessible sites within or outside the Ig locus.
类别转换重组涉及两个重复 DNA 序列之间的重组，这两个重复 DNA 序列称为开关（S）区，其长度、内容和重复密度各不相同。B 细胞表达的 Abs 通过体细胞高频突变和类别转换重组多样化。类别转换重组和体细胞高频突变都是由激活诱导胞嘧啶脱氨酶（AID）启动的，AID 优先识别某些热点，这些热点在 S 区中更为丰富。我们发现，在小鼠中去除最大的 S 区 Sgamma1（10kb），可导致供体 Smu 区的突变积累和短距离 S 内重组。此外，在三硝基苯甲醛-卵清蛋白免疫的小鼠和体外抗 CD40 加 IL-4 刺激的 B 细胞中，检测到 IgE 水平升高。我们提出，AID 的可用性和靶向性可能部分受到其 DNA 底物的调节。因此，转录活跃的 S 区，如 Sgamma1，可能为 AID 蛋白提供一个足够的吸收池，以将 AID 从 Ig 基因座内或外的其他可及位点上滴定掉。
