Schroeder H W, Wang J Y
Department of Medicine, University of Alabama, Birmingham 35294.
Proc Natl Acad Sci U S A. 1990 Aug;87(16):6146-50. doi: 10.1073/pnas.87.16.6146.
The ability to respond to specific antigens develops in a programmed fashion. Although the antibody repertoire in adults is presumably generated by stochastic combinatorial joining of rearranged heavy variable, diversity, and joining (VH-DH-JH) and light (VL-JL) chains, experimental evidence in the mouse has shown nonrandom utilization of variable gene segments during ontogeny and in response to specific antigens. In this study, we have performed sequence analysis of 104-day human fetal liver-derived, randomly isolated constant region C+ mu transcripts and demonstrate a consistent preference during fetal life for a small subset of three highly conserved VH3 family gene segments. In addition, the data show that this preferential gene segment utilization extends to the DHQ52 and the JH3 and JH4 loci. Sequence analysis of two "sterile" DH-JH transcripts suggests that transcriptional activation of the JH-proximal DHQ52 element may precede initiation of DH-JH rearrangement and influence fetal DH utilization. Sequence comparisons reveal striking nucleotide polymorphism in allelic gene segments which is poorly reflected in the peptide sequence, implying considerable evolutionary selection pressure. Although vertebrate species utilize a variety of strategies to generate their antibody repertoire, preferential utilization of VH3 elements is consistently found during early development. These data support the hypothesis that VH3 gene segments play an essential role in the development of the immune response.
对特定抗原作出反应的能力以一种程序化的方式发展。虽然成人体内的抗体库大概是由重排的重链可变区、多样性区和连接区（VH-DH-JH）以及轻链（VL-JL）的随机组合连接产生的，但小鼠实验证据表明，在个体发育过程中以及对特定抗原作出反应时，可变基因片段的利用并非随机。在本研究中，我们对来自104天龄人类胎儿肝脏、随机分离的恒定区C+μ转录本进行了序列分析，并证明在胎儿期，一小部分高度保守的VH3家族基因片段始终受到偏好。此外，数据表明这种对基因片段的优先利用延伸至DHQ52以及JH3和JH4基因座。对两个“无义”DH-JH转录本的序列分析表明，JH近端DHQ52元件的转录激活可能先于DH-JH重排的起始，并影响胎儿期DH的利用。序列比较揭示了等位基因片段中显著的核苷酸多态性，而这种多态性在肽序列中反映较差，这意味着存在相当大的进化选择压力。虽然脊椎动物物种利用多种策略来产生其抗体库，但在早期发育过程中始终能发现对VH3元件的优先利用。这些数据支持了VH3基因片段在免疫反应发育中起重要作用这一假说。
