Preferential utilization of conserved immunoglobulin heavy chain variable gene segments during human fetal life.
Preferential utilization of conserved immunoglobulin heavy chain variable gene segments during human fetal life.
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DOI：
10.1073/pnas.87.16.6146
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发表时间：
1990-08
影响因子：
11.1
通讯作者：
H. Schroeder;Jin Yi Wang
中科院分区：
文献类型：
--
作者：
H. Schroeder;Jin Yi Wang
对特定抗原的反应能力以一种程序化的方式发展。虽然成人的抗体库可能是由重排的重变量、多样性和连接（VH-DH-JH）链和轻链（VL-JL）链的随机组合连接产生的，但小鼠的实验证据表明，在个体发育过程中和对特定抗原的反应中，可变基因片段的使用是非随机的。在这项研究中，我们对104天的人类胎儿肝脏来源的随机分离的恒定区C+ mu转录本进行了序列分析，并证明在胎儿生命期间对三个高度保守的VH3家族基因片段的一小部分具有一致的偏好。此外，数据显示，这种优先的基因片段利用延伸到DHQ52和JH3和JH4位点。对两个“不育”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重排的启动，并影响胎儿对DH的利用。序列比较揭示了等位基因片段的核苷酸多态性，这在肽序列中反映得很差，这意味着相当大的进化选择压力。尽管脊椎动物物种利用各种策略来产生抗体库，但在早期发育过程中始终发现对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的发展中起重要作用的假设。
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.