Generation of antibody diversity before and after immunization.
Generation of antibody diversity before and after immunization.
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免疫前后抗体多样性的产生。
DOI：
10.1111/j.1749-6632.1988.tb21619.x
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发表时间：
1988
影响因子：
5.2
通讯作者：
Malipiero,UV
中科院分区：
文献类型：
--
作者：
Gearhart,PJ;Lawler,AM;Levy,NS;Lebecque,SG;Malipiero,UV
免疫球蛋白可变基因是一个庞大的多基因家族，其成员在发育的不同时期重新排列。免疫系统的标志是多样性，观察B细胞如何重新排列生殖系基因，以建立一个超过16个特异性的库，是很有趣的。B细胞一开始没有重新排列基因或零多样性。哪些基因先重组？是否有一个重新排列的发展计划？基因库多样化的速度有多快，它是在分子水平上通过随机重新排列基因发生，还是在抗原选择后在细胞水平上发生？对个体发育早期B细胞中重排基因的分析提供了对库形成的惊人见解。尽管在种系中有1000多个重链（V,）的可变基因，但只有少数位于连接（JH）基因附近的基因被重排。虽然对kappa轻链（VK）可变基因的重排知之甚少，但初步数据表明，来自许多不同亚家族的基因被重排。对VK基因重排的进一步分析可能为某些B细胞在个体发育过程中出现程序化的现象提供分子基础。在体细胞突变的抗原刺激后，免疫球蛋白基因产生了额外的多样性。对于继发性反应中编码抗体的基因突变的结构特征，我们知道得很多。核苷酸取代聚集在DNA周围的一个离散区域，包括重排的V基因6；它们发生的频率约为1%；它们在IgG和IgA分子中比在I - gh分子中更常见。“阐明这种不寻常的机制显然需要对更动态的特征进行研究。我们通过试图识别一群正在积极经历体细胞突变的B细胞来解决这个问题。结果表明，原代注射抗原刺激B细胞后，突变发生早。突变后的抗体经过抗原的强烈选择，产生高亲和力的抗体。我们提出体细胞超突变的主要作用是增加亲和力，而不是产生新的特异性，从而允许其他基因产物参与免疫反应。”
Immunoglobulin variable genes are a large, multigene family whose members rearrange at different times in development. The hallmark of the immune system is diversity, and it is intriguing to observe how B cells, which start out with unrearranged genes or zero diversity, rearrange germline genes to build a repertoire of greater than lo6 specificities. Which genes rearrange first? Is there a developmental program to rearrangement? How quickly does the repertoire diversify, and does it occur at a molecular level by randomly rearranging genes or at a cellular level after selection by antigen? Analysis of rearranged genes in B cells early in ontogeny has provided striking insights into the formation of the repertoire. Despite over 1,000 variable genes for the heavy chain (V,) in the germline, only a few, located near the joining (JH) genes, are rearranged.’” Although less is known about rearrangement of variable genes for the kappa light chain (VK), preliminary data indicate that genes from many different subfamilies are rearranged. Further analyses of rearranged VK genes may provide a molecular basis for the phenomenon of the programmed appearance of certain B cells during ontogeny.‘Additional diversity is generated in immunoglobulin genes after antigen stimulation by somatic mutation. Much is known about the structural hallmarks of mutation in genes coding for antibodies from secondary responses. Nucleotide substitutions are clustered in a discrete region of DNA surrounding and including the rearranged V genesV6; they occur at a frequency of around 1%; and they are more common in IgG and IgA molecules than in I gh molecules.’The elucidation of this unusual mechanism clearly requires studies of a more dynamic character. We have approached this problem by attempting to identify a population of B cells that is actively undergoing somatic mutation. The results indicate that mutation occurs early after B cells are stimulated with a primary injection of antigen. Mutated antibodies then undergo intense selection by antigen to produce those with high affinity. We propose that the major effect of somatic hypermutation is to increase affinity and not to create new specificities that would allow other gene products to participate in an immune response.”