Souto-Carneiro M Margarida, Sims Gary P, Girschik Hermann, Lee Jisoo, Lipsky Peter E
Repertoire Analysis Group, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892-1820, USA.
J Immunol. 2005 Dec 1;175(11):7425-36. doi: 10.4049/jimmunol.175.11.7425.
The CDR3 of the Ig H chain (CDR3(H)) is significantly different in fetal and adult repertoires. To understand the mechanisms involved in the developmental changes in the CDR3(H) of Ig H chains, sets of nonproductive V(H)DJ(H) rearrangements obtained from fetal, full-term neonates and adult single B cells were analyzed and compared with the corresponding productive repertoires. Analysis of the nonproductive repertoires was particularly informative in assessing developmental changes in the molecular mechanisms of V(H)DJ(H) recombination because these rearrangements did not encode a protein and therefore their distribution was not affected by selection. Although a number of differences were noted, the major reasons that fetal B cells expressed Ig H chains with shorter CDR3(H) were both diminished TdT activity in the DJ(H) junction and the preferential use of the short J(H) proximal D segment D7-27. The enhanced usage of D7-27 by fetal B cells appeared to relate to its position in the locus rather than its short length. The CDR3(H) progressively acquired a more adult phenotype during ontogeny. In fetal B cells, there was decreased recurrent DJ(H) rearrangements before V(H)-DJ(H) rearrangement and increased usage of junctional microhomologies both of which also converted to the adult pattern during ontogeny. Overall, these results indicate that the decreased length and complexity of the CDR3(H) of fetal B cells primarily reflect limited enzymatic modifications of the joins as well as a tendency to use proximal D and J(H) segments during DJ(H) rearrangements.
免疫球蛋白重链的互补决定区3（CDR3(H)）在胎儿和成人的库中存在显著差异。为了了解免疫球蛋白重链CDR3(H)发育变化所涉及的机制，对从胎儿、足月新生儿和成人单个B细胞中获得的非 productive V(H)DJ(H)重排进行了分析，并与相应的 productive 库进行了比较。对非 productive 库的分析在评估V(H)DJ(H)重组分子机制的发育变化方面特别有意义，因为这些重排不编码蛋白质，因此它们的分布不受选择的影响。尽管注意到了一些差异，但胎儿B细胞表达具有较短CDR3(H)的免疫球蛋白重链的主要原因是DJ(H)连接处的末端脱氧核苷酸转移酶（TdT）活性降低以及优先使用靠近J(H)的短D片段D7-27。胎儿B细胞对D7-27的使用增加似乎与其在基因座中的位置有关，而不是其短长度。在个体发育过程中，CDR3(H)逐渐获得更接近成人的表型。在胎儿B细胞中，V(H)-DJ(H)重排之前DJ(H)重复重排减少，连接微同源性的使用增加，这两者在个体发育过程中也都转变为成人模式。总体而言，这些结果表明，胎儿B细胞CDR3(H)长度和复杂性的降低主要反映了连接的酶促修饰有限，以及在DJ(H)重排过程中使用近端D和J(H)片段的倾向。
