Dörner T, Brezinschek H P, Foster S J, Brezinschek R I, Farner N L, Lipsky P E
Department of Internal Medicine and Harold C. Simmons Arthritis Research Center, University of Texas Southwestern Medical Center, Dallas 75235, USA.
J Immunol. 1998 Mar 15;160(6):2831-41.
After Ag exposure, somatic hypermutation and subsequent selection play significant roles in shaping the peripheral B cell repertoire. However, the disparate impact of each process has not been completely delineated. To address this, the mutational patterns of a large panel of productive V(H)DJ(H) rearrangements of individual human B cells were analyzed and compared with those of a previously reported panel of nonproductive V(H)DJ(H) rearrangements. The productive V(H) rearrangements exhibited a significantly lower mutational frequency and a significantly smaller number of replacement mutations than the nonproductively rearranged genes, suggesting that structural constraints of the Ig molecule and selective influences both impacted the repertoire, militating against replacement mutations. Positive selection favored a mean of four to six replacements in complementarity-determining region 1 (CDR1) and CDR2, and less than two replacements in the framework regions (FRs). In contrast, the negative impact of replacement mutations generated an increased number of silent mutations within both the CDRs and FRs of the productive repertoire accompanied by a net increase in the ratio of replacement to silent mutations in the CDRs compared with that in the FRs. Moreover, there was a negative influence on the distribution of amino acid changes resulting from mutations of highly mutable codons, such as AGY, TAY, GTA, and GCT, preferentially leading to conservative changes in the expressed Ig repertoire. The results are consistent with the conclusion that the expressed repertoire is limited, compared with the potential generated by the mutational machinery, by the dual requirements of avoiding autoreactivity and satisfying structural constraints of an intact Ig molecule.
抗原暴露后，体细胞高频突变及随后的选择在塑造外周B细胞库中发挥着重要作用。然而，每个过程的不同影响尚未完全阐明。为了解决这一问题，分析了大量个体人类B细胞的有功能的V(H)DJ(H)重排的突变模式，并与先前报道的无功能的V(H)DJ(H)重排的模式进行了比较。有功能的V(H)重排比无功能重排的基因表现出显著更低的突变频率和更少的置换突变数量，这表明Ig分子的结构限制和选择性影响都对外周B细胞库产生了作用，不利于置换突变。阳性选择倾向于在互补决定区1（CDR1）和CDR2平均有4到6个置换，而在框架区（FR）少于2个置换。相反，置换突变的负面影响导致有功能的外周B细胞库的CDR和FR内沉默突变数量增加，同时与FR相比，CDR中置换与沉默突变的比例净增加。此外，对于由高度可变密码子（如AGY、TAY、GTA和GCT）突变产生的氨基酸变化分布存在负面影响，优先导致表达的Ig库中的保守变化。这些结果与以下结论一致：与突变机制产生的潜力相比，表达的外周B细胞库受到避免自身反应性和满足完整Ig分子结构限制这两个双重要求的限制。
