Human immunoglobulin classes and subclasses show variability in VDJ gene mutation levels
Human immunoglobulin classes and subclasses show variability in VDJ gene mutation levels
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DOI：
10.1038/icb.2014.44
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发表时间：
2014-09-01
影响因子：
4
通讯作者：
Collins, Andrew M.
中科院分区：
文献类型：
--
作者：
Jackson, Katherine J. L.;Wang, Yan;Collins, Andrew M.
体细胞点突变为B细胞的历史提供了线索，并且突变数量通常与抗体亲和力相关。我们最近提出了一种人类同种型功能模型，该模型部分基于突变分析，其中同种型转换的主要途径涉及B细胞依次经过四种免疫球蛋白（Ig）G亚类。这应该会导致同种型之间亲和力的可预测差异，并且这有助于解释不同同种型如何协同工作。该模型建立在对从巴布亚新几内亚村民中扩增的重排免疫球蛋白重链序列的分析基础上，结果显示与不同IgG亚类相关的序列中V区突变的平均数量存在极显著差异。为了确定突变水平和同种型之间的这种关系是否是一种更普遍的现象，本研究在澳大利亚悉尼的健康城市居民中进行。使用454焦磷酸测序技术从八个人身上获取表达除IgD和IgE之外所有同种型的细胞生成VDJ序列。这为研究产生了35118条独特的、有功能的VDJ序列。数据证实与逐渐更靠近3′端的Ig重链γ（IGHG）恒定区基因相关的VDJ基因显示出点突变水平的增加。IgA1和IgA2序列中V区突变的平均值相似。不同同种型之间突变模式也存在差异。尽管IgG2与不依赖T细胞的反应相关，但IgG2序列比其他IgG同种型显示出更显著的抗原选择的突变证据。IgA2中的抗原选择也比IgA1序列中显著更高，这增加了从IGHG2到IGHA2优先转换途径的可能性。
Somatic point mutations provide glimpses into B-cell histories, and mutation numbers generally correlate with antibody affinity. We recently proposed a model of human isotype function, based in part on mutation analysis, in which the dominant pathway of isotype switching involves B cells moving sequentially through the four immunoglobulin (Ig) G subclasses. This should result in predictable differences in affinity between isotypes, and this helps explain how different isotypes work together. The model built on analysis of rearranged immunoglobulin heavy chain sequences amplified from Papua New Guinean villagers, which showed highly significant differences in the mean number of V-REGION mutations in sequences, associated with the different IgG subclasses. To determine whether this relationship between mutation levels and isotypes is a more general phenomenon, the present study was conducted in healthy, urban residents of Sydney, Australia. VDJ sequences were generated from eight individuals, using 454 pyrosequencing, from cells expressing all isotypes except IgD and IgE. This resulted in 35 118 unique, productive VDJ sequences for the study. The data confirm that VDJ genes associated with progressively more 30 Ig heavy chain gamma (IGHG) constant region genes show increasing levels of point mutation. Mean V-REGION mutations in IgA1 and IgA2 sequences were similar. Patterns of mutations also differed between isotypes. Despite their association with T-independent responses, IgG2 sequences showed significantly more mutational evidence of antigen selection than other IgG isotypes. Antigen selection was also significantly higher in IgA2 than in IgA1 sequences, raising the possibility of a preferential switch pathway from IGHG2 to IGHA2.