Department of Pathology and Microbiology, University of Nebraska Medical Center , Omaha, NE , USA.
Department of Pediatrics, Philipps-University Marburg , Marburg , Germany.
Front Immunol. 2014 Jul 22;5:345. doi: 10.3389/fimmu.2014.00345. eCollection 2014.
VH replacement refers to RAG-mediated secondary recombination of the IgH genes, which renews almost the entire VH gene coding region but retains a short stretch of nucleotides as a VH replacement footprint at the newly generated VH-DH junction. To explore the biological significance of VH replacement to the antibody repertoire, we developed a Java-based VH replacement footprint analyzer program and analyzed the distribution of VH replacement products in 61,851 human IgH gene sequences downloaded from the NCBI database. The initial assignment of the VH, DH, and JH gene segments provided a comprehensive view of the human IgH repertoire. To our interest, the overall frequency of VH replacement products is 12.1%; the frequencies of VH replacement products in IgH genes using different VH germline genes vary significantly. Importantly, the frequencies of VH replacement products are significantly elevated in IgH genes derived from different autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, and allergic rhinitis, and in IgH genes encoding various autoantibodies or anti-viral antibodies. The identified VH replacement footprints preferentially encoded charged amino acids to elongate IgH CDR3 regions, which may contribute to their autoreactivities or anti-viral functions. Analyses of the mutation status of the identified VH replacement products suggested that they had been actively involved in immune responses. These results provide a global view of the distribution of VH replacement products in human IgH genes, especially in IgH genes derived from autoimmune diseases and anti-viral immune responses.
VH 替换是指 RAG 介导的 IgH 基因的二次重组，它更新了几乎整个 VH 基因编码区，但在新生成的 VH-DH 连接处保留了一小段核苷酸作为 VH 替换足迹。为了探索 VH 替换对抗体库的生物学意义，我们开发了一个基于 Java 的 VH 替换足迹分析程序，并分析了从 NCBI 数据库下载的 61851 个人类 IgH 基因序列中 VH 替换产物的分布。VH、DH 和 JH 基因片段的初步分配提供了人类 IgH 库的全面视图。令我们感兴趣的是，VH 替换产物的总体频率为 12.1%；使用不同 VH 胚系基因的 IgH 基因中 VH 替换产物的频率差异显著。重要的是，VH 替换产物的频率在源自不同自身免疫性疾病的 IgH 基因中显著升高，包括类风湿关节炎、系统性红斑狼疮和过敏性鼻炎，以及编码各种自身抗体或抗病毒抗体的 IgH 基因中。鉴定的 VH 替换足迹优先编码带电荷的氨基酸以延长 IgH CDR3 区，这可能有助于它们的自身反应性或抗病毒功能。对鉴定的 VH 替换产物的突变状态的分析表明，它们已积极参与免疫反应。这些结果提供了人类 IgH 基因中 VH 替换产物分布的全局视图，特别是在源自自身免疫性疾病和抗病毒免疫反应的 IgH 基因中。
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