Decreased frequency of somatic hypermutation and impaired affinity maturation but intact germinal center formation in mice expressing antisense RNA to DNA polymerase ζ
Decreased frequency of somatic hypermutation and impaired affinity maturation but intact germinal center formation in mice expressing antisense RNA to DNA polymerase ζ
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DOI：
10.4049/jimmunol.167.1.327
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发表时间：
2001-07-01
影响因子：
4.4
通讯作者：
Klinman, NR
中科院分区：
文献类型：
--
作者：
Diaz, M;Verkoczy, LK;Klinman, NR
为了研究DNA聚合酶ζ在体细胞高频突变中的作用，我们培育了转基因小鼠，这些小鼠针对小鼠REV3（编码该聚合酶的基因）的一部分表达反义RNA。这些小鼠表达高水平的反义RNA，显著降低了内源性小鼠REV3转录本的水平。在对半抗原 - 蛋白质复合物进行免疫后，转基因小鼠产生了强烈的抗体反应，完成了向IgG的转换，并形成了大量的生发中心。然而，在大多数转基因动物中，高亲和力抗体的产生被延迟。此外，转基因小鼠记忆B细胞的V - H基因中体细胞突变的积累减少，特别是在那些产生能增强B细胞受体对半抗原亲和力的氨基酸替换的基因中。这些数据表明DNA聚合酶ζ（一种非复制性聚合酶）在亲和力成熟过程中起作用，可能是通过在体细胞高频突变、克隆选择或两者中起作用。
To examine a role of DNA polymerase zeta in somatic hypermutation, we generated transgenic mice that express antisense RNA to a portion of mouse REV3, the gene encoding this polymerase. These mice express high levels of antisense RNA, significantly reducing the levels of endogenous mouse REV3 transcript. Following immunization to a hapten-protein complex, transgenic mice mounted vigorous Ab responses, accomplished the switch to IgG, and formed numerous germinal centers. However, in most transgenic animals, the generation of high affinity Abs was delayed. In addition, accumulation of somatic mutations in the V-H genes of memory B cells from transgenic mice was decreased, particularly among those that generate amino acid replacements that enhance affinity of the B cell receptor to the hapten. These data implicate DNA polymerase zeta, a nonreplicative polymerase, in the process of affinity maturation, possibly through a role in somatic hypermutation, clonal selection, or both.