Reshaping the murine immunoglobulin heavy chain repertoire with bovine DH genes
Reshaping the murine immunoglobulin heavy chain repertoire with bovine DH genes
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DOI：
10.1111/imm.13407
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发表时间：
2021-09-01
期刊：
影响因子：
6.4
通讯作者：
Zhao，Yaofeng
中科院分区：
文献类型：
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作者：
Di，Yu;Cai，Shuyi;Zhao，Yaofeng
由于VH片段的数量有限，牛依靠独特的长的DH基因片段来产生CDRH3的长度变异(3-70aa)，远远大于人类或小鼠。带有超长CDRH3s(>；50aa)的牛抗体具有不寻常的结构和与特殊抗原结合的能力。在这项研究中，我们用牛的水解酶基因替换了大多数小鼠内源性水解酶基因片段，产生了一个称为B-水解酶的小鼠品系。牛水解酶基因的使用显着增加了CDRH3的长度变异，从而增加了B-水解酶小鼠的Ig重链谱系。然而，在B-DH小鼠中没有观察到超长的CDRH3，这表明除了长的DH基因外，其他因素也参与了超长CDRH3的形成。尽管与野生型小鼠相比，B细胞发育范式发生了明显的变化，但B-DH小鼠对各种抗原的体液免疫反应正常。此外，尽管进行了物种间的DH基因替换，B-DH小鼠并不容易产生自身抗体。本研究中报道的B-DH小鼠提供了一种独特的模型来回答关于DH和VH基因的协同进化、VDJ重组和B细胞发育中的BCR选择等基本问题。
Having a limited number of VH segments, cattle rely on uniquely long DH gene segments to generate CDRH3 length variation (3–70 aa) far greater than that in humans or mice. Bovine antibodies with ultralong CDRH3s (>50 aa) possess unusual structures and abilities to bind to special antigens. In this study, we replaced most murine endogenous DH segments with bovine DH genes, generating a mouse line termed B‐DH. The use of bovine DH genes significantly increased the length variation of CDRH3 and consequently the Ig heavy chain repertoire in B‐DH mice. However, no ultralong CDRH3 was observed in B‐DH mice, suggesting that other factors, in addition to long DH genes, are also involved in the formation of ultralong CDRH3. The B‐DH mice mounted a normal humoral immune response to various antigens, although the B‐cell developmental paradigm was obviously altered compared with wild‐type mice. Additionally, B‐DH mice are not predisposed to the generation of autoantibodies despite the interspecies DH gene replacement. The B‐DH mice reported in this study provide a unique model to answer basic questions regarding the synergistic evolution of DH and VH genes, VDJ recombination and BCR selection in B‐cell development.