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.

中文翻译：

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用牛 DH 基因重塑小鼠免疫球蛋白重链库

由于 VH 片段数量有限，牛依靠独特的长 DH 基因片段来产生远大于人类或小鼠的 CDRH3 长度变异（3-70 aa）。具有超长 CDRH3 (>50 aa) 的牛抗体具有不寻常的结构和结合特殊抗原的能力。在这项研究中，我们用牛 DH 基因替换了大多数鼠内源性 DH 片段，产生了一个称为 B-DH 的小鼠系。牛 DH 基因的使用显着增加了 B-DH 小鼠中 CDRH3 的长度变化，从而增加了 Ig 重链库。然而，在B-DH小鼠中未观察到超长CDRH3，这表明除了长DH基因外，其他因素也参与了超长CDRH3的形成。B-DH 小鼠对各种抗原产生了正常的体液免疫反应，尽管与野生型小鼠相比，B 细胞发育范式明显改变。此外，尽管存在种间 DH 基因置换，但 B-DH 小鼠并不倾向于产生自身抗体。本研究报道的 B-DH 小鼠提供了一个独特的模型来回答有关 B 细胞发育中 DH 和 VH 基因协同进化、VDJ 重组和 BCR 选择的基本问题。