State Key Laboratory of Agrobiotechnology, College of Biological Sciences, National Engineering Laboratory for Animal Breeding, China Agricultural University, Beijing, China.
Immunology. 2022 Jan;165(1):74-87. doi: 10.1111/imm.13407. Epub 2021 Sep 1.
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.
牛只有有限数量的 VH 片段，因此依赖独特的长 DH 基因片段来产生远远超过人类或小鼠的 CDRH3 长度变异（3-70 个氨基酸）。具有超长 CDRH3（>50 个氨基酸）的牛抗体具有独特的结构和结合特殊抗原的能力。在这项研究中，我们用牛的 DH 基因替换了大多数小鼠内源性的 DH 片段，产生了一种称为 B-DH 的小鼠品系。使用牛的 DH 基因显著增加了 CDRH3 的长度变异，从而增加了 B-DH 小鼠的 Ig 重链库。然而，在 B-DH 小鼠中没有观察到超长的 CDRH3，这表明除了长 DH 基因外，还有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 细胞发育模式明显改变。此外，尽管进行了种间 DH 基因替换，B-DH 小鼠也不容易产生自身抗体。本研究中报道的 B-DH 小鼠为回答有关 DH 和 VH 基因协同进化、VDJ 重组和 B 细胞发育中 BCR 选择的基本问题提供了一个独特的模型。
