近日，浙江大学邵建忠小组的最新研究提出了解码斑马鱼的免疫球蛋白谱揭示了古代脊椎动物适应性免疫多样化的独特范式。相关论文于2026年8月11日发表在《遗传学报》杂志上。

使用斑马鱼作为早期脊椎动物模型，课题组系统地剖析了古代IgM和IgZ抗体库的不同多样化策略。虽然这两种同型具有共同的V基因库，但在独立的V(D)J重组过程中，它们表现出谱系特异性的V/J图谱偏差。重链重排采用重组-激活基因-非同源末端连接（RAG-NHEJ）途径，IgM表现出比IgZ更大的连接多样性。抗原驱动体细胞超突变（SHM）主要通过激活诱导胞苷脱氨酶（AID）引发的碱基切除修复/错配修复在原始生发中心样细胞中靶向IgM。

然而，在互补决定区和框架区之间的无偏靶向，以及受约束的CXCR5-CXCL13信号传导，限制了突变频率和亲和成熟。值得注意的是，研究小组发现了一个由APOBEC2a介导的不依赖于艾滋病的SHM途径，该途径特异性靶向TCG/CGT基序。

此外，轻链V-J重组是通过微同源介导的末端连接进行的，与重链相比，这限制了CDR3的多样性。相反，IgZ⁺ B细胞倾向于浆细胞分化，表现出松散的组织分布，并经历最小的抗原驱动SHM，与快速粘膜防御一致。他们的发现揭示了硬骨鱼的保守和独特的多样化机制，阐明了早期脊椎动物平衡受体多样性和自我耐受性的分层进化策略。

研究人员表示，适应性免疫多样化的进化起源仍然是免疫学的一个核心问题。

附：英文原文

Title: Decoding immunoglobulin repertoires in zebrafish reveals distinct paradigms for adaptive immune diversification in ancient vertebrates

Author: anonymous

Issue&Volume: 2026/08/11

Abstract: The evolutionary origins of adaptive immune diversification remain a central question in immunology. Using zebrafish as an early vertebrate model, we systematically dissect the distinct diversification strategies of ancient IgM and IgZ antibody repertoires. While both isotypes share a common V gene pool, they exhibit lineage-specific V/J usage biases during independent V(D)J recombination. Heavy-chain rearrangement employs the recombination-activating gene–non-homologous end joining (RAG–NHEJ) pathway, with IgM demonstrating greater junctional diversity than IgZ. Antigen-driven somatic hypermutation (SHM) primarily targets IgM via activation-induced cytidine deaminase (AID)-primed base excision repair/mismatch repair within primitive germinal center-like clusters. However, unbiased targeting across complementarity determining and framework regions, together with constrained CXCR5–CXCL13 signaling, limits mutation frequency and affinity maturation.

Notably, we identify an AID-independent SHM pathway mediated by APOBEC2a that specifically targets TCG/CGT motifs. Furthermore, light-chain V–J recombination is uniquely processed via microhomology-mediated end joining, restricting CDR3 diversity compared with heavy-chain. Conversely, IgZ+ B cells are biased toward plasma cell differentiation, exhibit loosely organized distribution, and undergo minimal antigen-driven SHM, aligning with rapid mucosal defense. Our findings reveal both conserved and distinct diversification mechanisms in teleosts, illuminating layered evolutionary strategies balancing receptor diversity and self-tolerance in early vertebrates.

DOI: 10.1016/j.jgg.2026.08.005

Source: https://www.sciencedirect.com/science/article/abs/pii/S1673852726002687