Saini Jasmine, Hershberg Uri
School of Biomedical Engineering Sciences and Health Systems, Drexel University, Philadelphia, PA 19104, United States.
School of Biomedical Engineering Sciences and Health Systems, Drexel University, Philadelphia, PA 19104, United States; Department of Microbiology and Immunology, College of Medicine, Drexel University, Philadelphia, PA 19104, United States.
Mol Immunol. 2015 May;65(1):157-67. doi: 10.1016/j.molimm.2015.01.001. Epub 2015 Feb 6.
The exceptional ability of B cells to diversify through somatic mutation and improve affinity of the repertoire toward the antigens is the cornerstone of adaptive immunity. Somatic mutation is not evenly distributed and exhibits certain micro-sequence specificities. We show here that the combination of somatic mutation targeting and the codon usage in human B cell receptor (BCR) Variable (V) genes create expected patterns of mutation and post mutation changes that are focused on their complementarity determining regions (CDR). T cell V genes are also skewed in targeting mutations but to a lesser extent and are lacking the codon usage bias observed in BCRs. This suggests that the observed skew in T cell receptors is due to their amino acid usage, which is similar to that of BCRs. The mutation targeting and the codon bias allow B cell CDRs to diversify by specifically accumulating nonconservative changes. We counted the distribution of mutations to CDR in 4 different human datasets. In all four cases we found that the number of actual mutations in the CDR correlated significantly with the V gene mutation biases to the CDR predicted by our models. Finally, it appears that the mutation bias in V genes indeed relates to their long-term survival in actual human repertoires. We observed that resting repertoires of B cells overexpressed V genes that were especially biased toward focused mutation and change in the CDR. This bias in V gene usage was somewhat relaxed at the height of the immune response to a vaccine, presumably because of the need for a wider diversity in a primary response. However, older patients did not retain this flexibility and were biased toward using only highly skewed V genes at all stages of their response.
B细胞通过体细胞突变实现多样化并提高其对抗原的亲和力的非凡能力是适应性免疫的基石。体细胞突变并非均匀分布，而是表现出一定的微序列特异性。我们在此表明，人类B细胞受体（BCR）可变（V）基因中的体细胞突变靶向与密码子使用的结合产生了预期的突变模式以及突变后聚焦于互补决定区（CDR）的变化。T细胞V基因在靶向突变方面也存在偏向，但程度较小，并且缺乏在BCR中观察到的密码子使用偏好。这表明在T细胞受体中观察到的偏向是由于其氨基酸使用情况，这与BCR的情况类似。突变靶向和密码子偏向使B细胞CDR能够通过特异性积累非保守变化而实现多样化。我们统计了4个人类不同数据集中CDR的突变分布。在所有4种情况下，我们发现CDR中实际突变的数量与我们模型预测的V基因对CDR的突变偏向显著相关。最后，似乎V基因中的突变偏向确实与其在实际人类库中的长期存活有关。我们观察到，静息B细胞库中过表达的V基因尤其偏向于在CDR中发生聚焦突变和变化。在对疫苗的免疫反应高峰期，V基因使用中的这种偏向有所缓解，大概是因为在初次反应中需要更广泛的多样性。然而，老年患者并不保留这种灵活性，在其反应的所有阶段都偏向于仅使用高度偏向的V基因。
