Phylogenetic analysis of the human antibody repertoire reveals quantitative signatures of immune senescence and aging
Phylogenetic analysis of the human antibody repertoire reveals quantitative signatures of immune senescence and aging
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DOI：
10.1073/pnas.1617959114
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发表时间：
2017-01-31
影响因子：
11.1
通讯作者：
Quake, Stephen R.
中科院分区：
文献类型：
--
作者：
de Bourcy, Charles F. A.;Angel, Cesar J. Lopez;Quake, Stephen R.
老年人体液免疫力下降，表现为对感染的易感性增加和疫苗反应减弱。为了研究免疫挑战过程中衰老对b细胞受体（BCR）库进化的影响，我们使用系统发育距离度量法分析了接种流感疫苗前后年轻人和老年人的Ig重链转录序列。我们确定，在过去的几十年里，BCR谱变得越来越专门化，但可塑性却越来越小。在50%的老年人中，保留库中有很大的空间被少数回忆谱系占据，这些谱系在疫苗应答期间没有下降，并且含有超突变的IgD(+) B细胞。与年轻受试者相比，年龄较大的受试者表现出朴素曲目的收缩和谱系内多样化的减少，这表明增加新反应的基质减少，以及体细胞超突变对BCR特异性的微调减少。此外，在一些老年受试者中，更大比例的库显示过早停止密码子，这表明衰老可能会对B细胞区分功能性和非功能性受体的能力产生负面影响。最后，我们观察到，在老年受试者的疫苗应答中，与保守突变相比，激进突变的发生率降低，这表明原始抗原原原性的积累可能限制了paratope进化的可及空间。我们的研究结果揭示了影响免疫衰老的环境和衰老因素的复杂相互作用，并提供了衰老对免疫库影响的直接分子表征。
The elderly have reduced humoral immunity, as manifested by increased susceptibility to infections and impaired vaccine responses. To investigate the effects of aging on B-cell receptor (BCR) repertoire evolution during an immunological challenge, we used a phylogenetic distance metric to analyze Ig heavy-chain transcript sequences in both young and elderly individuals before and after influenza vaccination. We determined that BCR repertoires become increasingly specialized over a span of decades, but less plastic. In 50% of the elderly individuals, a large space in the repertoire was occupied by a small number of recall lineages that did not decline during vaccine response and contained hypermutated IgD(+) B cells. Relative to their younger counterparts, older subjects demonstrated a contracted naive repertoire and diminished intralineage diversification, signifying a reduced substrate for mounting novel responses and decreased fine-tuning of BCR specificities by somatic hypermutation. Furthermore, a larger proportion of the repertoire exhibited premature stop codons in some elderly subjects, indicating that aging may negatively affect the ability of B cells to discriminate between functional and nonfunctional receptors. Finally, we observed a decreased incidence of radical mutations compared with conservative mutations in elderly subjects' vaccine responses, which suggests that accumulating original antigenic sin may be limiting the accessible space for paratope evolution. Our findings shed light on the complex interplay of environmental and gerontological factors affecting immune senescence, and provide direct molecular characterization of the effects of senescence on the immune repertoire.