de Bourcy Charles F A, Angel Cesar J Lopez, Vollmers Christopher, Dekker Cornelia L, Davis Mark M, Quake Stephen R
Department of Applied Physics, Stanford University, Stanford, CA 94305.
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305.
Proc Natl Acad Sci U S A. 2017 Jan 31;114(5):1105-1110. doi: 10.1073/pnas.1617959114. Epub 2017 Jan 17.
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.
老年人的体液免疫功能下降，表现为对感染的易感性增加以及疫苗反应受损。为了研究衰老对免疫挑战期间B细胞受体（BCR）库进化的影响，我们使用系统发育距离度量分析了流感疫苗接种前后年轻和老年个体的Ig重链转录序列。我们确定，在几十年的时间跨度内，BCR库变得越来越专业化，但可塑性降低。在50%的老年人中，库中的一个大空间被少数记忆谱系占据，这些谱系在疫苗反应期间没有减少，并且包含高突变的IgD B细胞。相对于年轻个体，老年受试者的初始库收缩，谱系内多样化减少，这意味着产生新反应的底物减少，以及通过体细胞超突变对BCR特异性的微调减少。此外，在一些老年受试者中，库中有更大比例的序列出现过早终止密码子，这表明衰老可能对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，我们观察到老年受试者疫苗反应中与保守突变相比，激进突变的发生率降低，这表明累积的原始抗原罪可能限制了互补决定区进化的可用空间。我们的研究结果揭示了影响免疫衰老的环境和老年学因素之间的复杂相互作用，并提供了衰老对免疫库影响的直接分子特征。
