期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 5, 页码 1105-1110出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1617959114
关键词
aging; antibody repertoire; influenza vaccine; CMV; UniFrac
资金
- NIH Grant [U19 AI057229]
- NIH/National Center for Research Resources Clinical and Translational Science Award [UL1 RR025744]
- International Fulbright Science and Technology Award
- Melvin & Joan Lane Stanford Graduate Fellowship
- Paul and Daisy Soros Fellowship for New Americans
- Howard Hughes Medical Institute (HHMI) Medical Research Fellows Program
- Stanford's Medical Scientist Training and Medical Scholars Research Programs
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.
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