Key Points
SHM hot- and cold-spot biases are largely consistent between different age and sex groups.
A shift in SHM targeting is observed between young and older male subjects.
This shift in SHM targeting influences the Ig amino acid composition.
Abstract
Aged individuals, particularly males, display an impaired level of Ab response compared with their younger counterparts, yet the molecular mechanisms responsible for the discrepancy are not well understood. We hypothesize that some of this difference may be linked to B cell somatic hypermutation (SHM) targeting, including error-prone DNA repair activities that are crucial to Ab diversification. To examine the effects of aging on SHM targeting, we analyzed B cell Ig repertoire sequences from 27 healthy male and female human subjects aged 20–89. By studying mutation patterns based on 985,069 mutations obtained from 123,415 sequences, we found that the SHM mutability hierarchies on microsequence motifs (i.e., SHM hot/cold spots) are mostly consistent between different age and sex groups. However, we observed a lower frequency in mutations involving Phase II SHM DNA repair activities in older males, but not in females. We also observed, from a separate study, a decreased expression level of DNA mismatch repair genes involved in SHM in older individuals compared with younger individuals, with larger fold changes in males than in females. Finally, we showed that the balance between Phase I versus Phase II SHM activities impacts the resulting Ig phenotypes. Our results showed that the SHM process is altered in some older individuals, providing insights into observed clinical differences in immunologic responses between different age and sex groups.
Footnotes
This work was supported by grants from the National Institutes of Health (R03AI092379 and R01AI104739) to S.H.K. and a Natural Sciences and Engineering Research Council of Canada postgraduate fellowship (NSERC PGS-M) to A.C. The Yale University Biomedical High Performance Computing Center is funded by National Institutes of Health Grants RR19895 and RR029676-01. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- AID
- activation-induced cytidine deaminase
- AIRR-seq
- adaptive immune receptor repertoire sequencing
- BER
- base-excision repair
- GC
- germinal center
- GTEx
- Genotype-Tissue Expression
- MMR
- mismatch repair
- RNA-seq
- RNA-sequencing
- SHM
- somatic hypermutation.
- Received May 22, 2020.
- Accepted October 25, 2020.
- Copyright © 2020 by The American Association of Immunologists, Inc.
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