title: Phylogenetic analysis of the human antibody repertoire reveals quantitative signatures of immune senescence and aging.
abstract: 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.
authors.affiliation: Department of Applied Physics, Stanford University, Stanford, CA 94305.
authors.forename: Charles F A
authors.initials: CF
authors.lastname: de Bourcy
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Cesar J Lopez
authors.initials: CJ
authors.lastname: Angel
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, CA 94305.
authors.forename: Christopher
authors.initials: C
authors.lastname: Vollmers
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Cornelia L
authors.initials: CL
authors.lastname: Dekker
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305.|Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305.|Howard Hughes Medical Institute, Chevy Chase, MD 20815.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Davis
authors.affiliation: Department of Applied Physics, Stanford University, Stanford, CA 94305; quake@stanford.edu.|Department of Bioengineering, Stanford University, Stanford, CA 94305.|Chan Zuckerberg Biohub, San Francisco, CA 94158.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Quake
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000276:immunology*; D000914:Antibodies, Viral / Q000096:biosynthesis / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology*; D019070:Cell Lineage; D002908:Chronic Disease; D018389:Codon, Nonsense; D003587:Cytomegalovirus / Q000276:immunology; D003586:Cytomegalovirus Infections / Q000276:immunology; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D005803:Genes, Immunoglobulin; D006801:Humans; D007072:Immunoglobulin D / Q000235:genetics / Q000276:immunology; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D009980:Influenza A virus / Q000276:immunology; D009981:Influenza B virus / Q000276:immunology; D007252:Influenza Vaccines / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011947:Receptors, Antigen, B-Cell / Q000235:genetics*; D014611:Vaccination; D055815:Young Adult
chemical_list: D000914:Antibodies, Viral; D018389:Codon, Nonsense; D007072:Immunoglobulin D; D007143:Immunoglobulin Heavy Chains; D007252:Influenza Vaccines; D011947:Receptors, Antigen, B-Cell
keywords: CMV; UniFrac; aging; antibody repertoire; influenza vaccine