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.aging | antibody repertoire | influenza vaccine | CMV | UniFrac T he deterioration of immune function with age, a process referred to as immunosenescence, is well recognized. Notable changes contributing to immunosenescence include, among others, decreased proliferation of lymphocytes, reduced T-cell receptor repertoire, and defects in antibody production (1, 2). This phenomenon contributes to an age-related increase in susceptibility to viral and bacterial infections and decreased response to vaccination (3-5). Indeed, individuals over the age of 65 y are less than half as protected by standard influenza vaccines as younger individuals (6), and pneumonia and influenza represent the fourth most common cause of death among aging individuals (4).Antibody-mediated immunity is the result of an evolutionary arms race between the pathogens to which an individual is exposed and antibody-producing B cells. A tremendous diversity of potential antibody affinities is generated by the mechanisms of V(D)J recombination, random junctional insertions/deletions, and somatic hypermutation (7). Preferential proliferation of activated B cells upon encounter with a cognate antigen then exerts a selective pressure for B-cell receptors (BCRs) with a high binding affinity to the antigen (7). The clonal history of B cells circulating in the blood c...

Dynamics of the human antibody repertoire after B cell depletion in systemic sclerosis

“…1E). To compare the initial B cell repertoire with the reconstituted repertoire after depletion, we applied the phylogenetic distance metric UniFrac (29), whose use on immune repertoire data was recently demonstrated (30). As expected, we found that group A displayed greater preinfusion-to-postinfusion distances than group B (Fig.…”

Reconstructing Antibody Repertoires from Error-Prone Immunosequencing Reads

“…As an alternative to computational error correction of immunosequencing datasets, biologists use unique molecular barcoding (33, 34), an experimental approach that allows one to correct most amplification and sequencing errors, thus enabling analysis of low-abundance receptor sequences (46, 9, 35, 27, 36, 37, 38). This approach is based on attaching a short unique barcode (12–17 nt) to each RNA molecule, so that all amplified copies of this molecule contain the same barcode.…”

“…The Unique Molecular Identifiers (UMIs) barcoding technology (33, 34) allows one to analyze low-abundant receptor sequences and to error-correct amplification errors (35, 27, 36, 37, 38). Barcoding and non-barcoding protocols have different requirements with respect to repertoire construction algorithms; e.g., while aggressive error-correction works well for barcoded Rep-seq datasets, it results in overcorrection and loss of natural diversity for non-barcoded datasets.…”

Longitudinal analysis of the antibody repertoire of a Zika virus-infected patient revealed dynamic changes in antibody response

“…Recently, next-generation sequencing (NGS)-based antibody repertoire analysis has been used to provide a systemic view of humoral responses to antigen stimuli [13] such as viral infections [19] and vaccination [17,20,21]. Understanding the mechanism and dynamics underlying antibody generation can facilitate vaccine design and improve the prognosis of infectious diseases [13,22].…”