B‐cell diversity decreases in old age and is correlated with poor health status

Gibson, Kate L.; Wu, Yu-Chang Bryan; Barnett, Yvonne; Duggan, Orla; Vaughan, R. W.; Kondeatis, E; Nilsson, Bengt J.; Wikby, Anders; Kipling, David; Dunn-Walters, Deborah K.

doi:10.1111/j.1474-9726.2008.00443.x

Cited by 375 publications

(292 citation statements)

References 35 publications

Supporting

Mentioning

270

Contrasting

Unclassified

Order By: Relevance

“…S3B). repertoire structure not found in young subjects, where one or several B-cell lineages are expanded to abnormal proportions (8,23). This finding is confirmed by our data (Fig.…”

Section: Resultssupporting

confidence: 91%

See 1 more Smart Citation

Phylogenetic analysis of the human antibody repertoire reveals quantitative signatures of immune senescence and aging

Bourcy

Angel

Vollmers

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

116

123

View full text Add to dashboard Cite

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...

show abstract

“…S3B). repertoire structure not found in young subjects, where one or several B-cell lineages are expanded to abnormal proportions (8,23). This finding is confirmed by our data (Fig.…”

Section: Resultssupporting

confidence: 91%

“…IGH repertoire diversity, corrected for uncaptured sequences using the Chao1 estimator (21), was seen to decrease with age (Fig. 3A), consistent with previous studies (8,23). A recently proposed estimator for the unseen fraction of sequences (33) gave similar results (Fig.…”

Section: Resultssupporting

confidence: 88%

Phylogenetic analysis of the human antibody repertoire reveals quantitative signatures of immune senescence and aging

Bourcy

Angel

Vollmers

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

116

123

View full text Add to dashboard Cite

show abstract

“…Indeed, an increased oligoclonality and a reduced frequency of somatic hypermutation in the elderly response to pneumococcal vaccination has been reported (Kolibab et al 2005). The consequence is a collapse in B cell diversity in elderly people which is correlated with poor health status in these subjects (Gibson et al 2009).…”

Section: Introductionmentioning

confidence: 99%

B cell immunosenescence: different features of naive and memory B cells in elderly

et al. 2011

Self Cite

View full text Add to dashboard Cite

Elderly people show a reduced protection against new infections and a decreased response to vaccines as a consequence of impairment of both cellular and humoral immunity. In this paper we have studied memory/naïve B cells in the elderly, evaluating surface immunoglobulin expression, production of the pro-and anti-inflammatory cytokines, tumor necrosis factor (TNF)-a and interleukin (IL)-10, and presence of somatic hypermutation, focusing on the IgG ? IgD -CD27 -double negative (DN) B cells that are expanded in the elderly. Our results show that naïve B cells from young donors need a sufficiently strong stimulus to be activated ''in vitro'', while naïve B cells from old subjects are able to produce IL-10 and TNF-a when stimulated ''physiologically'' (a-CD40/IL-4), suggesting that these cells might play a role in the control of the immuno-inflammatory environment in the elderly. In addition, in the elderly there is an accumulation of DN B cells with a reduced rate of somatic hypermutation. Thus, DN B lymphocytes may be exhausted cells that are expanded and accumulate as a by-product of persistent stimulation or impaired germinal center formation.

show abstract

“…Previous studies have, for example: revealed the association of certain germline genotypes with susceptibility to such diseases as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and multiple sclerosis (MS) (5,6); found correlations of age with a reduced Ig clonal diversity and less intense response to immune challenge (7,8); found overly expanded clones in cases of lymphoma (9,10); and discovered convergent Ig evolution across subjects in response to certain immune challenges (11,12). These repertoire-sequencing (Rep-Seq) studies have benefitted from improvements in sequencing technologies, which allow for the generation of millions of reads per run (13).…”

mentioning

confidence: 99%

Automated analysis of high-throughput B-cell sequencing data reveals a high frequency of novel immunoglobulin V gene segment alleles

Gadala-Maria

Yaari

Uduman³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

206

253

View full text Add to dashboard Cite

Individual variation in germline and expressed B-cell immunoglobulin (Ig) repertoires has been associated with aging, disease susceptibility, and differential response to infection and vaccination. Repertoire properties can now be studied at large-scale through next-generation sequencing of rearranged Ig genes. Accurate analysis of these repertoire-sequencing (Rep-Seq) data requires identifying the germline variable (V), diversity (D), and joining (J) gene segments used by each Ig sequence. Current V(D)J assignment methods work by aligning sequences to a database of known germline V(D)J segment alleles. However, existing databases are likely to be incomplete and novel polymorphisms are hard to differentiate from the frequent occurrence of somatic hypermutations in Ig sequences. Here we develop a Tool for Ig Genotype Elucidation via Rep-Seq (TIgGER). TIgGER analyzes mutation patterns in Rep-Seq data to identify novel V segment alleles, and also constructs a personalized germline database containing the specific set of alleles carried by a subject. This information is then used to improve the initial V segment assignments from existing tools, like IMGT/HighV-QUEST. The application of TIgGER to Rep-Seq data from seven subjects identified 11 novel V segment alleles, including at least one in every subject examined. These novel alleles constituted 13% of the total number of unique alleles in these subjects, and impacted 3% of V(D)J segment assignments. These results reinforce the highly polymorphic nature of human Ig V genes, and suggest that many novel alleles remain to be discovered. The integration of TIgGER into Rep-Seq processing pipelines will increase the accuracy of V segment assignments, thus improving B-cell repertoire analyses.next-generation sequencing | B-cell repertoire | adaptive immunity | somatic hypermutation | variable gene segment T he production by B cells of immunoglobulin (Ig) proteins, which are expressed on the cell surface as B-cell receptors and secreted by subsets of B cells as antibodies, is a key component of the adaptive immune system in humans. Through their specific binding to an enormously diverse range of foreign bodies, Ig proteins are able to elicit further immunological response and provide protection. These proteins are assembled in B cells from two pairs of polypeptide chains, termed heavy and light. The antigen-binding portions of these genes are created through the somatic recombination of gene segments, termed variable (V), diversity (D), and joining (J). During the recombination process, one each of the ∼46 V, 23 D, and 6 J gene segments (1) recombine to make the antigen-binding region of the heavy chain; the light chain is created by a similar process, although involving one of two different loci (λ and κ) containing V and J genes only. Over three million different Ig sequences can be created through this V(D)J recombinatorial process alone (2). The potential diversity of these sequences is further expanded to the order of trillions (2) when combined with the random insert...

show abstract

B‐cell diversity decreases in old age and is correlated with poor health status

Cited by 375 publications

References 35 publications

Phylogenetic analysis of the human antibody repertoire reveals quantitative signatures of immune senescence and aging

Phylogenetic analysis of the human antibody repertoire reveals quantitative signatures of immune senescence and aging

B cell immunosenescence: different features of naive and memory B cells in elderly

Automated analysis of high-throughput B-cell sequencing data reveals a high frequency of novel immunoglobulin V gene segment alleles

Contact Info

Product

Resources

About