Effects of Aging, Cytomegalovirus Infection, and EBV Infection on Human B Cell Repertoires

Wang, Chen; Liu, Yi; Xu, Lan T.; Jackson, Katherine; Roskin, Krishna M.; Pham, Tho D.; Laserson, Jonathan; Marshall, Eleanor L.; Seo, Katie; Lee, Ji-Yeun; Furman, David; Koller, Daphne; Dekker, Cornelia L.; Davis, Mark M.; Fire, Andrew; Boyd, Scott D.

doi:10.4049/jimmunol.1301384

Cited by 163 publications

(190 citation statements)

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“…These observations demonstrate, on a phylogenetic level, the continual specialization undergone by the B-cell repertoire over a lifetime, accelerated by chronic infection. This finding is consistent with reports of persistent clonal expansions in the elderly over the long term (at visits separated by a year) (10).…”

Section: Resultssupporting

confidence: 93%

“…2C). The degree of expansion, elevated mutation loads, and persistence in the face of vaccine challenge all suggest that the superlineages have existed in the affected participants for a long time, a notion consistent with previous reports of clonal expansions persisting over the course of at least an entire year in the elderly (10).…”

Section: Resultssupporting

confidence: 87%

“…Here, only lineages present at both day 0 and day 28 were considered, and lineage radii from pooled day 0 and day 28 sequences were compared with radii from day 0 sequences. similar or, on the contrary, slightly elevated in the elderly [it is known that elderly individuals' memory cells tend to be more highly mutated (8,10)]. The distribution of the observed premature stop codons across IGH regions also differed between young and elderly individuals: In the elderly, stop codons occurred more often outside the CDR3 ( Fig.…”

Section: Resultsmentioning

confidence: 92%

“…Elderly individuals' B-cell repertoires have been reported to exhibit restricted clonal diversity, oligoclonal character, increased baseline mutation levels, and persistent clonal expansions in previous studies of IGH sequence diversity (8,10). However, previous work was limited by small numbers of elderly individuals analyzed (8), did not analyze in detail the composition of the oligoclonal lineages (8), or did not study the effect of applying an immune stimulus such as a vaccine (10).…”

mentioning

confidence: 99%

“…However, previous work was limited by small numbers of elderly individuals analyzed (8), did not analyze in detail the composition of the oligoclonal lineages (8), or did not study the effect of applying an immune stimulus such as a vaccine (10). Furthermore, previous B-cell repertoire studies have focused only on isolated aspects of B-cell mutation counts, V/D/J-gene use levels, lineage sizes, and convergent CDR3 sequences (8,(10)(11)(12)(13) without analyzing the character of mutations and without using the full phylogenetic information inherent in the IGH repertoire to quantify dissimilarities between immune systems.…”

mentioning

confidence: 99%

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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.

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112

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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...

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Section: Resultssupporting

confidence: 93%

Section: Resultssupporting

confidence: 87%

Section: Resultsmentioning

confidence: 92%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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.

Self Cite

112

114

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Associations between early‐life and in utero infections and cytomegalovirus‐positive acute lymphoblastic leukemia in children

Gallant

Arroyo

Metayer

et al. 2022

Intl Journal of Cancer

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Childhood infections and cytomegalovirus (CMV) are associated with pediatric acute lymphoblastic leukemia (ALL). CMV dysregulates the host immune system and alters the immune response to subsequent antigenic exposures. We suspect that this immune dysregulation contributes to increased numbers of symptomatic infections in childhood allowing for expansion of pre‐leukemic clones. We explored the association between childhood infections, maternal infections during pregnancy and CMV‐positive ALL. Using a droplet digital PCR assay, we screened diagnostic ALL bone marrow samples from the California Childhood Leukemia Study (1995‐2015) for the presence of CMV DNA identifying CMV‐positive and CMV‐negative cases. We performed a case‐only analysis (n = 524) comparing the number and types of childhood infections and maternal infections during pregnancy between CMV‐positive and CMV‐negative ALL cases using logistic regression. With increasing numbers of infections in the first 12 months of life, children were more likely to classify to the highest tertile of CMV DNA in the bone marrow at diagnosis (OR: 1.04, 95% CI: 1.01‐1.08). Specifically, those reporting cough or flu in the first 12 months were more likely to be CMV‐positive at ALL diagnosis (OR: 2.15, 95% CI: 1.06‐4.37 and OR: 2.06, 95% CI: 1.17‐3.63 respectively). Furthermore, those with a history of maternal infection during pregnancy were more likely to be CMV‐positive (OR: 2.12, 95% CI: 1.24‐3.62). We hypothesize that children with underlying immune dysregulation develop more symptomatic infections in childhood and ultimately CMV‐positive ALL; this underlying immune dysregulation may be due to early immune system alterations via CMV exposure (in utero or early infancy) proposing a potential link between CMV and ALL etiology.

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Examination of control asymptomatic cohorts reveals heightened anti‐EBV and HHV‐6 A/B dUTPase antibodies in the aging populations

Alharshawi

Cox

Ariza

2022

Journal of Medical Virology

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Members of the human Herpesviridae are found in high prevalence in the human virome. While these viruses are known to cause numerous disease pathologies in symptomatic individuals little is known concerning the role that these viruses may have in modulating the host immune system in asymptomatic "healthy" individuals, especially during the aging process. Examination of three cohorts of "healthy asymptomatic" individuals (n = 255) for the presence of antibodies against the herpesviruses deoxyuridine triphosphate nucleotidohydrolase (dUTPase) as a marker for lytic/abortive-lytic replication demonstrated that all cohorts exhibited differential anti-herpesvirus dUTPase antibodies positivity frequencies ranging from 40.4% to 84% with some individuals in these cohorts expressing antibodies to the dUTPases of multiple herpesviruses (17.2%-56%). Furthermore, our results demonstrate that there was a statistically significant difference in anti-human herpesvirus 6 A and 6B (HHV-6 A/B) dUTPase antibodies in Cohort 3 (age = 66.2 ± 15.02 years) versus Cohort 1 (age 46.88 ± 8.61 years), suggesting that reactivation of HHV-6 A/B is not attenuated by aging. It is well established/documented that herpesvirus dUTPases induce immune dysfunction, as such it is of critical importance that additional studies be performed to determine how these viral proteins alter immune responses in asymptomatic individuals.

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Effects of Aging, Cytomegalovirus Infection, and EBV Infection on Human B Cell Repertoires

Cited by 163 publications

References 50 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

Associations between early‐life and in utero infections and cytomegalovirus‐positive acute lymphoblastic leukemia in children

Examination of control asymptomatic cohorts reveals heightened anti‐EBV and HHV‐6 A/B dUTPase antibodies in the aging populations

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