Evidence of premature immune aging in patients thymectomized during early childhood

Sauce, Delphine; Larsen, Martin; Fastenackels, Solène; Duperrier, Anne; Keller, Michael; Grubeck‐Loebenstein, Beatrix; Ferrand, Christophe; Debré, Patrice; Sidi, Daniel; Appay, Victor

doi:10.1172/jci39269

Cited by 219 publications

(236 citation statements)

References 56 publications

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“…3B). This finding is reminiscent of results regarding relative numbers of memory T cells compared with naive T cells that have suggested CMV infection induces premature immune aging (34,35).…”

Section: Resultssupporting

confidence: 65%

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.

114

123

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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: 65%

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.

114

123

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“…29,31,32 In thymectomized young adults this pattern was strongly associated with seropositivity to CMV. 33 Kohler et al showed that the surface molecule CD31 (PECAM-1) can be used to discriminate between CD31C thymic naive and CD31¡ central naive CD4C T-cells in the peripheral blood of healthy humans. 31 Both CD31C thymic naive and CD31¡ central naive CD4C T-cells satisfy phenotypic and functional criteria for naive CD4C T-cells: expression of surface markers, such as CD45RA, CD27, CD28, CCR7 and CD62L and secretion of IL-2 without significant effector cytokine production (interferon-g and IL4) after stimulation.…”

Section: Immunology Of Aging In Hiv-infected Patientsmentioning

confidence: 99%

Immunosenescence and hurdles in the clinical management of older HIV-patients

2017

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People living with HIV (PLWH) who are treated with effective highly active antiretroviral therapy (HAART) have a similar life expectancy to the general population. Moreover, an increasing proportion of new HIV diagnoses are made in people older than 50 y. The number of older HIVinfected patients is thus constantly growing and it is expected that by 2030 around 70% of PLWH will be more than 50 y old. On the other hand, HIV infection itself is responsible for accelerated immunosenescence, a progressive decline of immune system function in both the adaptive and the innate arm, which impairs the ability of an individual to respond to infections and to give rise to long-term immunity; furthermore, older patients tend to have a worse immunological response to HAART.In this review we focus on the pathogenesis of HIV-induced immunosenescence and on the clinical management of older HIV-infected patients.

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“…Les jeunes adultes thymectomisés à la naissance représentent un groupe particulièrement informatif pour étudier les conséquences à long terme d'une thymectomie précoce et ainsi éva-luer l'importance du thymus au-delà de la production initiale du stock de cellules T. Des études préalables ont montré que les enfants thymectomisés avaient un nombre réduit de lymphocytes CD4 + et de TREC (TcR excision circle) 1 par rapport à un groupe contrôle [3-5] et que la réduction du nombre de cellules CD4 naïves était corrélée au temps écoulé depuis la thymectomie [6]. Nos propres travaux, menés chez 25 jeunes adultes (18 à 26 ans) ayant subi une ablation complète du thymus à la naissance lors d'une intervention correctrice d'une transposition des gros vaisseaux, révèlent également des altérations immunologiques assez profondes [7].…”

Section: La Fonction Thymiqueunclassified

“…Nous avons démontré que ce phé-notype immunitaire altéré était lié à une infection par le cytomégalovirus (CMV) et en particulier à l'établissement d'une réponse immunitaire cellulaire contre ce virus. Celle-ci est mise en évidence par la mesure de la sécrétion d'IFN (interféron)- en réponse aux peptides chevauchants recouvrants pp65 et IE1 [7]. On sait que cet herpès virus, qui est très prévalent dans la population générale et entraîne une infection persistante de son hôte, induit une très forte expansion des cellules mémoires T [8] associée à un recrutement continu du compartiment de cellules naïves [9].…”

Section: La Fonction Thymiqueunclassified

“…Malgré une certaine hétérogénéité parmi les donneurs étudiés, la fréquence des cellules naïves (CD45RA + CCR7 + CD27 + ) est particulière-ment faible au sein des populations CD4 et CD8, et cette diminution corrèle avec l'accumulation de cellules T mémoi-res fortement différenciées CD57 + dites sénescentes. De plus, ces patients ont un profil cytokinique particulier avec une abondance de molécules de type pro-inflammatoire, IL(interleukine)-1, IL-8, éotaxine 2 , dont les niveaux atteignent ceux que l'on observe chez des personnes plus âgées [7]. Malgré leur jeune âge, un sous-groupe de patients (correspondant à un tiers des patients analysés) présente des altérations particulièrement marquées au niveau du compartiment cellulaire T, équivalentes à celles de personnes âgées de plus de 75 ans : moins de 20 % des Figure 1.…”

Section: Thymectomie Et Anomalies Du Système Immunitaireunclassified

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