The ageing immune system: is it ever too old to become young again?

Dorshkind, Kenneth; Montecino‐Rodriguez, Encarnacion; Signer, Robert A.J.

doi:10.1038/nri2471

Cited by 378 publications

(316 citation statements)

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“…At this point, it is worthwhile noting that in humans, as well as in mice, B-cell production in the bone marrow decreases with age and correlates with an increased incidence of auto-antibodies in the serum [5,[38][39][40][41]. In order to test the hypothesis that decreased B-cell production in the bone marrow increases the chance of developing auto-immunity, other mutant mice in which bone marrow B-cell development is reduced should be analyzed.…”

Section: Tolerance Checkpoints In B-cell Development Large Pre-bii Cellsmentioning

confidence: 99%

“…Thus competition for newly formed B cells to enter the peripheral B-cell pool is far less in surrogate light chain deficient mice than in WT mice. Therefore, it could be envisaged that negative selection of immature auto-reactive B cells in the bone marrow of these mice is less stringent, resulting in higher titers of auto-antibodies.At this point, it is worthwhile noting that in humans, as well as in mice, B-cell production in the bone marrow decreases with age and correlates with an increased incidence of auto-antibodies in the serum [5,[38][39][40][41]. In order to test the hypothesis that decreased B-cell production in the bone marrow increases the chance of developing auto-immunity, other mutant mice in which bone marrow B-cell development is reduced should be analyzed.…”

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confidence: 99%

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Tolerance checkpoints in B‐cell development: Johnny B good

et al. 2009

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B-cell development up to the immature B-cell stage takes place in the bone marrow, while final maturation into mature B cells occurs in the spleen. During differentiation, the precursor and immature B cells have to pass several checkpoints, including those in which they are censored for being auto-reactive, and therefore being potentially dangerous. Numerous studies have shown that the immature B-cell stage in the bone marrow and the transitional B-cell stages in the spleen comprise distinct checkpoints at which autoreactivity is censored. Recently, evidence has been provided that the large pre-BII stage in the bone marrow, at which the pre-BCR is expressed, is yet another B-cell tolerance checkpoint. Here, we review these findings and speculate on directions for possible further experimentation.Key words: B cells . Negative selection . Positive selection . Receptor editing . Tolerance Introduction B-cell development, as it takes place in the bone marrow and spleen, can be subdivided into various stages based on the expression of different cell-surface and intra-cellular markers, the cell cycle profile and the rearrangement status of the cell's Ig-heavy (IgH) and Ig-light (IgL) chains [1][2][3][4]. In Fig. 1, the different stages of B-cell development in the bone marrow and spleen and the most important cell-surface markers by which different subpopulations can be distinguished are depicted. Moreover, the stages in which censoring for auto-reactivity takes place are shown in gray.The earliest B-lineage cell type found in the bone marrow is the pro/pre-BI cell. This cell type is characterized by the expression of CD19 and CD117 (c-kit) and the IgH chain loci are in a rearranged D-J configuration [4][5][6]. Under physiological conditions, these cells are already committed to the B-cell lineage. However, their commitment can be reversed by the ablation of the B-cell identity gene Pax5 [7][8][9]. Pro/pre-BI cells are the direct precursors of large pre-BII cells, which have lost CD117 expression and gained the expression of CD25 [3]. At this stage of differentiation, the IgH chain loci are V to D-J rearranged and those that have done this successfully (synthesized a m-heavy (mH) chain) are positively selected within this compartment. This positive selection is mediated by the pre-BCR, which is composed of the mH chain and the surrogate light chain proteins . Moreover, the pre-BCR induces a strong proliferation of these positively selected pre-B cells [12,13]. A very recent report indicates that the pre-BCR might also be involved in the censoring of B-cell auto-reactivity [16]. These findings will be discussed in the section Large pre-BII cells.Pre-BCR signaling down-modulates transcription of the surrogate light chain genes , and thereby extinguishes its own expression. Upon down-modulation of surface pre-BCR expression, cells stop proliferating and enter the small pre-BII compartment [3]. At this developmental stage, [18][19][20]. It is at this stage of development that, for the first time, cells are censored for t...

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Section: Tolerance Checkpoints In B-cell Development Large Pre-bii Cellsmentioning

confidence: 99%

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confidence: 99%

Tolerance checkpoints in B‐cell development: Johnny B good

et al. 2009

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“…Responses to vaccination are also less effective in the elderly. These manifestations are thought to reflect an age‐related functional decline in the immune system (Dorshkind et al ., 2009). An integrated understanding of the aging immune system is therefore essential for the delivery of optimal healthcare to the elderly population.…”

Section: Introductionmentioning

confidence: 99%

Reduced naïve CD 8 ⁺ T ‐cell priming efficacy in elderly adults

et al. 2015

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SummaryAging is associated with impaired vaccine efficacy and increased susceptibility to infectious and malignant diseases. CD8+ T‐cells are key players in the immune response against pathogens and tumors. In aged mice, the dwindling naïve CD8+ T‐cell compartment is thought to compromise the induction of de novo immune responses, but no experimental evidence is yet available in humans. Here, we used an original in vitro assay based on an accelerated dendritic cell coculture system in unfractioned peripheral blood mononuclear cells to examine CD8+ T‐cell priming efficacy in human volunteers. Using this approach, we report that old individuals consistently mount quantitatively and qualitatively impaired de novo CD8+ T‐cell responses specific for a model antigen. Reduced CD8+ T‐cell priming capacity in vitro was further associated with poor primary immune responsiveness in vivo. This immune deficit likely arises as a consequence of intrinsic cellular defects and a reduction in the size of the naïve CD8+ T‐cell pool. Collectively, these findings provide new insights into the cellular immune insufficiencies that accompany human aging.

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“…9 Aging of the immune system, referred to as immunosenescence, is characterized by a decrease in cell-mediated immune function and a reduction of humoral immune responses. 10,11 Clinically, immunosenescence is partially responsible for increased prevalence and severity of infectious diseases as well as low efficacy of vaccinations in elderly patients. 10 Age-related decreases in immunosurveillance against cancer has also been suggested as a contributing factor to increased cancer rates, such as lung cancer, in elderly patients.…”

Section: Introductionmentioning

confidence: 99%

“…10,11 Clinically, immunosenescence is partially responsible for increased prevalence and severity of infectious diseases as well as low efficacy of vaccinations in elderly patients. 10 Age-related decreases in immunosurveillance against cancer has also been suggested as a contributing factor to increased cancer rates, such as lung cancer, in elderly patients. 12 Furthermore, preclinical studies in animal models have indicated that antitumor immunotherapeutic interventions are less effective in aged animals.…”

Section: Introductionmentioning

confidence: 99%