Age-associated B cells (ABC) inhibit B lymphopoiesis and alter antibody repertoires in old age

Riley, Richard L.; Khomtchouk, Kelly; Blomberg, Bonnie B.

doi:10.1016/j.cellimm.2017.04.008

Cited by 43 publications

(38 citation statements)

References 58 publications

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“…Regarding the necessary elements that are involved in ABCs generation besides T‐bet, the initial characterization of this B cell subset demonstrated that TLR7, TLR9, and MyD88, but not IFN‐αR, are required for the accumulation of these cells . Following analyses exhibited that T‐bet expression in ABCs was more efficiently induced by synergistic signaling given by BCR crosslinking, TLR7 and TLR9 ligation plus IL‐4, IL‐21, and IFN‐γ stimulation . Additionally, it was recently demonstrated that their emergence is also dependent on MHC class II and CD40/CD40L interactions…”

Section: Age‐associated B Cellsmentioning

confidence: 99%

“…ABCs functional potential is extended to practically all B cell effector mechanisms including plasma cell differentiation and Ab production, Ag presentation, and cytokine secretion …”

Section: Age‐associated B Cellsmentioning

confidence: 99%

“…105 Following analyses exhibited that T-bet expression in ABCs was more efficiently induced by synergistic signaling given by BCR crosslinking, TLR7 and TLR9 ligation plus IL-4, IL-21, and IFN-stimulation. 101,106 Additionally, it was recently demonstrated that their emergence is also dependent on MHC class II and CD40/CD40L interactions. 107 ABCs functional potential is extended to practically all B cell effector mechanisms including plasma cell differentiation and Ab production, Ag presentation, and cytokine secretion.…”

Section: Age-associated B Cellsmentioning

confidence: 99%

“…107 ABCs functional potential is extended to practically all B cell effector mechanisms including plasma cell differentiation and Ab production, Ag presentation, and cytokine secretion. 100,106,108,109 ABCs innate-like nature is exemplified by poor responsiveness to BCR and CD40 ligation, despite they possess IgM surface-levels comparable to those seen in conventional FO B cells; instead, they efficiently respond to TLR7 and TLR9 ligation, both innate receptors that synergize with BCR signaling to induce stronger proliferation outcomes. 100 ABCs mainly secrete Igs after TLRs (but not BCR only) stimulation 103,110 ; thus being able to rapidly differentiate into Ab-secreting plasma cells preferentially switched to IgG2a or IgG2c classes.…”

Section: Age-associated B Cellsmentioning

confidence: 99%

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Innate-like B cell subsets during immune responses: Beyond antibody production

Romero‐Ramírez

Navarro-Hernandez

Cervantes‐Díaz

et al. 2018

Journal of Leukocyte Biology

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B lymphocytes are recognized for their crucial role in the adaptive immunity since they represent the only leukocyte lineage capable of differentiating into Ab‐secreting cells. However, it has been demonstrated that these lymphocytes can exert several Ab‐independent functions, including engulfing and processing Ags for presentation to T cells, secreting soluble mediators, providing co‐stimulatory signals, and even participating in lymphoid tissues development. Beyond that, several reports claiming the existence of multiple B cell subsets contributing directly to innate immune responses have appeared. These “innate‐like” B lymphocytes, whose phenotype, development pathways, tissue distribution, and functions are in most cases notoriously different from those of conventional B cells, are crucial to early protective responses against pathogens by exerting “crossover” defensive strategies that blur the established boundaries of innate and adaptive branches of immunity. Examples of these mechanisms include the rapid secretion of the polyspecific natural Abs, increased susceptibility to innate receptors‐mediated activation, cytokine secretion, downstream priming of other innate cells, usage of specific variable immunoglobulin gene‐segments, and other features. As these new insights emerge, it is becoming preponderant to redefine the functionality of B cells beyond their classical adaptive‐immune tasks.

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Section: Age‐associated B Cellsmentioning

confidence: 99%

“…ABCs functional potential is extended to practically all B cell effector mechanisms including plasma cell differentiation and Ab production, Ag presentation, and cytokine secretion …”

Section: Age‐associated B Cellsmentioning

confidence: 99%

Section: Age-associated B Cellsmentioning

confidence: 99%

Section: Age-associated B Cellsmentioning

confidence: 99%

See 2 more Smart Citations

Innate-like B cell subsets during immune responses: Beyond antibody production

Romero‐Ramírez

Navarro-Hernandez

Cervantes‐Díaz

et al. 2018

Journal of Leukocyte Biology

View full text Add to dashboard Cite

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“…Their accumulation is accelerated by HCD and this is not prevented by ES-62: rather, perhaps reflecting their reported relatively high PC-reactivity, they are increased in both the male and female ES-62-treated HCD-treated cohorts. This may simply reflect the increased levels of anti-PC antibodies arising as a consequence of chronic exposure to the PCcontaining ES-62 in these cohorts (Figure 8f-i), but which could possibly serendipitously help to protect against bacterial infection in old age54 . Interestingly, therefore, we have found HCD to reduce the levels of anti-PC antibodies in male and female mice, with this reaching statistical significance with respect to the levels of anti-PC IgG antibodies in male mice relative to the chow-fed counterparts at d340 (*p<0.05).…”

mentioning

confidence: 99%

Parasitic worm-derived ES-62 promotes health- and life-span in high calorie diet-fed mice

Crowe

Doonan

et al. 2019

Preprint

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The recent extension of human lifespan has not been matched by equivalent improvements in late-life health due to the corresponding increase in ageingassociated comorbidities and obesity, conditions exacerbated by the widespread adoption of the high calorie Western diet (HCD). Chronic low-grade inflammation underpins ageing-induced ill-health and thus we have focused on ES-62, an immunomodulator secreted by the parasitic worm Acanthocheilonema viteae that we have previously shown to have potent anti-inflammatory properties, as a novel therapeutic strategy. ES-62 was tested in a mouse model of HCD-accelerated ageing and found to ameliorate pathophysiological, inflammatory and metabolic parameters, when administered at only 1 µg/week. Strikingly, ES-62 also substantially increased the median survival of male HCD-mice. This extension was not observed with female mice and indeed, ES-62 treatment resulted in distinct gender-specific healthspan signatures. Combined with a machine learning approach, such signatures signpost candidate parameters key to promoting both healthspan and lifespan.Adoption of the modern Western diet (high fat and high sugar) has significantly contributed to a global pandemic in metabolic syndrome, obesity, type-2 diabetes and cardiovascular disease; ageing-associated conditions that impact on both wellbeing (healthspan) and lifespan 1,2 . This increasing major public health problem reflects, at least in part, that such a high calorie diet (HCD) disrupts the gut microbiome, with the consequent intestinal inflammation and loss of barrier integrity driving chronic systemic inflammation that appears to dysregulate immunometabolic pathways, accelerating the ageing process and reducing lifespan 1,3-7 . Interestingly, epidemiological data suggest that Western diet-associated diseases are rising fastest in in the developing world 2,8 , regions where parasitic worms (helminths) and other infectious agents are being eradicated 9 . Helminths promote their survival by releasing excretory-secretory (ES) products that, by dampening inflammation and promoting tissue repair, act to prevent worm expulsion but also limit host pathology 10 . Thus, the relatively rapid eradication of these parasites appears to have resulted in hyper-active host immune systems, characterised by chronic low-grade inflammation that may (further) contribute to development of obesity and associated metabolic syndrome co-morbidities, as well as allergic and autoimmune inflammatory disorders, in developing and urbanised countries 10 . Whilst this has questioned the wisdom of current mass parasite eradication programs, it has emphasised the potential of utilising worm infections or ES to treat a wide range of noncommunicable diseases that are characterised by chronic inflammation [11][12][13] . Indeed, we have shown that a single, defined ES protein, ES-62, can suppress pathology in mouse models of allergic and autoimmune inflammatory diseases 9,10,14-16 . ES-62 achieves this by virtue of immunomodulatory phosphorylcholine groups attached...

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