Age-associated alterations in inducible gene transcription in human CD4+ T lymphocytes

Bektas, Arsun; Zhang, Yongqing; Wood, William H.; Becker, Kevin G.; Madara, Karen; Ferrucci, Luigi; Sen, Ranjan

doi:10.18632/aging.100522

Cited by 25 publications

(34 citation statements)

References 43 publications

(51 reference statements)

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“…A more complete understanding of T cell function will lead to new avenues for immunotherapeutic development. Previous studies have examined changes in human naïve and memory CD4 + T cell phenotypes following mitogen activation using microarrays and found 100–300 genes differentially expressed between states313233. Our study establishes proof-of-concept for the potential of GMine to dramatically advance this or similar fields, taking advantage of the new direct digital NanoString technology which is free from the inherent biases of PCR.…”

Section: Discussionsupporting

confidence: 58%

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Mining, visualizing and comparing multidimensional biomolecular data using the Genomics Data Miner (GMine) Web-Server

Proietti

Zakrzewski

Watkins

et al. 2016

Sci Rep

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Genomics Data Miner (GMine) is a user-friendly online software that allows non-experts to mine, cluster and compare multidimensional biomolecular datasets. Various powerful visualization techniques are provided, generating high quality figures that can be directly incorporated into scientific publications. Robust and comprehensive analyses are provided via a broad range of data-mining techniques, including univariate and multivariate statistical analysis, supervised learning, correlation networks, clustering and multivariable regression. The software has a focus on multivariate techniques, which can attribute variance in the measurements to multiple explanatory variables and confounders. Various normalization methods are provided. Extensive help pages and a tutorial are available via a wiki server. Using GMine we reanalyzed proteome microarray data of host antibody response against Plasmodium falciparum. Our results support the hypothesis that immunity to malaria is a higher-order phenomenon related to a pattern of responses and not attributable to any single antigen. We also analyzed gene expression across resting and activated T cells, identifying many immune-related genes with differential expression. This highlights both the plasticity of T cells and the operation of a hardwired activation program. These application examples demonstrate that GMine facilitates an accurate and in-depth analysis of complex molecular datasets, including genomics, transcriptomics and proteomics data.

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Section: Discussionsupporting

confidence: 58%

“…To our knowledge this has not been described or investigated previously; with prior studies investigating only a single lineage. to our knowledge, previous studies investigated only a single lineage31323334. The rapid post activation phenotype comprised a cytotoxic gene signature across both CD8 + and CD4 + T cells.…”

Section: Discussionmentioning

confidence: 99%

Mining, visualizing and comparing multidimensional biomolecular data using the Genomics Data Miner (GMine) Web-Server

Proietti

Zakrzewski

Watkins

et al. 2016

Sci Rep

View full text Add to dashboard Buy / Rent full text

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“…For example, gene-expression studies show that CD4 + lymphocytes from older individuals have higher intrinsic activation of the NF-κB pathways than those from younger individuals 120 . After stimulation with anti-CD3, the production of pro-inflammatory cytokines in vitro is lower in cells from older individuals than in cells from younger individuals 120 , a phenomenon that might be related to altered metabolic activity 121 . However, because these studies have been performed only in small populations, their relevance to inflammageing is unknown.…”

Section: Risk Factors and Causes Of Inflammageingmentioning

confidence: 99%

Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

2018

Self Cite

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Most older individuals develop inflammageing, a condition characterized by elevated levels of blood inflammatory markers that carries high susceptibility to chronic morbidity, disability, frailty, and premature death. Potential mechanisms of inflammageing include genetic susceptibility, central obesity, increased gut permeability, changes to microbiota composition, cellular senescence, NLRP3 inflammasome activation, oxidative stress caused by dysfunctional mitochondria, immune cell dysregulation, and chronic infections. Inflammageing is a risk factor for cardiovascular diseases (CVDs), and clinical trials suggest that this association is causal. Inflammageing is also a risk factor for chronic kidney disease, diabetes mellitus, cancer, depression, dementia, and sarcopenia, but whether modulating inflammation beneficially affects the clinical course of non-CVD health problems is controversial. This uncertainty is an important issue to address because older patients with CVD are often affected by multimorbidity and frailty — which affect clinical manifestations, prognosis, and response to treatment — and are associated with inflammation by mechanisms similar to those in CVD. The hypothesis that inflammation affects CVD, multimorbidity, and frailty by inhibiting growth factors, increasing catabolism, and interfering with homeostatic signalling is supported by mechanistic studies but requires confirmation in humans. Whether early modulation of inflammageing prevents or delays the onset of cardiovascular frailty should be tested in clinical trials.

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“…It is important to understand that the impact of these life experiences may be fundamentally different in humans and mice and that murine model systems have only partial applicability to human conditions. Comparative studies of inducible gene expression profiles in human and mouse cells have led to the recognition of noteworthy species differences, with most of the age-associated changes found in human CD4 T cells not reproduced in murine cells [17]. The human response pattern included a defect in the sustained inducibility of NF-κB target genes in the elderly, suggesting a defect in mounting inflammatory responses.…”

Section: T Cell Aging – Mechanisms and Consequencesmentioning

confidence: 99%

T-cell aging in rheumatoid arthritis

Weyand

Yang

Goronzy³

2014

Current Opinion in Rheumatology

113

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Purpose of review With progressive age, the immune system and the propensity for abnormal immunity change fundamentally. Individuals >50 years of age are more susceptible to infection and cancer, but also at higher risk for chronic inflammation and immune-mediated tissue damage. The process of immunosenescence is accelerated in rheumatoid arthritis. Recent findings Premature T cell senescence occurs not only in RA, it has also been involved in morbidity and mortality of chronic HIV infection. Senescent cells acquire the “senescence associated secretory phenotype (SASP)”, which promotes and sustains tissue inflammation. Molecular mechanisms underlying T cell aging are beginning to be understood. Besides the contraction of T cell diversity due to uneven clonal expansion, senescent T cells have defects in balancing cytoplasmic kinase and phosphatase activities, changing their activation thresholds. Also, leakiness in repairing DNA lesions and uncapped telomeres imposes genomic stress. Age-induced changes in the tissue microenvironment may alter T cell responses. Summary Gain- and loss-of-function in senescent T cells undermine protective immunity and create the conditions for chronic tissue inflammation, a combination typically encountered in RA. Genetic programs involved in T cell signaling and DNA repair are of high interest in the search for underlying molecular defects.

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Age-associated alterations in inducible gene transcription in human CD4+ T lymphocytes

Cited by 25 publications

References 43 publications

Mining, visualizing and comparing multidimensional biomolecular data using the Genomics Data Miner (GMine) Web-Server

Mining, visualizing and comparing multidimensional biomolecular data using the Genomics Data Miner (GMine) Web-Server

Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

T-cell aging in rheumatoid arthritis

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