Gene Expression Analysis Reveals Age and Ethnicity Signatures Between Young and Old Adults in Human PBMC

Abstract Background: Human immune system functions over an entire lifetime, yet how and why the immune system becomes less effective with age are not well understood. Therefore, the aim of this study is to exploit a large-scale population-based strategy to systematically identify genes and pathways differentially expressed as a function of chronological age. Despite the importance of age and race in shaping immune cell numbers and functions, it is unclear whether Asian and Caucasian immune systems go through similar gene expression changes throughout their lifespan, and to what extent these aging-associated variations are shared among ethnicities. Results: Here, we characterize peripheral blood mononuclear cells transcriptome from 19 healthy adults of RNA-seq data and 153 healthy subjects of micoarray data with 21~90 years of age using the weighted gene correlation network analyses (WGCNA). These data reveal a set of insightful gene expression modules and representative gene biomarkers for human immune system aging from Asian and Caucasian ancestry, respectively. Among them, the aging-specific modules may show an age-related gene expression variation spike around early-seventies. In addition, we find the top hub genes including NUDT7, CLPB, OXNAD1 and MLLT3 are shared between Asian and Caucasian aging related modules and further validated in human PBMCs from different age groups. Conclusion: Overall, our findings reveal how age and race differentially affect the immune systems between Asian and Caucasian, as well as discovered a common genetic variant that greatly impacts normal PBMC aging between Asian and Caucasian.

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Identification of age and ethnicity specific gene expression biomarkers for immune aging

10.1101/2021.02.22.432179 ◽

2021 ◽

Author(s):

Yang Hu ◽

Yudai Xu ◽

Lipeng Mao ◽

Wen Lei ◽

Jian Xiang ◽

...

Keyword(s):

Gene Expression ◽

Immune System ◽

Mononuclear Cells ◽

Specific Gene ◽

Human Immune System ◽

Peripheral Blood Mononuclear ◽

Network Analyses ◽

Age Related ◽

Human Immune ◽

The Impact

ABSTRACTHuman immune system functions over an entire lifetime, yet how and why the immune system becomes less effective with age are not well understood. Here, we characterize peripheral blood mononuclear cells transcriptome from 172 healthy adults with 21~90 years of age using RNA-seq and the weighted gene correlation network analyses (WGCNA). These data reveal a set of insightful gene expression modules and representative gene biomarkers for human immune system aging from Asian and Caucasian ancestry, respectively. Among them, the aging-specific modules show an age-related gene expression variation spike around early-seventies. In addition, it is not known whether Asian and Caucasian immune systems go through similar gene expression changes throughout their lifespan, and to what extent these aging-associated changes are shared among ethnicities. We find the top hub genes including NUDT7, CLPB, OXNAD1 and MLLT3 are shared between Asian and Caucasian aging related modules and further validated in human PBMCs from different age groups. Overall, the impact of age and race on transcriptional variation elucidated from this study provide insights into the transcriptional driver of immune aging.

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Sexual-dimorphism in human immune system aging

10.1101/755702 ◽

2019 ◽

Author(s):

Eladio J. Márquez ◽

Cheng-han Chung ◽

Radu Marches ◽

Robert J. Rossi ◽

Djamel Nehar-Belaid ◽

...

Keyword(s):

Immune System ◽

Mononuclear Cells ◽

Immune Cell ◽

Rna Seq ◽

Human Immune System ◽

Peripheral Blood Mononuclear ◽

Cell Functions ◽

Age Related ◽

Male Specific

AbstractDifferences in immune function and responses contribute to health- and life-span disparities between sexes. However, the role of sex in immune system aging is not well understood. Here, we characterize peripheral blood mononuclear cells from 172 healthy adults 22-93 years of age using ATAC-seq, RNA-seq, and flow-cytometry. These data reveal a shared epigenomic signature of aging including declining naïve T cell and increasing monocyte/cytotoxic cell functions. These changes were greater in magnitude in men and accompanied by a male-specific genomic decline in B-cell specific loci. Age-related epigenomic changes first spike around late-thirties with similar timing and magnitude between sexes, whereas the second spike is earlier and stronger in men. Unexpectedly, genomic differences between sexes increase after age 65, with men having higher innate and pro-inflammatory activity and lower adaptive activity. Impact of age and sex on immune cell genomes can be visualized at https://immune-aging.jax.org to provide insights into future studies.

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Enabling out-of-clinic human immunity studies via single-cell profiling of capillary blood

10.1101/2020.07.25.210468 ◽

2020 ◽

Author(s):

Tatyana Dobreva ◽

David Brown ◽

Jong Hwee Park ◽

Matt Thomson

Keyword(s):

Gene Expression ◽

Immune System ◽

Environmental Factors ◽

Single Cell ◽

Immune Cell ◽

Cell Types ◽

Capillary Blood ◽

Specific Gene ◽

Human Immune ◽

Over Time

AbstractAn individual’s immune system is driven by both genetic and environmental factors that vary over time. To better understand the temporal and inter-individual variability of gene expression within distinct immune cell types, we developed a platform that leverages multiplexed single-cell sequencing and out-of-clinic capillary blood extraction to enable simplified, cost-effective profiling of the human immune system across people and time at single-cell resolution. Using the platform, we detect widespread differences in cell type-specific gene expression between subjects that are stable over multiple days.SummaryIncreasing evidence implicates the immune system in an overwhelming number of diseases, and distinct cell types play specific roles in their pathogenesis.1,2 Studies of peripheral blood have uncovered a wealth of associations between gene expression, environmental factors, disease risk, and therapeutic efficacy.4 For example, in rheumatoid arthritis, multiple mechanistic paths have been found that lead to disease, and gene expression of specific immune cell types can be used as a predictor of therapeutic non-response.12 Furthermore, vaccines, drugs, and chemotherapy have been shown to yield different efficacy based on time of administration, and such findings have been linked to the time-dependence of gene expression in downstream pathways.21,22,23 However, human immune studies of gene expression between individuals and across time remain limited to a few cell types or time points per subject, constraining our understanding of how networks of heterogeneous cells making up each individual’s immune system respond to adverse events and change over time.

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Human immune system variation during one year

10.1101/2020.01.22.915025 ◽

2020 ◽

Cited By ~ 1

Author(s):

Tadepally Lakshmikanth ◽

Sayyed Auwn Muhammad ◽

Axel Olin ◽

Yang Chen ◽

Jaromir Mikes ◽

...

Keyword(s):

Immune System ◽

Individual Variation ◽

Immune Cell ◽

Metabolic Health ◽

Individual Feature ◽

Human Immune System ◽

Principal Curve ◽

Human Immune ◽

One Year ◽

Over Time

SUMMARYThe human immune system varies extensively between individuals, but variation within individuals over time has not been well characterized. Systems-level analyses allow for simultaneous quantification of many interacting immune system components, and the inference of global regulatory principles. Here we present a longitudinal, systems-level analysis in 99 healthy adults, 50 to 65 years of age and sampled every 3rd month during one year. We describe the structure of inter-individual variation and characterize extreme phenotypes along a principal curve. From coordinated measurement fluctuations, we infer relationships between 115 immune cell populations and 750 plasma proteins constituting the blood immune system. While most individuals have stable immune systems, the degree of longitudinal variability is an individual feature. The most variable individuals, in the absence of overt infections, exhibited markers of poor metabolic health suggestive of a functional link between metabolic and immunologic homeostatic regulation.HIGHLIGHTSLongitudinal variation in immune cell composition during one yearInter-individual variation can be described along a principal curveImmune cell and protein relationships are inferredVariability over time is an individual feature correlating with markers of poor metabolic health

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Recent Advancements and Applications of Human Immune System Mice in Preclinical Immuno-Oncology

Toxicologic Pathology ◽

10.1177/0192623319886304 ◽

2019 ◽

Vol 48 (2) ◽

pp. 302-316 ◽

Cited By ~ 4

Author(s):

Michelle Curran ◽

Maelle Mairesse ◽

Alba Matas-Céspedes ◽

Bethany Bareham ◽

Giovanni Pellegrini ◽

...

Keyword(s):

Immune System ◽

New Technologies ◽

Immune Cell ◽

Human Immune System ◽

Immunodeficient Mice ◽

Graft Versus Host ◽

Human Immune ◽

And Function ◽

Human Cytokines

Significant advances in immunotherapies have resulted in the increasing need of predictive preclinical models to improve immunotherapeutic drug development, treatment combination, and to prevent or minimize toxicity in clinical trials. Immunodeficient mice reconstituted with human immune system (HIS), termed humanized mice or HIS mice, permit detailed analysis of human immune biology, development, and function. Although this model constitutes a great translational model, some aspects need to be improved as the incomplete engraftment of immune cells, graft versus host disease and the lack of human cytokines and growth factors. In this review, we discuss current HIS platforms, their pathology, and recent advances in their development to improve the quality of human immune cell reconstitution. We also highlight new technologies that can be used to better understand these models and how improved characterization is needed for their application in immuno-oncology safety, efficacy, and new modalities therapy development.

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Ikaros-Associated Diseases: From Mice to Humans and Back Again

Frontiers in Pediatrics ◽

10.3389/fped.2021.705497 ◽

2021 ◽

Vol 9 ◽

Author(s):

Brigette Boast ◽

Cristiane de Jesus Nunes-Santos ◽

Hye Sun Kuehn ◽

Sergio D. Rosenzweig

Keyword(s):

Immune System ◽

Immune Dysregulation ◽

Single Amino Acid ◽

Human Immune System ◽

Immune Systems ◽

Associated Diseases ◽

Normal Expression ◽

Extreme Phenotypes ◽

Human Immune ◽

Entire Gene

The normal expression of Ikaros (IKZF1) is important for the proper functioning of both the human and murine immune systems. Whilst our understanding of IKZF1 in the immune system has been greatly enhanced by the study of mice carrying mutations in Ikzf1, analyses of human patients carrying germline IKZF1 mutations have been instrumental in understanding its biological role within the human immune system and its effect on human disease. A myriad of different mutations in IKZF1 have been identified, spanning across the entire gene causing differential clinical outcomes in patients including immunodeficiency, immune dysregulation, and cancer. The majority of mutations in humans leading to IKAROS-associated diseases are single amino acid heterozygous substitutions that affect the overall function of the protein. The majority of mutations studied in mice however, affect the expression of the protein rather than its function. Murine studies would suggest that the complete absence of IKZF1 expression leads to severe and sometimes catastrophic outcomes, yet these extreme phenotypes are not commonly observed in patients carrying IKZF1 heterozygous mutations. It is unknown whether this discrepancy is simply due to differences in zygosity, the role and regulation of IKZF1 in the murine and human immune systems, or simply due to a lack of similar controls across both groups. This review will focus its analysis on the current literature surrounding what is known about germline IKZF1 defects in both the human and the murine immune systems, and whether existing mice models are indeed accurate tools to study the effects of IKZF1-associated diseases.

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Comprehensive multi-omics single-cell data integration reveals greater heterogeneity in the human immune system

10.1101/2021.07.25.453651 ◽

2021 ◽

Author(s):

Congmin Xu ◽

Junkai Yang ◽

Astrid Kosters ◽

Benjamin R Babcock ◽

Peng Qiu ◽

...

Keyword(s):

Immune System ◽

Single Cell ◽

Immune Cell ◽

Cell Types ◽

Cell Receptor ◽

Surface Proteins ◽

Cell Type ◽

Human Immune System ◽

Receptor Repertoire ◽

Human Immune

Single-cell transcriptomics enables the definition of diverse human immune cell types across multiple tissue and disease contexts. Still, deeper biological understanding requires comprehensive integration of multiple single-cell omics (transcriptomic, proteomic, and cell receptor repertoire). To improve the identification of diverse cell types and the accuracy of cell-type classification in our multi-omics single-cell datasets, we developed SuPERR-seq, a novel analysis workflow to increase the resolution and accuracy of clustering and allow for the discovery and characterization of previously hidden cell subsets. We show that by incorporating information from cell-surface proteins and immunoglobulin transcript counts, we accurately remove cell doublets and prevent widespread cell-type misclassification. This approach uniquely improves the identification of heterogeneous cell types in the human immune system, including a novel subset of antibody-secreting cells in the bone marrow.

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A Cell for the Ages: Human γδ T Cells across the Lifespan

International Journal of Molecular Sciences ◽

10.3390/ijms21238903 ◽

2020 ◽

Vol 21 (23) ◽

pp. 8903

Author(s):

Brandi L. Clark ◽

Paul G. Thomas

Keyword(s):

T Cells ◽

Immune Cell ◽

Γδ T Cells ◽

Human Immune System ◽

Age Related ◽

A Cell ◽

Human Immune ◽

Induced Immunity ◽

Cell Functionality ◽

Effect Of Age

The complexity of the human immune system is exacerbated by age-related changes to immune cell functionality. Many of these age-related effects remain undescribed or driven by mechanisms that are poorly understood. γδ T cells, while considered an adaptive subset based on immunological ontogeny, retain both innate-like and adaptive-like characteristics. This T cell population is small but mighty, and has been implicated in both homeostatic and disease-induced immunity within tissues and throughout the periphery. In this review, we outline what is known about the effect of age on human peripheral γδ T cells, and call attention to areas of the field where further research is needed.

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COVIEdb: A database for potential immune epitopes of coronaviruses

10.1101/2020.05.24.096164 ◽

2020 ◽

Author(s):

Jingcheng Wu ◽

Wenfan Chen ◽

Jingjing Zhou ◽

Wenyi Zhao ◽

Shuqing Chen ◽

...

Keyword(s):

Immune System ◽

Large Scale ◽

Vaccine Development ◽

Protein Sequences ◽

T Cell Epitopes ◽

Human Immune System ◽

The World ◽

Human Immune ◽

Human Coronaviruses ◽

Novel Coronavirus

Abstract2019 novel coronavirus (2019-nCoV) has caused large-scale pandemic COVID-19 all over the world. It’s essential to find out which parts of the 2019-nCoV sequence are recognized by human immune system for vaccine development. And for the prevention of the potential outbreak of similar coronaviruses in the future, vaccines against immunogenic epitopes shared by different human coronaviruses are essential. Here we predict all the potential B/T-cell epitopes for SARS-CoV, MERS-CoV, 2019-nCoV and RaTG13-CoV based on the protein sequences. We found YFKYWDQTY in ORF1ab protein, VYDPLQPEL and TVYDPLQPEL in spike (S) protein might be pan-coronavirus targets for vaccine development. All the predicted results are stored in a database COVIEdb (http://biopharm.zju.edu.cn/coviedb/).

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