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Biomedicines
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Epigenetic Regulation of the Immune System
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Epigenetic Regulation of the Immune System

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 19000

Special Issue Editor

Dr. Marie Černá

E-Mail Website
Guest Editor
Department of Medical Genetics, Third Faculty of Medicine, Charles University, Ruska 87, Vinohrady, 10000 Prague, Czech Republic
Interests: epigenetics of human; etiopatogenesis of multifactorial diseases; immunogenetics of autoimmunity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

The term epigenetics was first introduced by Conrad Waddington in 1942. For long half century, it was not quite clear its significance in gene expression, cell differentiation and heritability. Until modern technologies of the beginning of the 21st century have opened a new area of research. Epigenetic modifications of the genome allow reaction of cells to external signals by alternation of gene activity, by modifying gene expression. Epigenome, in fact, controls accessibility of DNA for transcription factors that regulate level of gene expression. By this way epigenetic regulations are responsible for the cell differentiation that is so critical in the immune system.

Innate and adaptive immune responses are components of an integrated system of host defense in which numerous cells and molecules function cooperatively. Immune responses are regulated by a system of positive feedback loops that amplify the reaction and by control mechanisms that prevent inappropriate or pathologic reactions. All regulations are under control of epigenetic mechanisms.

Immunity declines during ageing, as shown by the increased susceptibility to infection. Deterioration of immune reactions mirrors alteration of cell function, particularly T lymphocytes. With aging there is progressive accumulation of epigenetic damage as a direct consequence of evolved limitations in the genetic and epigenetic settings of maintenance and repair functions.

We encourage to submit research and review papers about the epigenetic modulation in various immune responses. We believe that this Special Issue will reflect the new exciting era of epigenetics and show its role in the immune function.

Dr. Marie Černá
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • immune responses
  • innate immunity
  • adaptive immunity
  • cell differentiation
  • cellular senescence
  • gene expression
  • DNA methylation
  • histone modifications
  • RNA-mediated gene silencing

Related Special Issue

Published Papers (7 papers)

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Research

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13 pages, 1465 KiB  
Article
The Immunological Epigenetic Landscape of the Human Life Trajectory
by Iva Juříčková, Michael Hudec, Felix Votava, Jan Vosáhlo, Saak Victor Ovsepian, Marie Černá and Valerie Bríd O’Leary
Biomedicines 2022, 10(11), 2894; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10112894 - 11 Nov 2022
Viewed by 1162
Abstract
Adaptive immunity changes over an individual’s lifetime, maturing by adulthood and diminishing with old age. Epigenetic mechanisms involving DNA and histone methylation form the molecular basis of immunological memory during lymphocyte development. Monocytes alter their function to convey immune tolerance, yet the epigenetic [...] Read more.
Adaptive immunity changes over an individual’s lifetime, maturing by adulthood and diminishing with old age. Epigenetic mechanisms involving DNA and histone methylation form the molecular basis of immunological memory during lymphocyte development. Monocytes alter their function to convey immune tolerance, yet the epigenetic influences at play remain to be fully understood in the context of lifespan. This study of a healthy genetically homogenous cohort of children, adults and seniors sought to decipher the epigenetic dynamics in B-lymphocytes and monocytes. Variable global cytosine methylation within retro-transposable LINE-1 repeats was noted in monocytes compared to B-lymphocytes across age groups. The expression of the human leukocyte antigen (HLA)-DQ alpha chain gene HLA-DQA1*01 revealed significantly reduced levels in monocytes in all ages relative to B-lymphocytes, as well as between lifespan groups. High melting point analysis and bisulfite sequencing of the HLA-DQA1*01 promoter in monocytes highlighted variable cytosine methylation in children and seniors but greater stability at this locus in adults. Further epigenetic evaluation revealed higher histone lysine 27 trimethylation in monocytes from this adult group. Chromatin immunoprecipitation and RNA pulldown demonstrated association with a novel lncRNA TINA with structurally conserved similarities to the previously recognized epigenetic modifier PARTICLE. Seeking to interpret the epigenetic immunological landscape across three representative age groups, this study focused on HLA-DQA1*01 to expose cytosine and histone methylation alterations and their association with the non-coding transcriptome. Such insights unveil previously unknown complex epigenetic layers, orchestrating the strength and weakening of adaptive immunity with the progression of life. Full article
(This article belongs to the Special Issue Epigenetic Regulation of the Immune System)
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25 pages, 1584 KiB  
Article
Expression Profile of mRNAs and miRNAs Related to the Oxidative-Stress Phenomenon in the Ishikawa Cell Line Treated Either Cisplatin or Salinomycin
by Szymon Januszyk, Paweł Mieszczański, Hubert Lurka, Dorota Sagan, Dariusz Boroń and Beniamin Oskar Grabarek
Biomedicines 2022, 10(5), 1190; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10051190 - 20 May 2022
Cited by 3 | Viewed by 2146
Abstract
The oxidative stress phenomenon is a result of anticancer therapy. The aim of this study was the assessment of gene expression profile changes, and to determine the miRNAs regulating genes’ transcriptional activity in an Ishikawa endometrial cancer culture exposed to cisplatin or salinomycin, [...] Read more.
The oxidative stress phenomenon is a result of anticancer therapy. The aim of this study was the assessment of gene expression profile changes, and to determine the miRNAs regulating genes’ transcriptional activity in an Ishikawa endometrial cancer culture exposed to cisplatin or salinomycin, compared to a control culture. The molecular analysis comprised the microarray technique (mRNAs and micro RNA (miRNA), the real-time quantitative reverse transcription reaction (RTqPCR), enzyme-linked immunosorbent assay (ELISA) reactions, and Western blot. NR4A2, MAP3K8, ICAM1, IL21, CXCL8, CCL7, and SLC7A11 were statistically significantly differentiated depending not only on time, but also on the drug used in the experiment. The conducted assessment indicated that the strongest links were between NR4A2 and hsa-miR-30a-5p and has-miR-302e, MAP3K8 and hsa-miR-144-3p, CXCL8 and hsa-miR-140-3p, and SLC7A11 and hsa-miR-144-3p. The obtained results suggest that four mRNAs—NR4A2, MAP3K8, CXCL8 and SLC7A11—and four miRNAs—hsa-miR-30a-5p, hsa-miR-302e, hsa-miR-144-3p and hsa-miR-140-3—changed their expressions regardless of the chemotherapeutic agent used, which suggests the possibility of their use in monitoring the severity of oxidative stress in endometrial cancer. However, considering the results at both the mRNA and the protein level, it is most likely that the expressions of NR4A2, MAP3K8, CXCL8 and SLC7A11 are regulated by miRNA molecules as well as other epigenetic mechanisms. Full article
(This article belongs to the Special Issue Epigenetic Regulation of the Immune System)
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15 pages, 582 KiB  
Article
Variances in the Expression of mRNAs and miRNAs Related to the Histaminergic System in Endometrioid Endometrial Cancer
by Michał Czerwiński, Anna Bednarska-Czerwińska, Paweł Ordon, Magdalena Gradzik, Marcin Oplawski, Dariusz Boroń, Hanna Zientek, Oskar Ogloszka and Beniamin Oskar Grabarek
Biomedicines 2021, 9(11), 1535; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9111535 - 26 Oct 2021
Cited by 4 | Viewed by 2099
Abstract
Research has indicated higher concentrations of histamine and polyamine in endometrioid tissue in comparison with healthy tissue. The aim of this study was to evaluate changes in the expression patterns of messenger RNA (mRNAs) and microRNA (miRNAs) related to the histaminergic system in [...] Read more.
Research has indicated higher concentrations of histamine and polyamine in endometrioid tissue in comparison with healthy tissue. The aim of this study was to evaluate changes in the expression patterns of messenger RNA (mRNAs) and microRNA (miRNAs) related to the histaminergic system in endometrial samples and whole blood in women with endometrioid endometrial cancer. The study group consisted of 30 women with endometrioid endometrial cancer qualified for hysterectomy (G1 well-differentiated, 15 cases; G2 moderately differentiated, 8 cases; and G3 poorly differentiated, 7 cases). The control group included 30 women with no neoplastic changes during routine gynecological examinations. The molecular analysis consisted of the microarray analysis of mRNAs and miRNAs related to the histaminergic system, reverse-transcription quantitative polymerase chain reaction (RTqPCR), and enzyme-linked immunosorbent assay (ELISA). Out of 65 mRNAs connected with the histaminergic system, 10 differentiate the samples of tissue and blood obtained from patients with endometrioid endometrial cancer in comparison with the control group (p < 0.05). mRNA histamine receptor 1,3 (HRH1, HRH3), and solute carrier family 22 member 3 (SLC23A2) differentiating samples of endometrioid endometrial cancer independent of either G or control. The highest probability of interaction, based on the target score miRDB, between the selected miRNAs and mRNAs was found for the hybrids hsa-miR-1-3p and endothelin 1 (END1), hsa-miR-27a-5β and SLC23A2. The selected mRNA and miRNA transcripts seem to be promising for molecularly targeted therapies in the context of endometrioid endometrial cancer. Full article
(This article belongs to the Special Issue Epigenetic Regulation of the Immune System)
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17 pages, 7917 KiB  
Article
A Senescence Bystander Effect in Human Lung Fibroblasts
by David W. Waters, Michael Schuliga, Prabuddha S. Pathinayake, Lan Wei, Hui-Ying Tan, Kaj E. C. Blokland, Jade Jaffar, Glen P. Westall, Janette K. Burgess, Cecilia M. Prêle, Steven E. Mutsaers, Christopher L. Grainge and Darryl A. Knight
Biomedicines 2021, 9(9), 1162; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9091162 - 04 Sep 2021
Cited by 11 | Viewed by 3166
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterised by a dense fibrosing of the lung parenchyma. An association between IPF and cellular senescence is well established and several studies now describe a higher abundance of senescent fibroblasts and epithelial cells in the [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterised by a dense fibrosing of the lung parenchyma. An association between IPF and cellular senescence is well established and several studies now describe a higher abundance of senescent fibroblasts and epithelial cells in the lungs of IPF patients compared with age-matched controls. The cause of this abnormal accumulation of senescent cells is unknown but evidence suggests that, once established, senescence can be transferred from senescent to non-senescent cells. In this study, we investigated whether senescent human lung fibroblasts (LFs) and alveolar epithelial cells (AECs) could induce a senescent-like phenotype in “naïve” non-senescent LFs in vitro. Primary cultures of LFs from adult control donors (Ctrl-LFs) with a low baseline of senescence were exposed to conditioned medium (CM) from: (i) Ctrl-LFs induced to become senescent using H2O2 or etoposide; (ii) LFs derived from IPF patients (IPF-LFs) with a high baseline of senescence; or (iii) senescence-induced A549 cells, an AEC line. Additionally, ratios of non-senescent Ctrl-LFs and senescence-induced Ctrl-LFs (100:0, 0:100, 50:50, 90:10, 99:1) were co-cultured and their effect on induction of senescence measured. We demonstrated that exposure of naïve non-senescent Ctrl-LFs to CM from senescence-induced Ctrl-LFs and AECs and IPF-LFs increased the markers of senescence including nuclear localisation of phosphorylated-H2A histone family member X (H2AXγ) and expression of p21, IL-6 and IL-8 in Ctrl-LFs. Additionally, co-cultures of non-senescent and senescence-induced Ctrl-LFs induced a senescent-like phenotype in the non-senescent cells. These data suggest that the phenomenon of “senescence-induced senescence” can occur in vitro in primary cultures of human LFs, and provides a possible explanation for the abnormal abundance of senescent cells in the lungs of IPF patients. Full article
(This article belongs to the Special Issue Epigenetic Regulation of the Immune System)
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23 pages, 2951 KiB  
Article
Lower Functional and Proportional Characteristics of Cord Blood Treg of Male Newborns Compared with Female Newborns
by Viktor Černý, Olga Novotná, Petra Petrásková, Kateřina Hudcová, Kristýna Boráková, Ludmila Prokešová, Libuše Kolářová and Jiří Hrdý
Biomedicines 2021, 9(2), 170; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9020170 - 09 Feb 2021
Cited by 2 | Viewed by 2824
Abstract
Understanding the early events involved in the induction of immune tolerance to harmless environmental antigens and microbiota compounds could reveal potential targets for allergic disease therapy or prevention. Regulatory T cells (Treg), particularly induced Treg (iTreg), are crucial for the induction and maintenance [...] Read more.
Understanding the early events involved in the induction of immune tolerance to harmless environmental antigens and microbiota compounds could reveal potential targets for allergic disease therapy or prevention. Regulatory T cells (Treg), particularly induced Treg (iTreg), are crucial for the induction and maintenance of tolerance against environmental antigens including allergens. A decrease in the number and/or function of Treg or iTreg could represent an early predictor of allergy development. We analyzed proportional and functional properties of Treg in the cord blood of children of allergic mothers (neonates at high risk of allergy development) and healthy mothers (neonates with relatively low risk of allergy development). We observed a higher number of induced Treg in the cord blood of females compared to males, suggesting an impaired capacity of male immunity to set up tolerance to allergens, which could contribute to the higher incidence of allergy observed in male infants. The decreased proportion of iTreg in cord blood compared with maternal peripheral blood documents the general immaturity of the neonatal immune system. We observed a positive correlation in the demethylation of the Treg-specific demethylated region (TSDR) and the proportion of Treg in cord blood. Our data suggest that immaturity of the neonatal immune system is more severe in males, predisposing them to increased risk of allergy development. Full article
(This article belongs to the Special Issue Epigenetic Regulation of the Immune System)
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12 pages, 2475 KiB  
Article
Abnormal Hypermethylation of CpG Dinucleotides in Promoter Regions of Matrix Metalloproteinases Genes in Breast Cancer and its Relation to Epigenomic Subtypes and HER2 Overexpression
by Olga A. Simonova, Ekaterina B. Kuznetsova, Alexander S. Tanas, Viktoria V. Rudenko, Elena V. Poddubskaya, Tatiana V. Kekeeva, Ivan D. Trotsenko, Sergey S. Larin, Sergei I. Kutsev, Dmitry V. Zaletaev, Marina V. Nemtsova and Vladimir V. Strelnikov
Biomedicines 2020, 8(5), 116; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines8050116 - 10 May 2020
Cited by 10 | Viewed by 3130
Abstract
Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) substantially contribute to the regulation of intercellular interactions and thereby play a role in maintaining the tissue structure and function. We examined methylation of a subset of 5’-cytosine-phosphate-guanine-3’ (CpG) dinucleotides in promoter regions of the [...] Read more.
Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) substantially contribute to the regulation of intercellular interactions and thereby play a role in maintaining the tissue structure and function. We examined methylation of a subset of 5’-cytosine-phosphate-guanine-3’ (CpG) dinucleotides in promoter regions of the MMP2, MMP11, MMP14, MMP15, MMP16, MMP17, MMP21, MMP23B, MMP24, MMP25, MMP28, TIMP1, TIMP2, TIMP3, and TIMP4 genes by methylation-sensitive restriction enzyme digestion PCR. In our collection of 183 breast cancer samples, abnormal hypermethylation was observed for CpGs in MMP2, MMP23B, MMP24, MMP25, and MMP28 promoter regions. The non-methylated status of the examined CpGs in promoter regions of MMP2, MMP23B, MMP24, MMP25, and MMP28 in tumors was associated with low HER2 expression, while the group of samples with abnormal hypermethylation of at least two of these MMP genes was significantly enriched with HER2-positive tumors. Abnormal methylation of MMP24 and MMP25 was significantly associated with a CpG island hypermethylated breast cancer subtype discovered by genome-wide DNA bisulfite sequencing. Our results indicate that abnormal hypermethylation of at least several MMP genes promoters is a secondary event not directly functional in breast cancer (BC) pathogenesis. We suggest that it is elevated and/or ectopic expression, rather than methylation-driven silencing, that might link MMPs to tumorigenesis. Full article
(This article belongs to the Special Issue Epigenetic Regulation of the Immune System)
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Review

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21 pages, 1624 KiB  
Review
Central and Peripheral Immune Dysregulation in Posttraumatic Stress Disorder: Convergent Multi-Omics Evidence
by Diana L. Núñez-Rios, José J. Martínez-Magaña, Sheila T. Nagamatsu, Diego E. Andrade-Brito, Diego A. Forero, Carlos A. Orozco-Castaño and Janitza L. Montalvo-Ortiz
Biomedicines 2022, 10(5), 1107; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10051107 - 10 May 2022
Cited by 5 | Viewed by 3041
Abstract
Posttraumatic stress disorder (PTSD) is a chronic and multifactorial disorder with a prevalence ranging between 6–10% in the general population and ~35% in individuals with high lifetime trauma exposure. Growing evidence indicates that the immune system may contribute to the etiology of PTSD, [...] Read more.
Posttraumatic stress disorder (PTSD) is a chronic and multifactorial disorder with a prevalence ranging between 6–10% in the general population and ~35% in individuals with high lifetime trauma exposure. Growing evidence indicates that the immune system may contribute to the etiology of PTSD, suggesting the inflammatory dysregulation as a hallmark feature of PTSD. However, the potential interplay between the central and peripheral immune system, as well as the biological mechanisms underlying this dysregulation remain poorly understood. The activation of the HPA axis after trauma exposure and the subsequent activation of the inflammatory system mediated by glucocorticoids is the most common mechanism that orchestrates an exacerbated immunological response in PTSD. Recent high-throughput analyses in peripheral and brain tissue from both humans with and animal models of PTSD have found that changes in gene regulation via epigenetic alterations may participate in the impaired inflammatory signaling in PTSD. The goal of this review is to assess the role of the inflammatory system in PTSD across tissue and species, with a particular focus on the genomics, transcriptomics, epigenomics, and proteomics domains. We conducted an integrative multi-omics approach identifying TNF (Tumor Necrosis Factor) signaling, interleukins, chemokines, Toll-like receptors and glucocorticoids among the common dysregulated pathways in both central and peripheral immune systems in PTSD and propose potential novel drug targets for PTSD treatment. Full article
(This article belongs to the Special Issue Epigenetic Regulation of the Immune System)
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