scholarly journals Construction of Disease-specific Cytokine Profiles by Associating Disease Genes with Immune Responses

2021 ◽  
Author(s):  
Tianyun Liu ◽  
Shiyin Wang ◽  
Russ B Altman
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Inflammatory Responses ◽  
P Value ◽  
Specific Gene ◽  
High Confidence ◽  
Cytokine Profiles ◽  
Gene Sets ◽  
Human Genes ◽  
Disease Specific

AbstractThe pathogenesis of many inflammatory diseases is a coordinated process involving metabolic dysfunctions and immune response—usually modulated by the production of cytokines and associated inflammatory molecules. In this work, we seek to understand how genes involved in pathogenesis which are often not associated with the immune system in an obvious way communicate with the immune system. We have embedded a network of human protein-protein interactions (PPI) from the STRING database with 14,707 human genes using feature learning that captures high confidence edges. We have found that our predicted Association Scores derived from the features extracted from STRING’s high confidence edges are useful for predicting novel connections between genes, thus enabling the construction of a full map of predicted associations for all possible pairs between 14,707 human genes. In particular, we analyzed the pattern of associations for 126 cytokines and found that the six patterns of cytokine interaction with human genes are consistent with their functional classifications. In order to define the disease-specific roles of cytokines we have collected gene sets for 11,944 diseases from DisGeNET. We used these gene sets to predict disease-specific gene associations with cytokines by calculating the normalized average Association Scores between disease-associated gene sets and the 126 cytokines; this creates a unique profile of inflammatory genes (both known and predicted) for each disease. We validated our predicted cytokine associations by comparing them to known associations for 171 diseases. The predicted cytokine profiles correlate (p-value<0.05) with the known ones in 147 diseases. We further characterized the profiles of each disease by calculating an “Inflammation Score” that summarizes different modes of immune responses. Finally, by analyzing subnetworks formed between disease-specific pathogenesis genes, hormones, receptors, and cytokines, we identified the key genes responsible for interactions between pathogenesis and inflammatory responses. These genes and the corresponding cytokines used by different immune disorders suggest unique targets for drug discovery.

scholarly journals Transcriptomic Data Analysis Reveals a Down-Expression of Galectin-8 in Schizophrenia Hippocampus

2021 ◽  
Vol 11 (8) ◽  
pp. 973
Author(s):  
Maria Cristina Petralia ◽  
Rosella Ciurleo ◽  
Alessia Bramanti ◽  
Placido Bramanti ◽  
Andrea Saraceno ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Clinical Manifestations ◽  
Antipsychotic Agents ◽  
Standards Of Care ◽  
Specific Gene ◽  
Contributing Factors ◽  
Healthy Donors ◽  
Dorsolateral Prefrontal ◽  
Inflammatory Processes ◽  
Disease Specific

Schizophrenia (SCZ) is a severe psychiatric disorder with several clinical manifestations that include cognitive dysfunction, decline in motivation, and psychosis. Current standards of care treatment with antipsychotic agents are often ineffective in controlling the disease, as only one-third of SCZ patients respond to medications. The mechanisms underlying the pathogenesis of SCZ remain elusive. It is believed that inflammatory processes may play a role as contributing factors to the etiology of SCZ. Galectins are a family of β-galactoside-binding lectins that contribute to the regulation of immune and inflammatory responses, and previous reports have shown their role in the maintenance of central nervous system (CNS) homeostasis and neuroinflammation. In the current study, we evaluated the expression levels of the galectin gene family in post-mortem samples of the hippocampus, associative striatum, and dorsolateral prefrontal cortex from SCZ patients. We found a significant downregulation of LGALS8 (Galectin-8) in the hippocampus of SCZ patients as compared to otherwise healthy donors. Interestingly, the reduction of LGALS8 was disease-specific, as no modulation was observed in the hippocampus from bipolar nor major depressive disorder (MDD) patients. Prediction analysis identified TBL1XR1, BRF2, and TAF7 as potential transcription factors controlling LGALS8 expression. In addition, MIR3681HG and MIR4296 were negatively correlated with LGALS8 expression, suggesting a role for epigenetics in the regulation of LGALS8 levels. On the other hand, no differences in the methylation levels of LGALS8 were observed between SCZ and matched control hippocampus. Finally, ontology analysis of the genes negatively correlated with LGALS8 expression identified an enrichment of the NGF-stimulated transcription pathway and of the oligodendrocyte differentiation pathway. Our study identified LGALS8 as a disease-specific gene, characterizing SCZ patients, that may in the future be exploited as a potential therapeutic target.

scholarly journals Loss of critical developmental and human disease-causing genes in 58 mammals

2019 ◽  
Author(s):  
Yatish Turakhia ◽  
Heidi I. Chen ◽  
Amir Marcovitz ◽  
Gill Bejerano
Keyword(s):  
Evolutionary Biology ◽  
Large Scale ◽  
Gene Annotation ◽  
Synonymous Substitution ◽  
Specific Gene ◽  
High Confidence ◽  
Protein Coding ◽  
Congenital Diseases ◽  
Manual Curation ◽  
Human Genes

Gene losses provide an insightful route for studying the morphological and physiological adaptations of species, but their discovery is challenging. Existing genome annotation tools and protein databases focus on annotating intact genes and do not attempt to distinguish nonfunctional genes from genes missing annotation due to sequencing and assembly artifacts. Previous attempts to annotate gene losses have required significant manual curation, which hampers their scalability for the ever-increasing deluge of newly sequenced genomes. Using extreme sequence erosion (deletion and non-synonymous substitution) as an unambiguous signature of loss, we developed an automated approach for detecting high-confidence protein-coding gene loss events across a species tree. Our approach relies solely on gene annotation in a single reference genome, raw assemblies for the remaining species to analyze, and the associated phylogenetic tree for all organisms involved. Using the hg38 human assembly as a reference, we discovered over 500 unique human genes affected by such high-confidence erosion events in different clades across 58 mammals. While most of these events likely have benign consequences, we also found dozens of clade-specific gene losses that result in early lethality in outgroup mammals or are associated with severe congenital diseases in humans. Our discoveries yield intriguing potential for translational medical genetics and for evolutionary biology, and our approach is readily applicable to large-scale genome sequencing efforts across the tree of life.

scholarly journals Publisher Correction: c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4+ T cells

2019 ◽  
Vol 20 (3) ◽  
pp. 374-374
Author(s):  
Leona Gabryšová ◽  
Marisol Alvarez-Martinez ◽  
Raphaëlle Luisier ◽  
Luke S. Cox ◽  
Jan Sodenkamp ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Cd4 T Cells ◽  
Gene Networks ◽  
Specific Gene ◽  
Disease Specific

Immune and Inflammatory Responses to Stroke: Good Or Bad?

2008 ◽  
Vol 3 (4) ◽  
pp. 254-265 ◽  
Author(s):  
P. A. McCombe ◽  
S. J. Read
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Immune Responses ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Therapeutic Option ◽  
Regulatory Lymphocytes ◽  
The Brain ◽  
Pro Inflammatory Cytokines

Inflammatory and immune responses play important roles following ischaemic stroke. Inflammatory responses contribute to damage and also contribute to repair. Injury to tissue triggers an immune response. This is initiated through activation of the innate immune system. In stroke there is microglial activation. This is followed by an influx of lymphocytes and macrophages into the brain, triggered by production of pro-inflammatory cytokines. This inflammatory response contributes to further tissue injury. There is also a systemic immune response to stroke, and there is a degree of immunosuppression that may contribute to the stroke patient's risk of infection. This immunosuppressive response may also be protective, with regulatory lymphocytes producing cytokines and growth factors that are neuroprotective. The specific targets of the immune response after stroke are not known, and the details of the immune and inflammatory responses are only partly understood. The role of inflammation and immune responses after stroke is twofold. The immune system may contribute to damage after stroke, but may also contribute to repair processes. The possibility that some of the immune response after stroke may be neuroprotective is exciting and suggests that deliberate enhancement of these responses may be a therapeutic option.

scholarly journals High KDM1A Expression Associated with Decreased CD8+T Cells Reduces the Breast Cancer Survival Rate in Patients with Breast Cancer

2021 ◽  
Vol 10 (5) ◽  
pp. 1112
Author(s):  
Hyung Suk Kim ◽  
Byoung Kwan Son ◽  
Mi Jung Kwon ◽  
Dong-Hoon Kim ◽  
Kyueng-Whan Min
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
T Cells ◽  
Survival Rate ◽  
Immune Responses ◽  
Cancer Patients ◽  
Cd8 T Cells ◽  
Specific Gene ◽  
Breast Cancer Patients ◽  
Gene Sets

Background: Lysine-specific demethylase 1A (KDM1A) plays an important role in epigenetic regulation in malignant tumors and promotes cancer invasion and metastasis by blocking the immune response and suppressing cancer surveillance activities. The aim of this study was to analyze survival, genetic interaction networks and anticancer immune responses in breast cancer patients with high KDM1A expression and to explore candidate target drugs. Methods: We investigated clinicopathologic parameters, specific gene sets, immunologic relevance, pathway-based networks and in vitro drug response according to KDM1A expression in 456 and 789 breast cancer patients from the Hanyang university Guri Hospital (HYGH) and The Cancer Genome Atlas, respectively. Results: High KDM1A expression was associated with a low survival rate in patients with breast cancer. In analyses of immunologic gene sets, high KDM1A expression correlated with low immune responses. In silico flow cytometry results revealed low abundances of CD8+T cells and high programmed death-ligand 1 (PD-L1) expression in those with high KDM1A expression. High KDM1A expression was associated with a decrease in the anticancer immune response in breast cancer. In pathway-based networks, KDM1A was linked directly to pathways related to the androgen receptor signaling pathway and indirectly to the immune pathway and cell cycle. We found that alisertib effectively inhibited breast cancer cell lines with high KDM1A expression. Conclusions: Strategies utilizing KDM1A may contribute to better clinical management/research for patients with breast cancer.

Gene Expression Profiling of Age-Related Epstein-Barr Virus (EBV)-Associated B-Cell Lymphoproliferative Disorder Uncovers Alterations in Immune and Inflammatory Genes: Possible Implications for Pathogenesis,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3448-3448
Author(s):  
Harumi Kato ◽  
Kazuhito Yamamoto ◽  
Kennosuke Karube ◽  
Miyuki Katayama ◽  
Shinobu Tsuzuki ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Enrichment Score ◽  
P Value ◽  
Toll Like Receptor ◽  
Gene Set Enrichment ◽  
Gene Set ◽  
Age Related ◽  
Gene Sets

Abstract Abstract 3448 Age-related EBV-associated B-cell lymphoproliferative disorder (AR-EBLPD) is classified as a subtype of diffuse large cell lymphoma (DLBCL) according to the WHO classification. However, molecular genetic characterization of AR-EBLPD remains largely unknown. We studied expression profiles of 5 AR-EBLPD and 8 EB-negative DLBCL samples using the Agilent 44K human oligonucleotide microarray. Total RNA was extracted from fresh-frozen tumor samples. Each microarray slide was converted into datasets using the Agilent Micro Array Scanner and Feature extractions. Data was standardized with Z-scores. Differences in mRNA expression levels between two sample groups were calculated using a two-sided t-test. A total of 1973 probes showed a p-value less than 0.05 with less than a 25% false discovery rate (FDR). These probes included 1688 genes. The number of probes showing high expression in AR-EBLPD and EB-negative DLBCL was 804 (693 genes) and 1169 (995 genes), respectively. First, we selected the top 300 differentially expressed genes. Genes highly expressed in AR-EBLPD included IL6, TNFAIP3, HOPX, and SLAMF1. IL6 is known as a gene encoding a cytokine which functions in inflammation and the maturation of B lymphocytes, and TNFAIP3 is known as a negative regulatory gene of the NF-kB pathway. HOPX and SLAMF1 are reported as genes related to lymphocyte function or the immune system (Schwartzberg et al. Nature immunology 2009, Hawiger et al. Nature immunology 2011). For better characterization, we next performed Gene Ontology Analysis using the WEB-based GEne SeT AnaLysis Toolkit and found that categories of external stimulus and inflammatory responses were enriched in AR-EBLPD. The Kyoto Encyclopedia of Genes and Genomes (KEGG)-signaling analyses showed that pathways of the NOD-like receptor (p-value =1.30e-06), JAK-STAT (p-value =9.01e-06), and Toll-like receptor (p-value =0.0002) were characteristic of AR-EBLPD. These results implied that inflammation would be prominent in AR-EBLPD cases. For validation, we next performed Gene Set Enrichment Analysis (GSEA) using all the database of KEGG pathways (186 gene sets). Dominant gene sets in AR-EBLPD included the cytokine-cytokine receptor interaction [Normalized Enrichment Score (NES) =2.66, p-value<0.001], NOD-like receptor pathway (NES =2.26, p-value<0.001), TOLL-like receptor pathway (NES =2.14, p-value<0.001), and JAK-STAT pathway (NES =1.79, p-value<0.001). Since all the pathways were related to the NF-kB pathway, inflammatory responses were suggested to activate the NF-kB pathway or vice versa. For confirmation, we finally performed GSEA using gene sets of the NF-kB pathway, which were obtained from a gene set reported by an NIH group (Puente et al. Nature 2011) and 30 gene sets in the GSEA database, and found that the gene sets of the NF-kB pathway were enriched in AR-EBLPD (Figure 1). Our results suggested that the inflammatory and immune-related genes were enriched in AR-EBLPD and that activation of the genes may be associated with NF-kB activation. Aberrant immune and inflammatory responses could define the clinical presentations of AR-EBLPD cases. (Figure 1) Gene Set Enrichment Analysis of 5 AR-EBLPD and 8 EB-negative DLBCL samples. The NF-kB signature reported from an NIH group (Puente et al. Nature 2011) was enriched in AR-EBLPD [Normalized Enrichment Score (NES) =2.20, p-value<0.001]. Disclosures: No relevant conflicts of interest to declare.

scholarly journals c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4+ T cells

2018 ◽  
Vol 19 (5) ◽  
pp. 497-507 ◽  
Author(s):  
Leona Gabryšová ◽  
Marisol Alvarez-Martinez ◽  
Raphaëlle Luisier ◽  
Luke S. Cox ◽  
Jan Sodenkamp ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Cd4 T Cells ◽  
Gene Networks ◽  
Specific Gene ◽  
Disease Specific

scholarly journals Diet and Hygiene in Modulating Autoimmunity During the Pandemic Era

2022 ◽  
Vol 12 ◽  
Author(s):  
Leila Abdelhamid ◽  
Xin M. Luo
Keyword(s):  
Immune System ◽  
Environmental Factors ◽  
Immune Responses ◽  
Host Defense ◽  
Lupus Erythematosus ◽  
Inflammatory Responses ◽  
Immune Recognition ◽  
Systemic Autoimmunity ◽  
Hygiene Measures ◽  
Autoimmune Conditions

The immune system is an efficiently toned machinery that discriminates between friends and foes for achieving both host defense and homeostasis. Deviation of immune recognition from foreign to self and/or long-lasting inflammatory responses results in the breakdown of tolerance. Meanwhile, educating the immune system and developing immunological memory are crucial for mounting defensive immune responses while protecting against autoimmunity. Still to elucidate is how diverse environmental factors could shape autoimmunity. The emergence of a world pandemic such as SARS-CoV-2 (COVID-19) not only threatens the more vulnerable individuals including those with autoimmune conditions but also promotes an unprecedented shift in people’s dietary approaches while urging for extraordinary hygiene measures that likely contribute to the development or exacerbation of autoimmunity. Thus, there is an urgent need to understand how environmental factors modulate systemic autoimmunity to better mitigate the incidence and or severity of COVID-19 among the more vulnerable populations. Here, we discuss the effects of diet (macronutrients and micronutrients) and hygiene (the use of disinfectants) on autoimmunity with a focus on systemic lupus erythematosus.

scholarly journals Evaluation of Immunostimulant Activity and Inhibition of Cytokine Storm Activity of Proprietary Herbal Formulation Virulina®

2020 ◽  
Vol 11 (3) ◽  
pp. 10482-10492
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Inflammatory Responses ◽  
Cytokine Storm ◽  
Rat Serum ◽  
Storm Activity ◽  
Synthetic Drugs ◽  
Polycytidylic Acid ◽  
Factor Α

Immunostimulation is the strengthening of the immune system through the induction of non-specific immune responses. Synthetic drugs have harmful side effects, enormous costs, and are ineffectual in controlling several pathological disorders. Therefore, nowadays, herbal immunostimulants have been considered as a superior and less toxic opportunity for the management of disorders as well as their complications. The objective of the current investigation is the formulation of Virulina®-Natural Solutions (VL®-NS) polyherbal formulation and its evaluation for immunostimulant and cytokine storm inhibition activity. The immunostimulant & anti-inflammatory potential of Virulina® were determined by using in-vitro phagocytosis through polymorphonuclear analysis, indicating the invasion of leukocytes. In-vitro cytokine storm inhibitory activity was also performed using mouse macrophage cells (RAW264.7) treated with polyinosinic-polycytidylic acid to test the ability of Virulina® to attenuate the immune responses. The inflammatory responses were evaluated by the endotoxin-lipopolysaccharide (LPS) model following the endotoxin challenges of aggravating the inflammatory mediators (cytokines); thereby, the LPS derived from E. coli as antigen at a dose of 10 mgkg-1, i.p was used for the systemic inflammation. VL®-NS exhibited enhanced phagocytic efficacy at 100 mgml-1 in PMN function test. VL®-NS significantly decreases the expression of a cytokine such as interleukin-6, tumor necrosis factor-α & vascular endothelial growth factor in RAW264.7 cell culture. The increase in LPS-induced cytokine levels in rat serum was dose-dependently & significantly (p<0.05) inhibited by VL®-NS treatment. VL®-NS tend to be potent immunostimulant therapy as a superior and less toxic opportunity for the strengthening of the immune system for the management of several inflammatory disorders.

scholarly journals rs4143815-PDL1, a New Potential Immunogenetic Biomarker of Biochemical Recurrence in Locally Advanced Prostate Cancer after Radiotherapy

2019 ◽  
Vol 20 (9) ◽  
pp. 2082
Author(s):  
Chiara Zanusso ◽  
Eva Dreussi ◽  
Roberto Bortolus ◽  
Chiara Romualdi ◽  
Sara Gagno ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Immune System ◽  
Biochemical Recurrence ◽  
Advanced Prostate Cancer ◽  
Locally Advanced ◽  
Significant Snps ◽  
P Value ◽  
Training Set ◽  
Locally Advanced Prostate Cancer ◽  
New Biomarkers

Up to 30–50% of patients with locally advanced prostate cancer (PCa) undergoing radiotherapy (RT) experience biochemical recurrence (BCR). The immune system affects the RT response. Immunogenetics could define new biomarkers for personalization of PCa patients’ treatment. The aim of this study is to define the immunogenetic biomarkers of 10 year BCR (primary aim), 10 year overall survival (OS) and 5 year BCR (secondary aims). In this mono-institutional retrospective study, 549 Caucasian patients (a discovery set n = 418; a replication set n = 131) were affected by locally advanced PCa and homogeneously treated with RT. In the training set, associations were made between 447 SNPs in 77 genes of the immune system; and 10 year BCR and 10 year OS were tested through a multivariate Cox proportional hazard model. Significant SNPs (p-value < 0.05, q-value < 0.15) were analyzed in the replication set. Replicated SNPs were tested for 5 year BCR in both sets of patients. A polymorphism in the PDL1 gene (rs4143815) was the unique potential genetic variant of 10 year BCR (training set: p = 0.003, HR (95% CI) = 0.58 (0.41–0.83); replication set: p = 0.063, HR (95% CI) = 0.52 (0.26–1.04)) that was significantly associated with 5 year BCR (training set: p = 0.009, HR (95% CI) = 0.59 (0.40–0.88); replication set: p = 0.036, HR (95% CI) = 0.39 (0.16–0.94)). No biomarkers of OS were replicated. rs4143815-PDL1 arose as a new immunogenetic biomarker of BCR in PCa, giving new insights into the RT/immune system interaction, which could be potentially useful in new approaches using anti-PDL1 therapies for PCa.

Sign in / Sign up

Export Citation Format

Share Document