Immune System Genes Research Articles

Gene Silencing With siRNA (RNA Interference): A New Therapeutic Option During Ex Vivo Machine Liver Perfusion Preservation

RNA interference (RNAi) is a natural process of posttranscriptional gene regulation that has raised a lot of attention culminating with the Nobel Prize in Medicine in 2006. RNAi-based therapeutics have been tested in experimental transplantation to reduce ischemia/reperfusion injury (IRI) with success. Modulation of genes of the innate immune system, as well as apoptotic genes, and those involved in the nuclear factor kappa B pathways can reduce liver injury in rodent liver pedicle clamping and transplantation models of IRI. However, in vivo use of RNAi faces limitations regarding the method of administration, uptake, selectivity, and stability. Machine perfusion preservation, a more recent alternative approach for liver preservation showing superior results to static cold preservation, could be used as a platform for gene interference therapeutics. Our group was the first to demonstrate uptake of small interfering RNA (siRNA) during liver machine preservation under both normothermic and hypothermic perfusion. Administering siRNA in the perfusion solution during ex vivo machine preservation has several advantages, including more efficient delivery, lower doses and cost-saving, and none/fewer side effects to other organs. Recently, the first RNAi drug was approved by the US Food and Drug Administration for clinical use, opening a new avenue for new drugs with different clinical applications. RNAi has the potential to have transformational therapeutic applications in several areas of medicine including transplantation. We believe that machine preservation offers great potential to be the ideal delivery method of siRNA to the liver graft, and future studies should be initiated to improve the clinical applicability of RNAi in solid organ transplantation.

Down-regulation of IRF3 expression in Relapse-Remitting MS patients

Background: Relapsing-Remitting (RRMS) is the most common Multiple Sclerosis disease course. Interferon regulatory factor 3 (IRF3) as major regulators of immune system genes plays a critical role in the activation of type I interferons promoters, in particular IFNβ promoter. Hence we aimed to evaluate the expression rate of IRF3 in RRMS patients under different type of IFNβ treatment. Material and methods: In the present study total of 100 subjects participated. Blood samples of 25 patients with RRMS newly diagnosed who have not been treated with interferon components, 25 patients with RRMS treated with Interferon beta-1α (B1a), 25 patients with RRMS treated with Interferon beta-1β (B1b) and 25 control samples were collected. The samples were transferred at standard conditions to the Cellular and Molecular Research Center of Shahrekord University of Medical Sciences, RNA was extracted and converted to cDNA. To evaluate the expression of IRF3 the Real-Time PCR method using SYBR Green dye was done. The level of gene expression was measured by a comparative threshold cycle formula. The obtained data were analyzed using SPSS v15 software. Results: In the study we compared the IRF3 mRNA expression of all subjects in association with gender, which no significant difference was seen (P > 0.05). Also assessment of the gene mRNA level in study groups revealed that the B1b, B1a and new case group had the lowest expression respectively. Moreover, comparison of the mRNA level between new case and B1b groups showed remarkable difference (P 0.05). Conclusion: Perhaps the IFNβ recombinants decreases the IRF3 expression as a negative feedback mechanism. Overall the data reported here, supports the previous studies in important role of IRF3 in autoimmune inflammatory disease of CNS and Multiple Sclerosis.

Evidence of a hydraulically challenging reach serving as a barrier for the upstream migration of infection-burdened adult steelhead.

Anadromous fishes such as steelhead trout, Oncorhynchus mykiss, are exposed to a suite of infectious agents and migratory challenges during their freshwater migrations. We assessed infectious agent load and richness and immune system gene expression in gill tissue of Bulkley River (British Columbia, CA) steelhead captured at and upstream of a migratory barrier to evaluate whether infectious burdens impacted migration success. We further considered the potential influences of water temperature, sex and fish size on host infectious agents and transcription profiles. There were eight infectious agents detected in steelhead gill tissue, with high prevalence of the bacteria Candidatus Branchiomonas cysticola (80%) and Flavobacterium psychrophilum (95%) and the microparasite Sphaerothecum destruens (53%). Fish sampled at the falls had significantly greater relative loads of Ca. B. cysticola and F. psychrophilum, higher infectious agent richness and differential gene expression compared to fish captured upstream. Flavobacterium psychrophilum was only associated with immune gene expression (particularly humoral immunity) of fish sampled at the falls, while water temperature was positively correlated with genes involved in the complement system, metabolic stress and oxidative stress for fish captured upstream. This work highlights interesting differences in agent-host interactions across fisheries and suggests that hydraulic barriers may reduce the passage of fish with the heaviest infectious agent burdens, emphasizing the selective role of areas of difficult passage. Further, this work expands our knowledge of infectious agent prevalence in wild salmonids and provides insight into the relationships between infectious agents and host physiology.

Comparative genomics and transcriptomics of host-pathogen interactions in insects: evolutionary insights and future directions.

Classical evolutionary studies of protein-coding genes have established that genes in the canonical immune system are often among the most rapidly evolving within and between species. As more genomes and transcriptomes across insects are sequenced, it is becoming clear that duplications and losses of immune genes are also a likely consequence of host-pathogen interactions. Furthermore, particular species respond to diverse pathogenic challenges with a wide range of challenge-specific responses that are still poorly understood. Transcriptional studies, using RNA-seq to characterize the infection-regulated transcriptome of diverse insects, are crucial for additional progress in understanding the ecology and evolution of the full complexity of the host response.

Daily Regulation of Phototransduction, Circadian Clock, DNA Repair, and Immune Gene Expression by Heme Oxygenase in the Retina of Drosophila.

The daily expression of genes and the changes in gene expression after silencing the heme oxygenase (ho) gene were examined in the retina of Drosophila using microarray and SybrGreen qPCR (quantitative polymerase chain reaction) methods. The HO decrease in the morning upregulated 83 genes and downregulated 57 genes. At night, 80 genes were upregulated and 22 were downregulated. The top 20 genes downregulated after ho silencing in the morning modulate phototransduction, immune responses, autophagy, phagocytosis, apoptosis, the carbon monoxide (CO) response, the oxidative stress/UV response, and translation. In turn, the genes that upregulated at night were involved in translation—the response to oxidative stress, DNA damage, and phototransduction. Among the top 20 genes downregulated at night were genes involved in phototransduction, immune responses, and autophagy. For some genes, a low level of HO had an opposite effect in the morning compared to those at night. Silencing ho also changed the expression of circadian clock genes, while the HO decrease during the night enhanced the expression of immune system genes. The results showed that the cyclic expression of HO is important for controlling several processes in the retina, including neuroprotection and those involved in the innate immune system.

Immunomodulatory effects of antipsychotic treatment on gene expression in first-episode psychosis

Previous studies suggest immunological alterations in patients with first-episode psychosis (FEP). Some studies show that antipsychotic compounds may cause immunomodulatory effects. To evaluate the immunological changes and the possible immunomodulatory effects in FEP, we recruited patients with FEP (n = 67) and matched controls (n = 38), aged 18–40 years, from the catchment area of the Helsinki University Hospital and the City of Helsinki, Finland. Fasting peripheral blood samples were collected between 8 and 10 a.m. in 10 ml PAXgene tubes. We applied the NanoString nCounter in-solution hybridization technology to determine gene expression levels of 147 candidate genes reflecting activation of the immune system. Cases had higher gene expression levels of BDKRB1 and SPP1/osteopontin compared with controls. Of the individual medications used as monotherapy, risperidone was associated with a statistically significant upregulation of 11 immune system genes, including cytokines and cytokine receptors (SPP1, IL1R1, IL1R2), pattern recognition molecules (TLR1, TLR2 and TLR6, dectin-1/CLEC7A), molecules involved in apoptosis (FAS), and some other molecules with functions in immune activation (BDKRB1, IGF1R, CR1). In conclusion, risperidone possessed strong immunomodulatory properties affecting mainly innate immune response in FEP patients, whereas the observed effects of quetiapine and olanzapine were only marginal. Our results further emphasize the importance of understanding the immunomodulatory mechanisms of antipsychotic treatment, especially in terms of specific compounds, doses and duration of medication in patients with severe mental illness. Future studies should evaluate the response pre- and post-treatment, and the possible role of this inflammatory activation for the progression of psychiatric and metabolic symptoms.

Intragenus (Homo) variation in a chemokine receptor gene (CCR5).

Humans have a comparatively higher rate of more polymorphisms in regulatory regions of the primate CCR5 gene, an immune system gene with both general and specific functions. This has been interpreted as allowing flexibility and diversity of gene expression in response to varying disease loads. A broad expression repertoire is useful to humans—the only globally distributed primate—due to our unique adaptive pattern that increased pathogen exposure and disease loads (e.g., sedentism, subsistence practices). The main objective of the study was to determine if the previously observed human pattern of increased variation extended to other members of our genus, Homo. The data for this study are mined from the published genomes of extinct hominins (four Neandertals and two Denisovans), an ancient human (Ust’-Ishim), and modern humans (1000 Genomes). An average of 15 polymorphisms per individual were found in human populations (with a total of 262 polymorphisms). There were 94 polymorphisms identified across extinct Homo (an average of 13 per individual) with 41 previously observed in modern humans and 53 novel polymorphisms (32 in Denisova and 21 in Neandertal). Neither the frequency nor distribution of polymorphisms across gene regions exhibit significant differences within the genus Homo. Thus, humans are not unique with regards to the increased frequency of regulatory polymorphisms and the evolution of variation patterns across CCR5 gene appears to have originated within the genus. A broader evolutionary perspective on regulatory flexibility may be that it provided an advantage during the transition to confrontational foraging (and later hunting) that altered human-environment interaction as well as during migration to Eurasia and encounters with novel pathogens.

Falling in love is associated with immune system gene regulation

Although falling in love is one of the most important and psychologically potent events in human life, the somatic implications of new romantic love remain poorly understood. Psychological, immunological, and reproductive perspectives offer competing predictions of the specific transcriptional regulatory shifts that might accompany the experience of falling in love. To characterize the impact of romantic love on human genome function, we conducted genome-wide transcriptome profiling of 115 circulating immune cell samples collected from 47 young women over the course of a 2-year longitudinal study. Analyses revealed a selective alteration in immune cell gene regulation characterized by up-regulation of Type I interferon response genes associated with CD1C+/BDCA-1+ dendritic cells (DCs) and CLEC4C+/BDCA-2+ DCs, and a reciprocal down-regulation of α-defensin-related transcripts associated with neutrophil granulocytes. These effects emerged above and beyond the effects of changes in illness, perceived social isolation, and sexual contact. These findings are consistent with a selective up-regulation of innate immune responses to viral infections (e.g., Type I interferons and DC) and with DC facilitation of sexual reproduction, and provide insight into the immunoregulatory correlates of one of the keystone experiences in human life.

Primary immunodeficiency diseases in a tuberculosis endemic region: challenges and opportunities.

While individual primary immunodeficiency diseases (PIDs) are rare, collectively they represent a significant burden of disease. Recent estimates show that about one million people in Africa suffer from a PID. However, data from African PID registries reflect only a small percentage of the estimated prevalence. This disparity is partly due to the lack of PID awareness and the masking of PIDs by the endemic pathogens. Over three million tuberculosis (TB) cases were reported in Africa in 2016, with many of these from southern Africa. Despite concerted efforts to address this high burden of disease, the underlying genetic correlates of susceptibility to TB remain poorly understood. High penetrance mutations in immune system genes can cause PIDs that selectively predispose individuals to TB and other mycobacterial diseases. Additionally, the identification of individuals at a heightened risk of developing TB or of presenting with severe or disseminated TB due to their genetic ancestry is crucial to promote a positive treatment outcome. The screening for and identification of PID mutations in TB-endemic regions by next-generation sequencing (NGS) represents a promising approach to improve the understanding of what constitutes an effective immune response to TB, as well as the range of associated PIDs and phenotypes.

Temperature modulates the immunological response of the sub-antarctic notothenioid fish Eleginops maclovinus injected with Piscirickettsia salmonis

Eleginops maclovinus is a eurythermic fish that under natural conditions lives in environments with temperatures ranging from 4 to 18 °C and can be usually captured near salmon farming areas. The aim of this study was to evaluate the effect of temperature over the innate and adaptive immune response of E. maclovinus challenged with Piscirickettsia salmonis following different treatments: C (control injection with culture medium at 12 °C), C+ (bacterial injection at 12 °C), 18 °C c/A + B (injection with culture medium in acclimation at 18 °C), 18 °C c/A + B (bacterial injection in acclimation at 18 °C), 18 °C s/A + M (injection with culture medium without acclimation at 18 °C) and 18 °C s/A + B (bacterial injection without acclimation at 18 °C). Each injection had 100 μL of culture medium or with 100 μL at a concentration 1 × 108 of live bacteria, sampling six fish per group at 4, 8, 12, 16 and 20 days post-injection (dpi). Expression of the mRNA related with the innate immune response gene (TLR1, TLR5, TLR8, NLRC3, NLRC5, MyD88 and IL-1β) as well as the adaptive immune response gene (MHCI, MHCII, IgMs and IgD) were measured in spleen and head kidney. Gene expression profiles were treatment-type and time dependent. Levels of Immunoglobulin M (IgM) increased in challenged groups with P. salmonis from day 8–20 post challenge, which suggest activation of B cells IgM + through P. salmonis epitope detection. Additionally, a rise in temperature from 12 °C (C+) to 18 °C (with/without acclimation) also resulted in antibody increment detected in serum with significant differences between “18 °C c/A + B” and “18 °C s/A + B” groups. This is the first study that evaluates the effect of temperature changes and mRNA expression related with immune system gene over time on E. maclovinus, a native wild life fish that cohabits in the salmon farming environment.

Simulation of the Dynamics of Primary Immunodeficiencies in B Cells.

Primary immunodeficiencies (PIDs) are a group of over 300 hereditary, heterogeneous, and mainly rare disorders that affect the immune system. Various aspects of immune system and PID proteins and genes have been investigated and facilitate systems biological studies of effects of PIDs on B cell physiology and response. We reconstructed a B cell network model based on data for the core B cell receptor activation and response processes and performed semi-quantitative dynamic simulations for normal and B cell PID failure modes. The results for several knockout simulations correspond to previously reported molecular studies and reveal novel mechanisms for PIDs. The simulations for CD21, CD40, LYN, MS4A1, ORAI1, PLCG2, PTPRC, and STIM1 indicated profound changes to major transcription factor signaling and to the network. Significant effects were observed also in the BCL10, BLNK, BTK, loss-of-function CARD11, IKKB, MALT1, and NEMO, simulations whereas only minor effects were detected for PIDs that are caused by constitutively active proteins (PI3K, gain-of-function CARD11, KRAS, and NFKBIA). This study revealed the underlying dynamics of PID diseases, confirms previous observations, and identifies novel candidates for PID diagnostics and therapy.

Effects of GandhPaalashi (Hedychium spicatum) on the expression of hepatic genes associated with biotransformation, antioxidant and immune systems in WLH cockerels fed indoxacarb

The objective of the present study was to evaluate the efficacy of Hedychium spicatum (HSRP) root powder, to ameliorate changes in gene expression in WLH cockerels fed indoxacarb. After 16 weeks of treatment, all birds from different groups were sacrificed humanly and collected the liver pieces in RNA later for expression study by RT-PCR to evaluate changes in the expression of genes involved in antioxidant function [catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione S-transferase (GST)], biotransformation [cytochrome P450 1A1 (CYP1A1)], and the immune system [interleukins 6 (IL-6)]. Changes in gene expression were determined using the quantitative real-time PCR technique. There were significant upregulation of IL-6, CYP1A1 and GPx genes in indoxacarb treated groups. There was significant down regulation of CAT and SOD genes in indoxacarb treated groups in comparison to control. Simultaneous treatments with HSRP produce ameliorative effect and restore the gene activities at par with control. The current study demonstrates protective effects of HSRP on changes in expression of antioxidant, biotransformation, and immune system genes in cockerels fed indoxacarb.

Genomic analysis of MHC-based mate choice in the monogamous California mouse.

Variation at Major Histocompatibility Complex (MHC) genes is thought to be an important mechanism underlying mate choice in vertebrates, with individuals typically predicted to prefer MHC-dissimilar reproductive partners. However, analyses based on individual MHC loci have generated contradictory results regarding the role of these genes in mate-choice decisions. To provide a more comprehensive assessment of relationships between MHC variation and mating behavior, we used an exome capture strategy to characterize variability at 13 MHC loci, 312 innate immune system genes, and 1044 nonimmune genes in 25 obligate monogamous pairs of California mice (Peromyscus californicus) from 2 free-living populations of this species in Monterey County, California. Pairwise genotypic comparisons and analyses of SNP-based allelic differences failed to detect disassortative mating based on MHC variability; reproductive partners were not more dissimilar than randomly generated male-female pairs at MHC, innate or nonimmune loci. Within populations, individuals tended to be more closely related at MHC genes than at innate or nonimmune genes. Consistent with the functional role of immunogenes, the 2 study populations were highly differentiated at MHC and innate genes but not at nonimmune loci. Collectively, our results suggest that MHC genetic variation in California mice reflects local differences in pathogen exposure rather than disassortative mating based on variability at MHC Class I and II genes.

Effect of β-Glucans in Diets on Growth, Survival, Digestive Enzyme Activity, and Immune System and Intestinal Barrier Gene Expression for Tropical Gar (Atractosteus tropicus) Juveniles

The application of β-1,3/1,6-glucan derived from yeast at five concentrations (0%, 0.5%, 1.0%, 1.5%, and 2.0%) in formulated diets was evaluated in juveniles for its effects on the growth, survival, digestive enzymatic activity, and expression of genes associated with the immune system (interlukin-10 (IL-10), transforming growth factor (TGF), occludin (OCC), mucin2 (MUC2), lysozyme (LYS), and nucleotide-binding and oligomerization domain 2 (NOD2)) in tropical gar (Atractosteus tropicus). For the experiment, three replicates of 30 fish per experimental unit (70 L) were cultivated for 62 days. The growth results showed no statistically significant differences in relation to weight and total length between treatments. The activity of digestive enzymes (alkaline proteases, trypsin, leucine aminopeptidase, and amylase) did not show significant differences between treatments, except for chymotrypsin activity, where fish fed 1.0% and 1.5% of β-glucans showed higher activities compared with the rest of the treatments. On the other hand, the analysis of gene expression did not show significant differences between treatments, although a tendency of increase in the expression of IL-10, TGF, MUC2, and OCC was observed with an addition of 1.5% of the prebiotic, but there was a decrease in the fish fed with 2% of the prebiotic. It is possible to include concentrations of between 0.5% and 1.5% of β-glucans in the diets for A. tropicus, with no detectable adverse effects on growth, survival, digestive enzyme activity, or specific gene expression. β-glucan 1,3/1,6 added at 1.0% and 1.5% in the diet significantly increases chymotrypsin activity.

Polymorphic Variants of Immune Response Genes as a Risk Factor for the Development of Primary Progressive Multiple Sclerosis

Objectives. To analyze the involvement of immune response genes in the pathogenesis of primary progressive multiple sclerosis (PPMS). Materials and methods. A representative cohort of 111 ethnically Russian patients with PPMS took part in a multicenter study. The involvement of immune system genes in the pathogenesis of PPMS was analyzed by investigating the associations of variants of cytokines genes and genes involved in antigen processing and presentation by antigen-presenting cells with the disease. Results and conclusions. Carriership of the IL4 genotype (rs2243250)*C/C and CLEC16A (rs6498169)*G/G was found to have a positive association with the development of PPMS in Russian patients. The association described in studies of other populations, HLA-DRB1*15 with a high risk of developing this form of MS, was confirmed.

Immune mechanisms induced by an HSV-1 mutant strain: Discrepancy analysis of the immune system gene profile in comparison with a wild-type strain

Herpes simplex virus is a prevalent pathogen of humans of various age groups. The fact that no prophylactic or therapeutic vaccine is currently available suggests a significant need to further investigate the immune mechanisms induced by the virus and various vaccine candidates. We previously generated an HSV-1 mutant strain, M3, with partial deletions in ul7, ul41 and LAT that produced an attenuated phenotype in mice. In the present study, we performed a comparative analysis to characterize the immune responses induced by M3 versus wild-type HSV-1 in a mouse model. Infection with wild-type HSV-1 triggered an inflammatory-dominated response and adaptive immunity suppression and was accompanied by severe pathological damage. In contrast, infection with M3 induced a systematic immune response involving full activation of both innate and adaptive immunity and was accompanied by no obvious pathological changes. Furthermore, the immune response induced by M3 protected mice from lethal challenge with wild-type strains of HSV-1 and restrained virus proliferation and impaired latency. These data are useful for further HSV-1 vaccine development using a mutant strain construction strategy.

Transcriptomic characterization of MRI contrast with focus on the T1-w/T2-w ratio in the cerebral cortex

Magnetic resonance (MR) images of the brain are of immense clinical and research utility. At the atomic and subatomic levels, the sources of MR signals are well understood. However, we lack a comprehensive understanding of the macromolecular correlates of MR signal contrast. To address this gap, we used genome-wide measurements to correlate gene expression with MR signal intensity across the cerebral cortex in the Allen Human Brain Atlas (AHBA). We focused on the ratio of T1-weighted and T2-weighted intensities (T1-w/T2-w ratio image), which is considered to be a useful proxy for myelin content. As expected, we found enrichment of positive correlations between myelin-associated genes and the ratio image, supporting its use as a myelin marker. Genome-wide, there was an association with protein mass, with genes coding for heavier proteins expressed in regions with high T1-w/T2-w values. Oligodendrocyte gene markers were strongly correlated with the T1-w/T2-w ratio, but this was not driven by myelin-associated genes. Mitochondrial genes exhibit the strongest relationship, showing higher expression in regions with low T1-w/T2-w ratio. This may be due to the pH gradient in mitochondria as genes up-regulated by pH in the brain were also highly correlated with the ratio. While we corroborate associations with myelin and synaptic plasticity, differences in the T1-w/T2-w ratio across the cortex are more strongly linked to molecule size, oligodendrocyte markers, mitochondria, and pH. We evaluate correlations between AHBA transcriptomic measurements and a group averaged T1-w/T2-w ratio image, showing agreement with in-sample results. Expanding our analysis to the whole brain results in strong positive T1-w/T2-w correlations for immune system, inflammatory disease, and microglia marker genes. Genes with negative correlations were enriched for neuron markers and synaptic plasticity genes. Lastly, our findings are similar when performed on T1-w or inverted T2-w intensities alone. These results provide a molecular characterization of MR contrast that will aid interpretation of future MR studies of the brain.

The Assessment of the Association Between Herpesviruses and Subgingival Bacterial Plaque by Real-time PCR Analysis

This study used a real-time PCR analysis to determine possible correlations between periodontal presence of human cytomegalovirus, Epstein-Barr virus and various putative parodontopathogenic bacteria. The study included 18 patients (aged 18-38 years) with aggressive periodontitis, 12 patients (ages 37 to 62) with chronic periodontitis and 30 periodontally healthy subjects (aged 21-54 years). Clinical periodontal evaluation included plaque index, gingival index, percentage of bleeding on probing sites, and probing depth. In each patient, a subgingival bacterial plaque sample was obtained from the deepest periodontal pocket. The real-time fluorogenic PCR detection system was used to determine the number of infectious agents. Human cytomegalovirus was detected in 17 sites with periodontal lesions and in two healthy periodontal sites, and the Epstein-Barr virus was detected in 19 sites with periodontal lesions and in 3 normal periodontal sites. Positive correlations were found between human cytomegalovirus and P. gingivalis, T. forsythia and C. rectus. The Epstein-Barr virus positively correlated with P. gingivalis and T. forsythia. Unfavorable changes in environmental exposure or alteration of the immune system genes can periodically suppress the host�s defence against periodontal aggression, which can then result in reactivation of resident herpesviruses and increased pro-inflammatory mediators followed by an increase in pathogenic bacteria.

Gene expression hallmarks of cellular ageing

Ageing leads to dramatic changes in the physiology of many different tissues resulting in a spectrum of pathology. Nonetheless, many lines of evidence suggest that ageing is driven by highly conserved cell intrinsic processes, and a set of unifying hallmarks of ageing has been defined. Here, we survey reports of age-linked changes in basal gene expression across eukaryotes from yeast to human and identify six gene expression hallmarks of cellular ageing: downregulation of genes encoding mitochondrial proteins; downregulation of the protein synthesis machinery; dysregulation of immune system genes; reduced growth factor signalling; constitutive responses to stress and DNA damage; dysregulation of gene expression and mRNA processing. These encompass widely reported features of ageing such as increased senescence and inflammation, reduced electron transport chain activity and reduced ribosome synthesis, but also reveal a surprising lack of gene expression responses to known age-linked cellular stresses. We discuss how the existence of conserved transcriptomic hallmarks relates to genome-wide epigenetic differences underlying ageing clocks, and how the changing transcriptome results in proteomic alterations where data is available and to variations in cell physiology characteristic of ageing. Identification of gene expression events that occur during ageing across distant organisms should be informative as to conserved underlying mechanisms of ageing, and provide additional biomarkers to assess the effects of diet and other environmental factors on the rate of ageing.

Molecular and clinical characterization of IDH associated immune signature in lower-grade gliomas

ABSTRACTBackground: Mutations in isocitrate dehydrogenase (IDH) affect the development and prognosis of gliomas. We investigated the role of IDH mutations in the regulation of immune phenotype in lower-grade gliomas (LGGs).Method and patients: A total of 1,008 cases with clinical and IDH mutation data from five cohorts were enrolled. Samples with RNA sequencing data from the Chinese Glioma Genome Atlas (CGGA) were used as training set, whereas RNA data from the Cancer Genome Atlas, Repository for Molecular Brain Neoplasia, GSE16011, and CGGA microarray databases were used for validation. R language tools and bioinformatics analysis were used for gene signature construction and biological function annotation.Results: We found that IDH mutations caused down-regulation of local immune response as among 332 immune system-related genes, 196(59.0%) were differentially expressed according to IDH mutation status. Nearly 70% of those differentially expressed genes exhibited prognostic value in LGGs. An immune response-based gene signature was constructed that distinguished cases with high- or low-risk of unfavorable prognosis and remained an independent prognostic factor in multivariate analyses in both training and validation cohorts. Samples from high-risk cases exhibited elevated expression of genes involved in immune response and NF-κB pathway activation. Furthermore, we found a strong correlation between the risk score and T cells, macrophage-related immune response, and expression of several prominent immune checkpoints.Conclusion: Our results indicated that mutant IDH is highly associated with the regulation of the immune microenvironment in LGGs. The observed immune system gene signature, which was sensitive to IDH mutation status, efficiently predicted patient survival.