Cross-disease innate gene signature: Emerging diversity and abundance in RA comparing to SLE and SSc

Overactivation of the innate immune system together with the impaired downstream pathway of type I interferon-responding genes is a hallmark of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc). To date, limited data on the cross-disease innate gene signature exists among those diseases. We compared therefore an innate gene signature of Toll-like receptors (TLRs), seven key members of the interleukin (IL)1/IL1R family, and CXCL8/IL8 in peripheral blood mononuclear cells from well-defined patients with active stages of RA (n=36, DAS28 >= 3.2), SLE (n=28, SLEDAI>6), and SSc (n=22, revisedEUSTARindex>2.25). Emerging diversity and abundance of the innate signature in RA patients were detected: RA was characterized by the upregulation of TLR3, TLR5, IL1RAP/IL1R3, IL18R1, and SIGIRR/IL1R8 when compared to SSc (Pcorr<0.02) and of TLR2, TLR5, and SIGIRR/IL1R8 when compared to SLE (Pcorr<0.02). Applying the association rule analysis, six rules (combinations and expression of genes describing disease) were identified for RA (most frequently included high TLR3 and/or IL1RAP/IL1R3) and three rules for SLE (low IL1RN and IL18R1) and SSc (low TLR5 and IL18R1). This first cross-disease study identified emerging heterogeneity in the innate signature of RA patients with many upregulated innate genes compared to that of SLE and SSc.Web of Science2019art. no. 357580

Increased Expression of Cell-Cell Signaling Genes by Stimulated Mononuclear Leukocytes in Patients with Previous Atherothrombotic Stroke A Whole Genome Expression Profile Study

Background/Aims: Inflammation plays an important role in atherosclerosis and stroke. Acute infections are recognized as trigger factors for ischemic stroke. Methods: In this whole genome expression profile study of 15 patients and 15 control subjects, we tested the hypothesis that patients with a history of atherothrombotic stroke show enhanced transcription of inflammatory genes in circulating leukocytes. RNA from unstimulated or lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs) was analyzed with Affymetrix U133A GeneChips using a pooling design. Expression of single genes and functional groups of genes was analyzed by global statistical tests. Results: A total of 10,197 probe sets showed positive calls. After correction for multiple testing no single probe set revealed significant differences either without or with LPS stimulation. However, significant global expression differences were found upon LPS stimulation for the group of genes that are involved in cell-cell signaling. Conclusion: LPS stimulation of PBMCs, a condition mimicking bacterial infection, induces differential expression of a group of cell-cell signaling genes in patients with previous atherothrombotic stroke. This finding can be caused by genetic differences between both groups, but acquired risk factors, medication and technical factors may also have contributed to the result. Copyright (C) 2009 S. Karger AG, Base

Metabolic syndrome influences cardiac gene expression pattern at the transcript level in male ZDF rats

Background: Metabolic syndrome (coexisting visceral obesity, dyslipidemia, hyperglycemia, and hypertension) is a prominent risk factor for cardiovascular morbidity and mortality, however, its effect on cardiac gene expression pattern is unclear. Therefore, we examined the possible alterations in cardiac gene expression pattern in male Zucker Diabetic Fatty (ZDF) rats, a model of metabolic syndrome. Methods: Fasting blood glucose, serum insulin, cholesterol and triglyceride levels were measured at 6, 16, and 25 wk of age in male ZDF and lean control rats. Oral glucose tolerance test was performed at 16 and 25 wk of age. At week 25, total RNA was isolated from the myocardium and assayed by rat oligonucleotide microarray for 14921 genes. Expression of selected genes was confirmed by qRT-PCR. Results: Fasting blood glucose, serum insulin, cholesterol and triglyceride levels were significantly increased, glucose tolerance and insulin sensitivity were impaired in ZDF rats compared to leans. In hearts of ZDF rats, 36 genes showed significant up-regulation and 49 genes showed down-regulation as compared to lean controls. Genes with significantly altered expression in the heart due to metabolic syndrome includes functional clusters of metabolism (e.g. 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 2; argininosuccinate synthetase; 2-amino-3ketobutyrate-coenzyme A ligase), structural proteins (e.g. myosin IXA; aggrecan1), signal transduction (e. g. activating transcription factor 3; phospholipase A2; insulin responsive sequence DNA binding protein-1) stress response (e.g. heat shock 70kD protein 1A; heat shock protein 60; glutathione S-transferase Yc2 subunit), ion channels and receptors (e.g. ATPase, (Na+)/K+ transporting, beta 4 polypeptide; ATPase, H+/K+ transporting, nongastric, alpha polypeptide). Moreover some other genes with no definite functional clusters were also changed such as e. g. S100 calcium binding protein A3; ubiquitin carboxy-terminal hydrolase L1; interleukin 18. Gene ontology analysis revealed several significantly enriched functional inter-relationships between genes influenced by metabolic syndrome. Conclusions: Metabolic syndrome significantly alters cardiac gene expression profile which may be involved in development of cardiac pathologies in the presence of metabolic syndrome

Inflammatory monocytes require type I interferon receptor signaling to activate NK cells via IL-18 during a mucosal viral infection

The requirement of type I interferon (IFN) for natural killer (NK) cell activation in response to viral infection is known, but the underlying mechanism remains unclear. Here, we demonstrate that type I IFN signaling in inflammatory monocytes, but not in dendritic cells (DCs) or NK cells, is essential for NK cell function in response to a mucosal herpes simplex virus type 2 (HSV-2) infection. Mice deficient in type I IFN signaling, Ifnar(-/-) and Irf9(-/-) mice, had significantly lower levels of inflammatory monocytes, were deficient in IL-18 production, and lacked NK cell-derived IFN-gamma. Depletion of inflammatory monocytes, but not DCs or other myeloid cells, resulted in lower levels of IL-18 and a complete abrogation of NK cell function in HSV-2 infection. Moreover, this resulted in higher susceptibility to HSV-2 infection. Although Il18(-/-) mice had normal levels of inflammatory monocytes, their NK cells were unresponsive to HSV-2 challenge. This study highlights the importance of type I IFN signaling in inflammatory monocytes and the induction of the early innate antiviral response

Global Transcriptomic Profiling of Bovine Endometrial Immune Response In Vitro. II. Effect of Bovine Viral Diarrhea Virus on the Endometrial Response to Lipopolysaccharide

Infection with noncytopathic bovine viral diarrhea virus (ncpBVDV) is associated with uterine disease and infertility. This study investigated the influence of ncpBVDV on immune functions of the bovine endometrium by testing the response to bacterial lipopolysaccharide (LPS). Primary cultures of mixed epithelial and stromal cells were divided into four treatment groups (control [CONT], BVDV, CONT+LPS, and BVDV+LPS) and infected with ncpBVDV for 4 days followed by treatment with LPS for 6 h. Whole-transcriptomic gene expression was measured followed by Ingenuity Pathway Analysis. Differential expression of 184 genes was found between CONT and BVDV treatments, showing interplay between induction and inhibition of responses. Up-regulation of TLR3, complement, and chemotactic and TRIM factors by ncpBVDV all suggested an ongoing immune response to viral infection. Down-regulation of inflammatory cytokines, chemokines, CXCR4, and serine proteinase inhibitors suggested mechanisms by which ncpBVDV may simultaneously counter the host response. Comparison between BVDV+LPS and CONT+LPS treatments showed 218 differentially expressed genes. Canonical pathway analysis identified the key importance of interferon signaling. Top down-regulated genes were RSAD2, ISG15, BST2, MX2, OAS1, USP18, IFIT3, IFI27, SAMD9, IFIT1, and DDX58, whereas TRIM56, C3, and OLFML1 were most up-regulated. Many of these genes are also regulated by IFNT during maternal recognition of pregnancy. Many innate immune genes that typically respond to LPS were inhibited by ncpBVDV, including those involved in pathogen recognition, inflammation, interferon response, chemokines, tissue remodeling, cell migration, and cell death/survival. Infection with ncpBVDV can thus compromise immune function and pregnancy recognition, thereby potentially predisposing infected cows to postpartum bacterial endometritis and reduced fertility

An Empirical Biomarker-based Calculator for Autosomal Recessive Polycystic Kidney Disease - The Nieto-Narayan Formula

Autosomal polycystic kidney disease (ARPKD) is associated with progressive enlargement of the kidneys fuelled by the formation and expansion of fluid-filled cysts. The disease is congenital and children that do not succumb to it during the neonatal period will, by age 10 years, more often than not, require nephrectomy+renal replacement therapy for management of both pain and renal insufficiency. Since increasing cystic index (CI; percent of kidney occupied by cysts) drives both renal expansion and organ dysfunction, management of these patients, including decisions such as elective nephrectomy and prioritization on the transplant waitlist, could clearly benefit from serial determination of CI. So also, clinical trials in ARPKD evaluating the efficacy of novel drug candidates could benefit from serial determination of CI. Although ultrasound is currently the imaging modality of choice for diagnosis of ARPKD, its utilization for assessing disease progression is highly limited. Magnetic resonance imaging or computed tomography, although more reliable for determination of CI, are expensive, time-consuming and somewhat impractical in the pediatric population. Using a well-established mammalian model of ARPKD, we undertook a big data-like analysis of minimally- or non-invasive serum and urine biomarkers of renal injury/dysfunction to derive a family of equations for estimating CI. We then applied a signal averaging protocol to distill these equations to a single empirical formula for calculation of CI. Such a formula will eventually find use in identifying and monitoring patients at high risk for progressing to end-stage renal disease and aid in the conduct of clinical trials.Comment: 3 tables and 8 figure

Transcriptome Analysis of CD4+ T Cells in Coeliac Disease Reveals Imprint of BACH2 and IFNγ Regulation

peer-reviewedData Availability: The raw sequencing reads (FASTQ files) and sequence read counts mapped to UCSC hg19 for each of the 74 transcriptomes sequenced in this study have been deposited at Gene Expression Omnibus (GEO) accession GSE69549.This project was funded by Science Foundation Ireland Grant number 09/IN.1/B2640 to RM.Genetic studies have to date identified 43 genome wide significant coeliac disease susceptibility (CD) loci comprising over 70 candidate genes. However, how altered regulation of such disease associated genes contributes to CD pathogenesis remains to be elucidated. Recently there has been considerable emphasis on characterising cell type specific and stimulus dependent genetic variants. Therefore in this study we used RNA sequencing to profile over 70 transcriptomes of CD4+ T cells, a cell type crucial for CD pathogenesis, in both stimulated and resting samples from individuals with CD and unaffected controls. We identified extensive transcriptional changes across all conditions, with the previously established CD gene IFNy the most strongly up-regulated gene (log2 fold change 4.6; Padjusted = 2.40x10-11) in CD4+ T cells from CD patients compared to controls. We show a significant correlation of differentially expressed genes with genetic studies of the disease to date (Padjusted = 0.002), and 21 CD candidate susceptibility genes are differentially expressed under one or more of the conditions used in this study. Pathway analysis revealed significant enrichment of immune related processes. Co-expression network analysis identified several modules of coordinately expressed CD genes. Two modules were particularly highly enriched for differentially expressed genes (P</iframe

PTSD and DNA Methylation in Select Immune Function Gene Promoter Regions: A Repeated Measures Case-Control Study of U.S. Military Service Members

Background: The underlying molecular mechanisms of PTSD are largely unknown. Distinct expression signatures for PTSD have been found, in particular for immune activation transcripts. DNA methylation may be significant in the pathophysiology of PTSD, since the process is intrinsically linked to gene expression. We evaluated temporal changes in DNA methylation in select promoter regions of immune system-related genes in U.S. military service members with a PTSD diagnosis, pre- and post-diagnosis, and in controls. Methods: Cases (n = 75) had a post-deployment diagnosis of PTSD in their medical record. Controls (n = 75) were randomly selected service members with no PTSD diagnosis. DNA was extracted from pre- and post-deployment sera. DNA methylation (%5-mC) was quantified at specific CpG sites in promoter regions of insulin-like growth factor 2 (IGF2), long non-coding RNA transcript H19, interleukin-8 (IL8), IL16, and IL18 via pyrosequencing. We used multivariate analysis of variance and generalized linear models to calculate adjusted means (adjusted for age, gender, and race) to make temporal comparisons of %5-mC for cases (pre- to post-deployment) versus controls (pre- to post-deployment). Results: There were significant differences in the change of %5-mC pre- to post-deployment between cases and controls for H19 (cases: +0.57%, controls: −1.97%; p = 0.04) and IL18 (cases: +1.39%, controls: −3.83%; p = 0.01). For H19 the difference was driven by a significant reduction in %5-mC among controls; for IL18 the difference was driven by both a reduction in %5-mC among controls and an increase in %5-mC among cases. Stratified analyses revealed more pronounced differences in the adjusted means of pre-post H19 and IL18 methylation differences for cases versus controls among older service members, males, service members of white race, and those with shorter deployments (6–12 months). Conclusion: In the study of deployed personnel, those who did not develop PTSD had reduced %5-mC levels of H19 and IL18 after deployment, while those who did develop PTSD had increased levels of IL18. Additionally, pre-deployment the people who later became cases had lower levels of IL18 %5-mC compared with controls. These findings are preliminary and should be investigated in larger studies

Tissue signals imprint ILC2 identity with anticipatory function.

Group 2 innate lymphoid cells (ILC2s) are distributed systemically and produce type 2 cytokines in response to a variety of stimuli, including the epithelial cytokines interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP). Transcriptional profiling of ILC2s from different tissues, however, grouped ILC2s according to their tissue of origin, even in the setting of combined IL-25-, IL-33-receptor-, and TSLP-receptor-deficiency. Single-cell profiling confirmed a tissue-organizing transcriptome and identified ILC2 subsets expressing distinct activating receptors, including the major subset of skin ILC2s, which were activated preferentially by IL-18. Tissue ILC2 subsets were unaltered in number and expression in germ-free mice, suggesting that endogenous, tissue-derived signals drive the maturation of ILC2 subsets by controlling expression of distinct patterns of activating receptors, thus anticipating tissue-specific perturbations occurring later in life