scholarly journals IFITM1 is differentially expressed in the blood of patients with Crohn’s Disease.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Regulatory T Cells ◽  
Whole Blood ◽  
Differentially Expressed Gene ◽  
Differentially Expressed ◽  
Interferon Signaling ◽  
Oligoadenylate Synthetase

The interferon pathway (1) is an innate immune signaling system that evolved to protect multicellular organisms from viral infections (2). The expression of multiple gene families is expressed following activation of interferon signaling (1); one of these is the antiviral interferon inducible transmembrane proteins, or IFITM gene family (3). Using publicly available datasets (4, 5), we identified the interferon induced transmembrane protein 1, IFITM1 (6-10), as a differentially expressed gene in the whole blood and CD4+ CD25+ regulatory T-cells of patients with Crohn’s Disease. IFITM1 was expressed at significantly higher levels in the whole blood and Treg of patients with Crohn's Disease than in non-affected control subjects. We previously reported that changes in gene expression of the double stranded ribonucleic acid sensor, 2’-5’-oligoadenylate synthetase, OAS2, were among the most significant quantitive differences in the gene expression of monocyte-derived macrophage and regulatory T-cells from patients with Crohn’s Disease when compared to those not affected. Together, these data suggest that a primary defect in the coordination of the host response to viral infection in the hematopoietic compartment, through nucleic acid sensing and subsequent interferon signaling may be fundamentally linked with the pathogenesis of Crohn’s Disease.

scholarly journals OP0021 IDENTIFICATION OF DIFFERENTIALLY EXPRESSED GENES IN EARLY RHEUMATOID ARTHRITIS PATIENTS RESPONDING TO TOCILIZUMAB

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 12.2-12
Author(s):  
I. Muller ◽  
M. Verhoeven ◽  
H. Gosselt ◽  
M. Lin ◽  
T. De Jong ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
T Cells ◽  
Gene Ontology ◽  
Regulatory T Cells ◽  
Early Rheumatoid Arthritis ◽  
Whole Blood ◽  
Differentially Expressed ◽  
Rna Seq ◽  
Double Blind

Background:Tocilizumab (TCZ) is a monoclonal antibody that binds to the interleukin 6 receptor (IL-6R), inhibiting IL-6R signal transduction to downstream inflammatory mediators. TCZ has shown to be effective as monotherapy in early rheumatoid arthritis (RA) patients (1). However, approximately one third of patients inadequately respond to therapy and the biological mechanisms underlying lack of efficacy for TCZ remain elusive (1). Here we report gene expression differences, in both whole blood and peripheral blood mononuclear cells (PBMC) RNA samples between early RA patients, categorized by clinical TCZ response (reaching DAS28 < 3.2 at 6 months). These findings could lead to identification of predictive biomarkers for TCZ response and improve RA treatment strategies.Objectives:To identify potential baseline gene expression markers for TCZ response in early RA patients using an RNA-sequencing approach.Methods:Two cohorts of RA patients were included and blood was collected at baseline, before initiating TCZ treatment (8 mg/kg every 4 weeks, intravenously). DAS28-ESR scores were calculated at baseline and clinical response to TCZ was defined as DAS28 < 3.2 at 6 months of treatment. In the first cohort (n=21 patients, previously treated with DMARDs), RNA-sequencing (RNA-seq) was performed on baseline whole blood PAXgene RNA (Illumina TruSeq mRNA Stranded) and differential gene expression (DGE) profiles were measured between responders (n=14) and non-responders (n=7). For external replication, in a second cohort (n=95 therapy-naïve patients receiving TCZ monotherapy), RNA-seq was conducted on baseline PBMC RNA (SMARTer Stranded Total RNA-Seq Kit, Takara Bio) from the 2-year, multicenter, double-blind, placebo-controlled, randomized U-Act-Early trial (ClinicalTrials.gov identifier: NCT01034137) and DGE was analyzed between 84 responders and 11 non-responders.Results:Whole blood DGE analysis showed two significantly higher expressed genes in TCZ non-responders (False Discovery Rate, FDR < 0.05): urotensin 2 (UTS2) and caveolin-1 (CAV1). Subsequent analysis of U-Act-Early PBMC DGE showed nine differentially expressed genes (FDR < 0.05) of which expression in clinical TCZ non-responders was significantly higher for eight genes (MTCOP12, ZNF774, UTS2, SLC4A1, FECH, IFIT1B, AHSP, and SPTB) and significantly lower for one gene (TND2P28M). Both analyses were corrected for baseline DAS28-ESR, age and gender. Expression of UTS2, with a proposed function in regulatory T-cells (2), was significantly higher in TCZ non-responders in both cohorts. Furthermore, gene ontology enrichment analysis revealed no distinct gene ontology or IL-6 related pathway(s) that were significantly different between TCZ-responders and non-responders.Conclusion:Several genes are differentially expressed at baseline between responders and non-responders to TCZ therapy at 6 months. Most notably, UTS2 expression is significantly higher in TCZ non-responders in both whole blood as well as PBMC cohorts. UTS2 could be a promising target for further analyses as a potential predictive biomarker for TCZ response in RA patients in combination with clinical parameters (3).References:[1]Bijlsma JWJ, Welsing PMJ, Woodworth TG, et al. Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial. Lancet. 2016;388(10042):343-55.[2]Bhairavabhotla R, Kim YC, Glass DD, et al. Transcriptome profiling of human FoxP3+ regulatory T cells. Human Immunology. 2016;77(2):201-13.[3]Gosselt HR, Verhoeven MMA, Bulatovic-Calasan M, et al. Complex machine-learning algorithms and multivariable logistic regression on par in the prediction of insufficient clinical response to methotrexate in rheumatoid arthritis. Journal of Personalized Medicine. 2021;11(1).Disclosure of Interests:None declared

scholarly journals 2′-5′-oligoadenylate synthetase 2 (OAS2) is differentially expressed in the blood of patients with Crohn’s disease.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Gene Expression ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Treatment Options ◽  
Gastrointestinal Disorder ◽  
The United States ◽  
Differentially Expressed ◽  
Inflammatory Disorder ◽  
Oligoadenylate Synthetase ◽  
Public Datasets

Crohn’s disease, a complex genetic inflammatory disorder of the gastrointestinal tract (1), has a prevalence of 214 per 100,000 in the United States (2), one of the highest in the world. Understanding of the interaction between genetic susceptibility loci (1) and triggers from the environment (3, 4) is growing but there are still no curative treatments for patients with Crohn’s disease (CD); some patients will fail even the most advanced treatment options (5). Though CD is considered a gastrointestinal disorder, hematologic disturbances are found in patients with Crohn’s disease and anemia is the most common extra-intestinal manifestation of Crohn’s disease (6). To understand the most significant gene expression changes in the hematologic system of patients with Crohn’s disease, we mined published and public datasets (7, 8) containing transcriptome data from the monocyte-derived macrophage (MDM) and multiplexed gene expression data from the regulatory T-cells (Treg) of patients with Crohn’s disease. We found that interferon-inducible nucleic acid sensor 2′-5′-oligoadenylate synthetase 2 (OAS2) (9) was among the most differentially expressed genes in both MDM and Treg from patients with Crohn’s disease. OAS2 expression was significantly lower in MDM and Treg from patients with Crohn’s disease compared to healthy controls. These data reveal compromised expression of an antiviral dsRNA sensor in the blood of patients with Crohn’s disease.

scholarly journals ZBTB6 is hyper-methylated and differentially expressed in the blood of patients with Crohn’s disease.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Gene Expression ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
The United States ◽  
Differentially Expressed ◽  
Economic Productivity ◽  
Unbiased Manner ◽  
Inflammatory Bowel ◽  
Disease Analysis ◽  
Broad Complex

Crohn’s disease, an inflammatory bowel disease of the gastrointestinal tract (1), causes significant morbidity and nearly 3.5 billion dollars in lost economic productivity in the United States (2) due to complications of the disease. We mined transcriptome and methylome datasets (3, 4) to understand, in an unbiased manner, the most significant changes in gene expression and DNA methylation in the hematopoietic system of patients with Crohn’s disease (CD). We identified the zinc finger and BTB (broad complex, tramtrack, bric-à-brac) domain-containing gene ZBTB6 (5, 6) as one of the most differentially expressed genes in the whole blood of patients with Crohn’s disease. Analysis of a separate data revealed that the ZBTB6 locus was one of the most differentially methylated sites globally in the blood of patients with Crohn’s disease when compared to the blood of healthy patients. ZBTB6 is differentially methylated and differentially expressed in the blood of patients with Crohn’s disease, and more significantly so than the vast majority of the human genome. These data point to inhibition of ZBTB6 gene expression by hyper-methylation of the ZBTB6 locus and suggest that titration of some function or transcriptional target of ZBTB6 may be an important event in the pathogenesis of Crohn’s disease.

scholarly journals Regulatory T-cell therapy in Crohn’s disease: challenges and advances

Gut ◽  
2020 ◽  
Vol 69 (5) ◽  
pp. 942-952 ◽  
Author(s):  
Jennie N Clough ◽  
Omer S Omer ◽  
Scott Tasker ◽  
Graham M Lord ◽  
Peter M Irving
Keyword(s):  
T Cells ◽  
Crohn’S Disease ◽  
T Cell ◽  
Crohn's Disease ◽  
Regulatory T Cells ◽  
Cell Therapy ◽  
Regulatory T Cell ◽  
Critical Role ◽  
Significant Proportion ◽  
T Cell Therapy

The prevalence of IBD is rising in the Western world. Despite an increasing repertoire of therapeutic targets, a significant proportion of patients suffer chronic morbidity. Studies in mice and humans have highlighted the critical role of regulatory T cells in immune homeostasis, with defects in number and suppressive function of regulatory T cells seen in patients with Crohn’s disease. We review the function of regulatory T cells and the pathways by which they exert immune tolerance in the intestinal mucosa. We explore the principles and challenges of manufacturing a cell therapy, and discuss clinical trial evidence to date for their safety and efficacy in human disease, with particular focus on the development of a regulatory T-cell therapy for Crohn’s disease.

scholarly journals DOP22 Integrative -omic analysis reveals microbiota mediated molecular mechanisms influencing host mucosal gene expression in Crohn’s Disease

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S061-S062
Author(s):  
P Sudhakar ◽  
T Andrighetti ◽  
S Verstockt ◽  
C Caenepeel ◽  
M Ferrante ◽  
...  
Keyword(s):  
Gene Expression ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Molecular Mechanisms ◽  
Bacterial Species ◽  
Differentially Expressed ◽  
Mucosal Barrier ◽  
Bacterial Proteins ◽  
The Impact ◽  
Hub Proteins

Abstract Background Mechanistic evidence linking gut microbial changes and host mucosal barrier responses in patients with Crohn’s disease (CD) is lacking. In this study, we used a computational approach to integrate gut microbial and intestinal gene expression in CD patients. Methods Bacterial species, bacterial genes/transcripts with enhanced abundances/transcriptional activity in CD (t-statistic of &gt; 2 and Q-value &lt; 0.05), as well as mucosal (ileum/rectum) differentially expressed genes (DEGs) between CD (n =43) and non-IBD (n=22) subjects were retrieved from the Inflammatory Bowel Disease Meta -Omics Database (IBDMDB). The impact of bacterial proteins on host gene expression was inferred using MicrobioLink, a computational tool for inferring microbe-host interactions. Drug target information was retrieved from OpenTargets. Paired 16S read-outs from stool samples and gene expression data from ileal biopsies in CD patients (n=20) and non-IBD controls (n=15), cross-sectionally collected at our IBD referral center, were used for independent validation. Results Across the 8 identified bacterial species enriched in CD, 3.7% (n= 743) of the orthologous groups were identified as being able to bind to human proteins. Network diffusion analysis uncovered bacterial proteins which could cumulatively modulate the expression of 42% of the genes differentially expressed in the ileum of CD patients. Topological and pathway analysis of the inferred signaling network modulated by the microbiota revealed several key hub proteins and immune-related pathways associated with IL-4, IL-2 and IL-13 signaling, receptor tyrosine-kinases, NFkB, and toll-like receptors including TLR4. Seventy-eight percent of the DEGs in our discovery cohort were also differentially expressed in the validation cohort (R2 = 0.907). Bacterial proteins post-translationally modifying host receptors resulted in the up-regulation of several pro-inflammatory cytokines via critical hub proteins such as NFkB (Figure 1). We observed different levels of locational specificity (from 35 to 61%) for the top regulators such as SPI1, STAT1 and NFKB1in terms of genes regulated by them in ileum and rectum. 24 proteins including ITGA4 and JAK1 from the ileal and rectal signaling networks are existing targets of CD drugs such as vedolizumab and tofacitinib, filgotinib and upadacitinib respectively. Conclusion Our findings outline the potential mechanisms of microbiome-induced host responses and provide insights into designing microbiome-mediated therapies to prevent and/or treat CD.

Characterization of FOXP3+CD4+ regulatory T cells in Crohn's disease

2007 ◽  
Vol 125 (3) ◽  
pp. 281-290 ◽  
Author(s):  
Masayuki Saruta ◽  
Qi T. Yu ◽  
Phillip R. Fleshner ◽  
Pierre-Yves Mantel ◽  
Carsten B. Schmidt-Weber ◽  
...  
Keyword(s):  
T Cells ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Regulatory T Cells
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