scholarly journals P014 Identification of Crohn’s disease immunopathotypes

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S137-S137
Author(s):  
H M Baer ◽  
E MacDonald ◽  
A Ferguson ◽  
A M Scott ◽  
M I Khan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Immune Responses ◽  
Mononuclear Cells ◽  
Local Immune Response ◽  
Cross Sectional ◽  
Treatment Responses ◽  
Colonic Biopsies

Abstract Background Crohn’s disease (CD) is a chronic inflammatory gastrointestinal condition, with globally increasing incidence. Patients with CD suffer from a loss of tolerance towards their commensal microbiota causing an aberrant immune response, occurring in a protracted relapse and remission cycle. Although a variety of frontline therapies is currently available, including targeted therapies such as biologic drugs, 30–40% of CD patients still require surgery to manage the disease. At present, the immunobiology of CD is not fully understood. However, differences in immune responses between patients might play an important role in diverse treatment responses. The aim of this study was to identify differences in peripheral and local immune responses of CD to understand differences in disease behaviour and treatment outcome. Methods Peripheral blood mononuclear cells and plasma were isolated from whole blood of a cross-sectional CD patient cohort (nCD = 12) and normal controls (NC, nNC = 28). Flow cytometry analysis and multiplex assays were used to quantify immune cell populations and cytokine levels, respectively. The local immune response was analysed by bulk RNA sequencing of mucosal colonic biopsies either from inflamed CD or normal tissue. Gene signatures were then followed up by validation in publicly deposited gene expression datasets (nCD = 36, nNC = 24), and by measurement of specific proteins using our archived samples. Results Peripheral immunophenotyping of the initial cross-sectional study displayed three different types of CD patients, characterised by either a decrease in leukocyte populations, an increase of cytokines, or a change in both. Analysis of the RNAseq data derived from colonic biopsies revealed four distinct clusters in genes associated with the immune response in CD patients. Further pathway analysis showed one cluster with an enriched B cell signature and another cluster with an elevated macrophage and neutrophil response. We utilised publicly available gene expression datasets to validate these signatures in a larger cohort and identified a selection of patients with an up-regulated pro-inflammatory macrophage response. Using correlation analysis, we suggest an immunopathotype with increased macrophage activation which is potentially associated with a more severe form of the disease. Conclusion We have identified distinct immunopathotypes in both the peripheral and local immune response of CD patients. Further investigation will correlate these distinct immune responses in CD with clinical parameters, to understand associations between diverse treatment responses and disease behaviours.

scholarly journals Endoscopic and Histopathological Findings of the Esophagus, Stomach, and Duodenum in Patients with Crohn’s Disease from a Reference Center in Bahia, Brazil

2021 ◽  
Vol 11 (2) ◽  
pp. 374-385
Author(s):  
Andrea Maia Pimentel ◽  
Luiz Antônio Rodrigues de Freitas ◽  
Rita de Cássia Reis Cruz ◽  
Isaac Neri de Novais Silva ◽  
Laíla Damasceno Andrade ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Mononuclear Cells ◽  
Erosive Esophagitis ◽  
Gastric Body ◽  
Polymorphonuclear Cells ◽  
Cross Sectional ◽  
Histopathological Findings ◽  
Focally Enhanced Gastritis ◽  
H Pylori

(1) The aim of the present study was to describe the endoscopic and histopathological findings in the esophagus, stomach, and duodenum in patients with Crohn’s disease. (2) Methods: This was a cross-sectional study that included patients receiving treatment from the inflammatory bowel disease outpatient clinic. Esophagogastroduodenoscopies with biopsies of the stomach and proximal duodenum were performed. Presence of Helicobacter pylori bacteria was assessed by Giemsa staining. (3) Results: We included 58 patients. Erosive esophagitis was identified in 25 patients (43.1%), gastritis was diagnosed in 32 patients (55.2%) and erosive duodenitis was found in eight (13.8%). The most frequent histopathological finding in the H. pylori-positive group was increased inflammatory activity in the gastric body and antrum, with a predominance of mononuclear and polymorphonuclear cells. In turn, the most frequent finding in the H. pylori-negative group was chronic inflammation with predominance of mononuclear cells. Focally enhanced gastritis was identified in four patients (6.9%), all of whom were negative for H. pylori. Granulomas were not observed. H. pylori infection was present in 19 patients (32.8%). (4) Conclusions: Nonspecific endoscopic and histological findings were frequent in patients with Crohn’s disease. Focally enhanced gastritis was uncommon and observed only in H. pylori-negative patients. The time from the diagnosis, patient age, and therapy in use may have influenced the nondetection of epithelioid granuloma.

scholarly journals The gene encoding the Wiskott-Aldrich syndrome (WAS) protein is transcriptionally repressed following stimulation of peripheral blood mononuclear cells with muramyl dipeptide.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Gene Expression ◽  
Pattern Recognition ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Mononuclear Cells ◽  
Muramyl Dipeptide ◽  
Gene Encoding ◽  
Peripheral Blood Mononuclear ◽  
Wiskott Aldrich Syndrome ◽  
Blood Mononuclear Cells

The nucleotide-binding oligomerization domain protein 2, NOD2, is the pattern recognition receptor for muramyl dipeptide, a component of the cell wall of both gram-positive and gram-negative bacteria (1, 2). Sensing of muramyl dipeptide by NOD2 triggers signal transduction downstream of the RIP2 kinase to transcriptionally activate a diverse innate immune gene expression program (3-5). Single nucleotide variants in NOD2 are the strongest genetic risk factors for developing Crohn’s Disease (6, 7), an inflammatory bowel disease (8). By mining a published dataset (9), we found that among the genes whose expression changed most significantly in peripheral blood mononuclear cells (PBMC) stimulated with muramyl dipeptide, genome-wide, was the gene encoding the Wiskott-Aldrich syndrome (WAS) protein (10), a regulator of actin polymerization in hematopoietic cells (11). The WAS gene is mutated in patients with Wiskott-Aldrich syndrome (12), a genetic disorder characterized by thrombocytopenia, eczema, immunodeficiency and lymphoid malignancies (13), and whose symptoms include bloody diarrhea (14, 15). WAS RNA message was transcriptionally repressed following exposure of PBMC to muramyl dipeptide. These data link together a gene, that when mutated in humans leads to gastrointestinal symptoms not dissimilar to those found in patients with Crohn’s Disease, with the ligand for the gene whose product encodes the single most significant genetic variant conferring risk for development of Crohn’s Disease, and further suggest that the actin cytoskeleton may be a central target of gene expression changes effected by NOD2 pattern recognition of MDP.

scholarly journals Impaired Toll-Like Receptor 3-Mediated Immune Responses from Macrophages of Patients Chronically Infected with Hepatitis C Virus

2012 ◽  
Vol 20 (2) ◽  
pp. 146-155 ◽  
Author(s):  
Feng Qian ◽  
Christopher R. Bolen ◽  
Chunxia Jing ◽  
Xiaomei Wang ◽  
Wei Zheng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Immune Responses ◽  
Mononuclear Cells ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
The United States ◽  
Toll Like Receptor

ABSTRACTHepatitis C virus (HCV) is the most common chronic blood-borne infection in the United States, with the majority of patients becoming chronically infected and a subset (20%) progressing to cirrhosis and hepatocellular carcinoma. Individual variations in immune responses may help define successful resistance to infection with HCV. We have compared the immune response in primary macrophages from patients who have spontaneously cleared HCV (viral load negative [VL−],n= 37) to that of primary macrophages from HCV genotype 1 chronically infected (VL+) subjects (n= 32) and found that macrophages from VL− subjects have an elevated baseline expression of Toll-like receptor 3 (TLR3). Macrophages from HCV patients were stimulatedex vivothrough the TLR3 pathway and assessed using gene expression arrays and pathway analysis. We found elevated TLR3 response genes and pathway activity from VL− subjects. Furthermore, macrophages from VL− subjects showed higher production of beta interferon (IFN-β) and related IFN response genes by quantitative PCR (Q-PCR) and increased phosphorylation of STAT-1 by immunoblotting. Analysis of polymorphisms in TLR3 revealed a significant association of intronic TLR3 polymorphism (rs13126816) with the clearance of HCV and the expression of TLR3. Of note, peripheral blood mononuclear cells (PBMCs) from the same donors showed opposite changes in gene expression, suggesting ongoing inflammatory responses in PBMCs from VL+ HCV patients. Our results suggest that an elevated innate immune response enhances HCV clearance mechanisms and may offer a potential therapeutic approach to increase viral clearance.

Elevated flagellin-specific immunoglobulins in Crohn's disease

2005 ◽  
Vol 288 (2) ◽  
pp. G403-G406 ◽  
Author(s):  
Shanthi V. Sitaraman ◽  
Jan-Michael Klapproth ◽  
Daniel A. Moore ◽  
Carol Landers ◽  
Stephan Targan ◽  
...  
Keyword(s):  
Immune Response ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Immune Responses ◽  
Acute Inflammation ◽  
Adaptive Immune Response ◽  
Toll Like Receptor ◽  
Adaptive Immune ◽  
Specific Antigens ◽  
Toll Like Receptor 5

Crohn's disease (CD) is driven by seemingly aberrant immune responses directed toward commensal enteric microflora. However, the specific antigens targeted by this immune response remain largely undefined. Herein, we demonstrate that common enteric flagellins are one such target of the CD-associated immune response. Thus flagellin may not only drive acute inflammation via activation of Toll-like receptor 5-mediated gene expression but may also serve as a target of the adaptive immune response that maintains the chronic inflammation characteristic of CD.

scholarly journals Effect of Anti-TNF Therapy on Mucosal Apoptosis Genes Expression in Crohn's Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Liliana Lykowska-Szuber ◽  
Michal Walczak ◽  
Marzena Skrzypczak-Zielinska ◽  
Joanna Suszynska-Zajczyk ◽  
Kamila Stawczyk-Eder ◽  
...  
Keyword(s):  
Gene Expression ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Mononuclear Cells ◽  
Mrna Level ◽  
Colon Tissue ◽  
Peripheral Blood Mononuclear ◽  
Effective Response ◽  
Genes Expression

Crohn's disease (CD) is a chronic immune-mediated disorder for which there is not a fully effective treatment. Moreover, biological therapy with anti-tumor necrosis factor-α (anti-TNF-α) monoclonal antibodies leads to an effective response in only 60–70% of patients. Our previous data suggested that specific loci polymorphism of the TNFRSF1B, FCGR3A, IL1R, IL1B, and FAS genes could be a predictor of the primary non-response to anti-TNF therapy in CD patients. In this work, we propose to explain this hypothesis by functional analysis in colon biopsies and in a cell culture model. Using the RT-qPCR analysis, we estimated the FCGR3A, IL1R, TNFRSF1B, IL1B, FAS, and ADAM17 genes mRNA level in colon biopsies material from inflamed and non-inflamed tissue from 21 CD patients (14 responders and 7 non-responders to anti-TNF therapy) and 6 controls, as well as in vitro in a peripheral blood mononuclear cells (PBMCs) from 14 CD patients (seven responders and seven non-responders to anti-TNF therapy) and eight controls cultured for 72 h with 10 μg/ml of anti-TNF antibody. Our findings demonstrated a significant down-regulation of TNFRSF1B gene expression in non-responders both in inflamed and in non-inflamed colon tissue, while the expression of the FCGR3A and IL1B genes was significantly up-regulated in non-responders in the inflamed colon region. In vitro research results indicate that the anti-TNF drug induced a significant decrease in TNFRSF1B, FCGR3A, and FAS gene expression in non-responders. These results show that altered TNFRSF1B, FCGR3A, and IL1B genes expression can be a predictor of the primary non-response to anti-TNF therapy in CD patients.

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