scholarly journals P085 Deep profiling of the circulating immune cell landscape in inflammatory bowel disease by mass cytometry

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S177-S177
Author(s):  
V Horn ◽  
Z Borek ◽  
E Mantzivi ◽  
M Urbicht ◽  
D Boesel ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Immune Cells ◽  
Bowel Disease ◽  
Immune Cell ◽  
Intestinal Inflammation ◽  
Therapy Monitoring ◽  
Mass Cytometry ◽  
Adaptive Immune Cells ◽  
Healthy Donors ◽  
Inflammatory Bowel

Abstract Background A complex interplay of innate and adaptive immune cells maintains intestinal homeostasis. In inflammatory bowel disease (IBD), the fragile balance between regulatory and inflammatory cell subsets breaks down. The latter are recruited to the gut where they sustain intestinal inflammation and lead to tissue destruction. Due to re-circulation and gut-homing processes, the circulating immune cell compartment experiences profound changes that reflect disease activity. Meanwhile, single-cell techniques like mass cytometry have become a powerful technology to shed a light on the heterogeneity and dynamics of immune cells. As obtaining intestinal biopsies from inflamed gut is invasive and poses patients at risk, diagnostics and therapy monitoring from ‘liquid biopsies’ would be a great advance. A deeper understanding of the circulating immune cell landscape in IBD pre- and post-treatment could significantly contribute to IBD patient management by early prediction of therapy response. Methods Whole blood from 24 IBD patients—including 16 ulcerative colitis (UC) and 6 Crohn’s disease (CD) patients before treatment—and 18 age- and sex-matched healthy donors (HDs) was incubated with proteomic stabiliser and frozen. Upon thawing, cell suspensions were Palladium barcoded, stained with a 37-marker panel and acquired on a Helios mass cytometer. The generated dataset was normalised, de-barcoded and subsequently analysed. Results Using dimensionality reduction and neural-network-based algorithms, we faithfully identified different circulating immune subsets in healthy donors and IBD patients. Our preliminary analysis revealed altered myeloid cell populations, like neutrophils and macrophages, in IBD patients. In line with an activation of the innate immune system, we observed a considerable increase in the neutrophil compartment compared with healthy donors. Moreover, patterns of marker expression within different subsets showed substantial differences between healthy donors, CD and UC patients. Conclusion Here, we show a mass cytometry panel that identifies the circulating immune cell landscape and shows major differences between healthy donors, CD and UC patients.

scholarly journals CCR8 Signaling via CCL1 Regulates Responses of Intestinal IFN-γ Producing Innate Lymphoid CelIs and Protects From Experimental Colitis

2021 ◽  
Vol 11 ◽  
Author(s):  
Le Kang ◽  
Angelika Schmalzl ◽  
Tamara Leupold ◽  
Miguel Gonzalez-Acera ◽  
Raja Atreya ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Immune Cells ◽  
Bowel Disease ◽  
Immune Cell ◽  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Lymphoid Cells ◽  
Protective Function ◽  
Inflammatory Bowel ◽  
Ifn Γ

A diverse spectrum of immune cells populates the intestinal mucosa reflecting the continuous stimulation by luminal antigens. In lesions of patients with inflammatory bowel disease, an aberrant inflammatory process is characterized by a very prominent infiltrate of activated immune cells producing cytokines and chemokines. These mediators perpetuate intestinal inflammation or may contribute to mucosal protection depending on the cellular context. In order to further characterize this complex immune cell network in intestinal inflammation, we investigated the contribution of the chemokine receptor CCR8 to development of colitis using a mouse model of experimental inflammation. We found that CCR8−/− mice compared to wildtype controls developed strong weight loss accompanied by increased histological and endoscopic signs of mucosal damage. Further experiments revealed that this gut protective function of CCR8 seems to be selectively mediated by the chemotactic ligand CCL1, which was particularly produced by intestinal macrophages during colitis. Moreover, we newly identified CCR8 expression on a subgroup of intestinal innate lymphoid cells producing IFN-γ and linked a functional CCL1/CCR8 axis with their abundance in the gut. Our data therefore suggest that this pathway supports tissue-specific ILC functions important for intestinal homeostasis. Modulation of this regulatory circuit may represent a new strategy to treat inflammatory bowel disease in humans.

OP27 High-dimensional mass cytometry reveals the immune cell landscape in inflammatory bowel disease

2019 ◽  
Vol 13 (Supplement_1) ◽  
pp. S020-S020
Author(s):  
V van Unen ◽  
N Li ◽  
T Abdelaal ◽  
Y Kooy-Winkelaar ◽  
L Ouboter ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Immune Cell ◽  
High Dimensional ◽  
Mass Cytometry ◽  
Inflammatory Bowel

scholarly journals The Regulation of Intestinal Inflammation and Cancer Development by Type 2 Immune Responses

2020 ◽  
Vol 21 (24) ◽  
pp. 9772
Author(s):  
Reyes Gamez-Belmonte ◽  
Lena Erkert ◽  
Stefan Wirtz ◽  
Christoph Becker
Keyword(s):  
Colorectal Cancer ◽  
Inflammatory Bowel Disease ◽  
Immune Responses ◽  
Immune Cells ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Clinical Care ◽  
Important Barrier ◽  
Inflammatory Bowel

The gut is among the most complex organs of the human body. It has to exert several functions including food and water absorption while setting up an efficient barrier to the outside world. Dysfunction of the gut can be life-threatening. Diseases of the gastrointestinal tract such as inflammatory bowel disease, infections, or colorectal cancer, therefore, pose substantial challenges to clinical care. The intestinal epithelium plays an important role in intestinal disease development. It not only establishes an important barrier against the gut lumen but also constantly signals information about the gut lumen and its composition to immune cells in the bowel wall. Such signaling across the epithelial barrier also occurs in the other direction. Intestinal epithelial cells respond to cytokines and other mediators of immune cells in the lamina propria and shape the microbial community within the gut by producing various antimicrobial peptides. Thus, the epithelium can be considered as an interpreter between the microbiota and the mucosal immune system, safeguarding and moderating communication to the benefit of the host. Type 2 immune responses play important roles in immune-epithelial communication. They contribute to gut tissue homeostasis and protect the host against infections with helminths. However, they are also involved in pathogenic pathways in inflammatory bowel disease and colorectal cancer. The current review provides an overview of current concepts regarding type 2 immune responses in intestinal physiology and pathophysiology.

scholarly journals Adipokine-Modulated Immunological Homeostasis Shapes the Pathophysiology of Inflammatory Bowel Disease

2020 ◽  
Vol 21 (24) ◽  
pp. 9564
Author(s):  
Yi-Wen Tsai ◽  
Shin-Huei Fu ◽  
Jia-Ling Dong ◽  
Ming-Wei Chien ◽  
Yu-Wen Liu ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Gastrointestinal Tract ◽  
Immune Cells ◽  
Bowel Disease ◽  
Health Concern ◽  
Adaptive Immune ◽  
Adaptive Immune Cells ◽  
Inflammatory Bowel ◽  
Colon Diseases ◽  
Immunological Homeostasis

Inflammatory colon diseases, which are a global health concern, include a variety of gastrointestinal tract disorders, such as inflammatory bowel disease and colon cancer. The pathogenesis of these colon disorders involves immune alterations with the pronounced infiltration of innate and adaptive immune cells into the intestines and the augmented expression of mucosal pro-inflammatory cytokines stimulated by commensal microbiota. Epidemiological studies during the past half century have shown that the proportion of obese people in a population is associated with the incidence and pathogenesis of gastrointestinal tract disorders. The advancement of understanding of the immunological basis of colon disease has shown that adipocyte-derived biologically active substances (adipokines) modulate the role of innate and adaptive immune cells in the progress of intestinal inflammation. The biomedical significance in immunological homeostasis of adipokines, including adiponectin, leptin, apelin and resistin, is clear. In this review, we highlight the existing literature on the effect and contribution of adipokines to the regulation of immunological homeostasis in inflammatory colon diseases and discuss their crucial roles in disease etiology and pathogenesis, as well as the implications of these results for new therapies in these disorders.

scholarly journals Inferring intestinal mucosal immune cell associated microbiome species and microbiota-derived metabolites in inflammatory bowel disease

2020 ◽  
Author(s):  
Rajagopalan Lakshmi Narasimhan ◽  
Allison A. Throm ◽  
Jesvin Joy Koshy ◽  
Keith Metelo Raul Saldanha ◽  
Harikrishnan Chandranpillai ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
T Cells ◽  
B Cells ◽  
Immune Cells ◽  
Bowel Disease ◽  
Immune Cell ◽  
Bacterial Species ◽  
Secondary Bile Acid ◽  
New Findings ◽  
Inflammatory Bowel

AbstractInflammatory bowel disease (IBD) is a complex, chronic inflammatory disease of the gastrointestinal tract with subtypes Crohn’s disease (CD) and ulcerative colitis (UC). While evidence indicates IBD is characterized by alterations in the composition and abundance of the intestinal microbiome, the challenge remains to specify bacterial species and their metabolites associated with IBD pathogenesis. By the integration of microbiome multi-omics data and computational methods, we provide analyses and methods for the first time to identify microbiome species and their metabolites that are associated with the human intestine mucosal immune response in patients with CD and UC at a systems level. First, we identified seven gut bacterial species and seventeen metabolites that are significantly associated with Th17 cellular differentiation and immunity in patients with active CD by comparing with those obtained in inactive CD and non-IBD controls. The seven species are Ruminococcus gnavus, Escherichia coli, Lachnospiraceae bacterium, Clostridium hathewayi, Bacteroides faecis, Bacteroides vulgatus, and Akkermansia muciniphila, and a few associated metabolites include the secondary bile acid lithocholate and three short-chain fatty acids (SCFAs): propionate, butyrate, and caproate. We next systematically characterized potential mechanistic relationships between the Th17-involved metabolites and bacterial species and further performed differential abundance analysis for both microbiome species and their metabolites in CD and UC relative to non-IBD controls with their metagenomic and metabolomic data. Based on the deconvolution of immune cell compositions from host intestinal bulk RNA-seq, we investigated changes in immune cell composition and abundance in CD and UC in comparison to non-IBD controls. Finally, we further extended our species and metabolite associations with immune cells from Th17 and Th2 cells to B cells, plasma B cells, plasmablasts, CD4+ T cells, and CD8+ T cells. While a set of associations of immune cells with bacterial species and metabolites was supported by published evidence, the new findings in this work will help to furthering our understanding of immune responses and pathogenesis in IBD.

TIPE2 Promotes Tumor Initiation But Inhibits Tumor Progression in Murine Colitis-Associated Colon Cancer

2021 ◽  
Author(s):  
Zienab Etwebi ◽  
Jason R Goldsmith ◽  
Mayassa Bou-Dargham ◽  
Yuhua Tian ◽  
Ryan Hood ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Colon Cancer ◽  
Tumor Progression ◽  
Immune Cells ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Suppressor Cells ◽  
The United States ◽  
Inflammatory Bowel ◽  
Chronic Intestinal Inflammation

Abstract Background Colorectal cancer (CRC) is the third leading cause of cancer in the United States, and inflammatory bowel disease patients have an increased risk of developing CRC due to chronic intestinal inflammation with it being the cause of death in 10% to 15% of inflammatory bowel disease patients. TIPE2 (TNF-alpha-induced protein 8-like 2) is a phospholipid transporter that is highly expressed in immune cells and is an important regulator of immune cell function. Methods The azoxymethane/dextran sulfate sodium murine model of colitis-associated colon cancer (CAC) was employed in Tipe2 –/– and wild-type mice, along with colonoid studies, to determine the role of TIPE2 in CAC. Results Early on, loss of TIPE2 led to significantly less numbers of visible tumors, which was in line with its previously described role in myeloid-derived suppressor cells. However, as time went on, loss of TIPE2 promoted tumor progression, with larger tumors appearing in Tipe2 –/– mice. This was associated with increased interleukin-22/STAT3 phosphorylation signaling. Similar effects were also observed in primary colonoid cultures, together demonstrating that TIPE2 also directly regulated colonocytes in addition to immune cells. Conclusions This work demonstrates that TIPE2 has dual effects in CAC. In the colonocytes, it works as a tumor suppressor. However, in the immune system, TIPE2 may promote tumorigenesis through suppressor cells or inhibit it through IL-22 secretion. Going forward, this work suggests that targeting TIPE2 for CRC therapy requires cell- and pathway-specific approaches and serves as a cautionary tale for immunotherapy approaches in general in terms of colon cancer, as intestinal inflammation can both promote and inhibit cancer.

scholarly journals Extracellular vesicles produced by the human commensal gut bacterium Bacteroides thetaiotaomicron affect host immune pathways in a cell-type specific manner that are altered in inflammatory bowel disease

2021 ◽  
Author(s):  
Lejla Gul ◽  
Dezso Modos ◽  
Sonia Fonseca ◽  
Matthew Madgwick ◽  
John P Thomas ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Extracellular Vesicles ◽  
Immune Cells ◽  
Bowel Disease ◽  
Immune Cell ◽  
Gut Health ◽  
Cell Type ◽  
Bacteroides Thetaiotaomicron ◽  
Cell Type Specific ◽  
Inflammatory Bowel

The gastrointestinal (GI) tract is inhabited by a complex microbial community, which contributes to its homeostasis. Disrupted microbiome can cause GI-related diseases, including inflammatory bowel disease, therefore identifying host-microbe interactions is crucial for better understanding gut health. Bacterial extracellular vesicles (BEVs), released into the gut lumen, can cross the mucus layer and access underlying immune cells. To study cross-kingdom communication between BEVs and host, we focused on the influence of BEVs, generated by Bacteroides thetaiotaomicron (VPI-5482), on host immune cells. Using single-cell RNA sequencing data and host-microbe protein-protein interaction networks, we examined the potential effect of BEVs on dendritic cells, macrophages and monocytes with particular focus on the Toll-like receptor (TLR) pathway. We identified biological processes affected in each immune cell type, and also cell-type specific processes (e.g myeloid cell differentiation). The TLR pathway analysis highlighted that BEV targets differ among cells and even between the same cells in healthy versus disease (ulcerative colitis) conditions. Our in silico findings were validated in BEV-monocyte co-cultures demonstrating the requirement for TLR4 in BEV-elicited NF-κB activation. This study demonstrates that both cell-type and health condition influence BEV-host communication. The results and the pipeline can facilitate BEV-based therapy development for the treatment of IBD.

scholarly journals The Role of Phosphoinositide 3-Kinase Signaling in Intestinal Inflammation

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Catherine M. Cahill ◽  
Jack T. Rogers ◽  
W. Allan Walker
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Kinase Signaling ◽  
Phosphatidylinositol 3 Kinase ◽  
Inflammatory Conditions ◽  
Adaptive Immune Cells ◽  
Inflammatory Bowel ◽  
Phosphatidylinositol 3

The phosphatidylinositol 3-kinase signaling pathway plays a central role in regulating the host inflammatory response. The net effect can either be pro- or anti-inflammatory depending on the system and cellular context studied. This paper focuses on phosphatidylinositol 3-kinase signaling in innate and adaptive immune cells of the intestinal mucosa. The role of phosphatidylinositol 3-kinase signaling in mouse models of inflammatory bowel disease is also discussed. With the development of new isoform specific inhibitors, we are beginning to understand the specific role of this complex pathway, in particular the role of the γ isoform in intestinal inflammation. Continued research on this complex pathway will enhance our understanding of its role and provide rationale for the design of new approaches to intervention in chronic inflammatory conditions such as inflammatory bowel disease.

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