Integrated Biology of the GI Tract
Gut Immunity
Primary Objectives
- How do intestinal epithelial cells interact with gut microbes, what is the outcome of these interactions, and can intestinal epithelial cells discriminate between different species of bacteria?
- How do intestinal epithelial cells and gut immune cells interact to promote host defences against invading organisms?
- What is the role of intestinal epithelial cells and immune cells in sampling and responding to gut antigens and are they different in disease-prone individuals?
- Which cells in the intestinal mucosa respond to food antigens and are responsible for triggering food allergies?
This research focuses on understanding the cellular and molecular basis of the host response to antigenic challenge. One hypothesis to be tested is that intestinal barrier function is the sum of interactions between the epithelium and local immune cells and that in response to enteric antigens, epithelial cells promote the development of appropriate host responses to harmless versus harmful antigens.
Molecular basis of interactions between intestinal colonic epithelial cells and the microbiota. Simon Carding
We have established a role for commensal bacteria in triggering the inflammatory process resulting in colitis which raised several questions. Important amongst these is what role does the intestinal epithelium play in responding to members of the microbiota and does it have the ability to distinguish between different species of bacteria? Addressing these questions is the focus of our research.
Role for NOD2 in regulating tissue renewal, barrier function and innate immune responses of the native human colonic epithelium. Joint UEA-IFR Project. Dr. Mark Williams (UEA); Simon Carding
By mediating communication between the immune system and the gut microbiota, the intestinal epithelium plays a pivotal role in regulating innate immunity and the development of tolerance. Maintenance of epithelial barrier function and tissue regeneration following injury underpins this vital role. A growing body of evidence supports the notion that perturbation of the mechanisms by which the epithelium detects the presence of bacterial structures leads to the disruption of barrier function and tissue regeneration, and is associated with the onset of IBD.
Establish the influence that epithelia-associated immune cells have on anti-microbial defences and antimicrobial protein (AMP) production. Simon Carding
We have been investigating epithelial-immune cell interactions in intestinal barrier function and in particular the role that γδ intestinal intraepithelial lymphocytes (iIELs) play in protecting against enteric pathogen invasion. From the profiling of genes expressed in the intestinal mucosa of Toxoplasma gondii-infected wild type and γδ iIEL-deficient mice, expression of the gene encoding a newly described AMP, Angiogenin 4 (Ang4) was found to be dramatically under-represented (>30-fold less compared to wild type levels) in epithelial cells of gd iIEL-deficient mice. How Ang4 production is regulated and the influence of γδ iiELs on its production is the focus of our research.
Establish the role of intestinal epithelial cells and mucosal immune cells in sampling and responding to enteric antigens. Claudio Nicoletti , Simon Carding, Anastasia Sobolewski
Our interests are in how antigens are taken up in the small and large intestine, respectively, and presented to the immune system as self or non-self, resulting in tolerance or inflammatory responses. The research here aims to investigate in more detail the pathways of antigen uptake in different regions of the intestine.
The gut is exposed to multiple foreign antigens but is rarely invoked into damaging inflammatory responses. The anatomical location in which intestinal antigens are captured and the phenotype of the capturing cell are likely to have important implications for the nature of any immune response that develops. The particular characteristics of soluble, particulate and pathogen-borne antigens will profoundly affect their fate but this will also be strongly influenced by the way they initially interact with the immune system. An objective of this study is to determine the contribution that epithelial cells (IEC) and dendritic cells (DC) make to antigen uptake in both the small and large intestine and to test the hypothesis that IECs play a central role in maintaining immune cell homeostasis by constraining T cell responses to self antigens and by initiating DC responses to non-self, pathogen-encoded antigens. Inappropriate or defective regulation of DC function could contribute to an inability to maintain or a breakdown in oral tolerance and the development of the chronic inflammation that is a hallmark of various intestinal disorders including Irritable Bowl Disease.
Immune epithelial cell cross talk in food allergy . Claudio Nicoletti
IEC-DC collaborations can shape ensuing immune responses, and a recent study has proposed that the inability of IEC to determine appropriate effector function of DCs is involved in the genesis of intestinal pathologies. Based on these findings we are proposing that IECs are of central importance in generating appropriate DC responses in the intestinal mucosa and that in allergic individuals inappropriate IEC activity is responsible for the generation of "allergic" DCs.
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