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Dendritic Cells as a Biomarker for Gut Pathology
[Thesis]. Manchester, UK: The University of Manchester; 2012.
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Abstract
Trichuris trichiura (T. Trichiura) is a large-intestinal dwelling nematode that affects over 1 billion people world-wide and thus has large global significance. Much of our understanding of T. trichiura infection comes from the study of the mouse model Trichuris muris (T. muris). However, how the immune system is initiated in response to helminth threat and how inflammation and pathology are resolved in T. muris infection still remain to be addressed. Here, I have attempted to provide insight into these questions.Previous work has shown resistance to T. muris infection is associated with the rapid recruitment of dendritic cells (DCs) to the colonic epithelium via epithelial production of CCL5 and CCL20. However, the epithelial-parasite interaction that drives chemokine production is not known. Pattern recognition receptor (PRRS) are critical mediators of pathogen recognition but there is no known (PRR) specific for T. muris. Here, we address the role of the cytosolic pattern recognition receptor Nod2, the location of which within the crypts correlates with the T. muris niche. In WT mice, in response to infection, there was a rapid influx of CD103+CD11c+ DCs into the colonic epithelium, whereas, this recruitment was impaired in Nod2 /- animals. In vitro and in vivo experiments confirmed the impairment in DC recruitment in Nod2-/- mice was attributable to the epithelial compartment. Subsequent work revealed decreased production of epithelial chemokines in the absence of functional Nod2. Thus, we have shown a novel role for Nod2 in the initiation the immune response to T. muris. We next addressed how pathology is regulated during T. muris infection. Firstly we investigated the role of arginase and Arg1-expressing macrophages in regulating pathology. My data showed that, unlike other gastrointestinal helminths, arginase and Arg1-expressing macrophages are not essential for resistance to T. muris or effective resolution of helminth-induced inflammation. I also addressed the role of DCs in the resolution of infection. DCs can regulate immune responses via the anti-inflammatory cytokine IL-10 and induction of regulatory T cells (Treg). I used an IL 10flox/floxCD11cCre transgenic model in which mice have DCs that cannot make IL-10. I found no role for CD11c+ cell mediated IL-10 production in the regulation of pathogen induced pathology in chronic T. muris infection. In summary I have been able to identify factors in the initiation of immunity to T. muris namely epithelial expression of Nod2. However, as arginase, Arg1-expressing macrophages and DC derived IL-10 appeared to play a redundant role in T. muris infection, the question as to how infection induced inflammation is resolved remains elusive.