Inflammatory bowel diseases (IBD) Crohn's Disease (CD) and Ulcerative Colitis (UC) are associated with substantialhealth burden in the United States. It is also knownthat IBD patients have elevated mucosal immune responses to theenteric microflora. Active flares of IBD are associated with, and thought to be mediated by, innate immunity,specifically neutrophil infiltration to the intestinalmucosa. Conversely, the chronicphase of IBD is associated with, andmaintained by, the increased mucosal presence of adaptive immune cells with a particularly important role for CD4+ T-cells. Several recent observations indicate that one underlying cause of such IBD-associated immune responses may bemutations in genes that mediate innate immunity. However, it is unclear whether the primary consequence of suchmutations is loss or gain of innate immune function. Bacterial protein flagellin, the monomeric subunit of flagella, is adominant innate immune activator of intestinal epithelial cells. My CCFA Research Fellowship sought to define therole of innate immunity to flagellin in murine models of gut inflammation. We hypothesized that mice lacking theflagellin receptor, toll-like receptor 5 (TLR5), might be protected from developing chronic inflammation. In contrast,we observed, that mice engineered to lack TLR5 develop spontaneous colitis. We hypothesize that TLR5KO colitisresults from an inability to control the commensal microflora,which results in activation of TLR4 and other innateimmune signaling pathways. However, our most recent observations suggest that such alterations are not sufficient todrive robust colitis in TLR5KO mice. Rather, we have preliminarily observed that TLR5KO colitis is associated with,and requires, alterations in adaptive immunity. We hypothesize that loss of TLR5 on gut epithelial cells results inlymphocytes acquiring a colitiogenic profile, which amplifies and sustains the inflammation triggered by activation ofinnate immunity. Alternatively, in light of the ambiguityregarding the role of TLR5 on antigen-presenting cells (APC)and increasing appreciation that TLRs can be expressed on T-cells, we will also consider the possibility that loss ofTLR5 on APC and/or T-cells results in a dysregulated adaptive immune response. We propose to investigate thesehypotheses by examining the alterations in adaptive immunity in TLR5K.Omice and defining which of these alterationsare necessary and/or sufficient to drive colitis. In addition to advancing the understanding of innate-immuneinteractions in the gut, an area germane to the pathogenesis of IBD, the immunology, I will learn from executing theseaims should greatly aid my long term potential as an IBD researcher.
This study proposed should delineate importance of adaptive immunity in innate immune deficient mousecolitis model. It will shed light on the crosstalk between innate and adaptive immunity that ultimatelyculminates in spontaneous colitis.
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