The contribution of T cell-derived cytokines and proteases to chronic inflammation in the human intestine
MetadataShow full item record
This Thesis explores aspects of disease pathogenesis in Crohn’s disease (CD) and ulcerative colitis (UC), investigates mechanisms of responsiveness to biologic treatment in inflammatory bowel disease (IBD), and describes the clinical and immunologic phenotype associated with a homozygous deletion in a disintegrin and a metalloproteinase (ADAM)17 gene. The role of interleukin (IL)-17A, IL-17E and IL-13 in human intestinal inflammation is not clear. IL-13 plays an important role in experimental colitis and in intestinal experimental fibrosis. However, contrasting observations exist on the levels and the role of IL-13 in inflamed IBD mucosa, and limited information is available on the role of IL-13 in CD intestinal fibrosis. We observed that IL-13 is not up-regulated in UC intestinal mucosa, and that it is unlikely to play a functional role in the mucosal pro-inflammatory response in the majority of patients with UC. Conversely, IL-17A is up-regulated in fibrostenosing CD intestine, and may contribute to intestinal fibrosis in CD. Our results indicate that IL-17E and IL-13 are not up-regulated in CD intestinal strictures, and are unlikely to play a role in intestinal fibrosis in CD. A considerable proportion of IBD patients do not respond to anti-tumour necrosis factor (TNF)- agents. Anti-TNF- agents exert their action in inflamed tissues, rich in matrix metalloproteinase (MMP)-3 and MMP-12, which in turn can degrade immunoglobulin (Ig)G1. We observed that MMP-3, MMP-12, and protein extracts from inflamed IBD mucosa, but not MMP-9, degrade the anti-TNF- agents infliximab, adalimumab and etanercept, however etanercept shows a higher susceptibility than infliximab and adalimumab. We also observed that a subgroup of IBD patients who did not respond to anti-TNF- agents have particularly high serum levels of MMP-3-/MMP-12-cleaved endogenous IgG and anti-hinge autoantibodies compared to IBD patients who subsequently responded to biologic therapy. 8 Finally, we observed that homozygous deletion in ADAM17 in humans is associated with a complex, neonatal-onset, multi-organ syndrome affecting mainly the skin, the intestine, and the cardiovascular system. In this condition, ADAM17 expression is down-regulated in the skin and in the duodenum, and soluble TNF- release by peripheral blood mononuclear cells (PBMCs) is substantially impaired. These results underline the heterogeneity characterising chronic intestinal inflammation, and may form the basis for subsequent studies with the aim to identify accurate serum biomarkers of disease progression and responsiveness to biologic therapy, and ultimately to develop effective strategies of patient stratification in IBD.
- Theses