P011 Distinct inflammatory signatures in primary sclerosing cholangitis associated with inflammatory bowel disease
A. Gwela1, P. Siddhanathi1, R. W. Chapman1, C. Arancibia1, S. P .L. Travis1, F. Powrie2, A. Geremia*1
1John Radcliffe Hospital, Department of Translational Gastroenterology, Oxford, United Kingdom, 2University of Oxford, Kennedy Institute for Rheumatology, Oxford, United Kingdom
Primary sclerosing cholangitis (PSC) is an idiopathic chronic disorder of the liver characterised by inflammation and stricturing of the intra- and extra-hepatic ducts, leading to cirrhosis. PSC is associated with inflammatory bowel disease (IBD) in 80% of patients. IBD in these patients has characteristic features, which include a usually quiescent course, with more frequent extensive and patchy colonic inflammation, backwash ileitis, and pouchitis after colectomy. Interestingly, these patients have a 4-fold increased risk of colorectal cancer compared with patients with ulcerative colitis (UC), and they are also at increased risk of hepatobiliary malignancies. Genetic studies have identified immune-related susceptibility genes that only partially overlap with those involved in IBD. All together, these observations suggest that PSC-associated IBD (PSC-IBD) may represent a pathogenetically distinct immunological disorder. In this study, we aimed to define better the immunological pathways involved in intestinal and systemic inflammation in these patients.
We collected blood samples and biopsies from patients with PSC-IBD, UC, and healthy subjects from the John Radcliffe Hospital in Oxford. Mucosal mRNA gene expression was assessed by qPCR. The systemic and intestinal cellular immune response was analysed by cell-surface and intra-cellular multicolour flow cytometry.
Patients with PSC-IBD and UC included in the study had mild to low inflammation at colonoscopy and similar CRP levels. We observed increased gene expression of Th1- and cancer-related genes, such as beta-catenin, in the colonic mucosa of PSC-IBD patients. Increased frequency of systemic and intestinal IFN-γ secreting T-cells was found in patients with PSC-IBD compared with UC patients and healthy controls. Differences were also observed in the T-cell chemokine expression profiles in the periphery. Interestingly, we found accumulation of innate lymphoid cells (ILC) in the colon of patients with PSC-IBD, associated with a reduction in the blood, suggesting intestinal recruitment of ILC to the gut.
Our data suggest that PSC-IBD represent a distinct immunological disorder from UC. Increased Th1 and ILC responses are observed in these patients and may contribute to inflammation and increased cancer risk.