PWE-046 TH17 cells dominate the colonic mucosal immune response in primary sclerosing cholangitis associated colitis

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Abstract

Introduction

Primary sclerosing cholangitis (PSC) is an idiopathic chronic cholestatic liver disease associated with ulcerative colitis (UC). PSC is thought to be a consequence of a genetically predisposition, dysregulated immune response and unknown factors including the gut microbiome. The colonic mucosal immune response in PSC associated colitis (PSC-UC), however, has been poorly defined. In this study, we analysed the characteristics of colonic mucosal CD4 T cells in patients with PSC-UC.

Methods

Colon biopsies were collected from patients with PSC-UC (n=13), UC (n=10) and controls (n=20). One patient with PSC-UC and one patient with UC was on biologics. Three patients with PSC and three with UC had colonic inflammation. Lamina propria mononuclear cells were analysed by flow cytometry.

Results

PSC-UC and UC were characterised by a significantly higher frequency of colonic mucosal CCR6 +CD161+Th17 cells compared to controls (17.5% vs 11.1%; p=0.009% and 21.02% vs 11.1%; p=0.01 respectively). CCR6-CXCR3+CCR5+Th1 cells were significantly lower in PSC-UC compared to controls (15.46% vs 24.50% respectively; p 0.01). CD127-CD25+FoxP3+T regulatory cell frequencies was elevated and CCR6-CCR5-CXCR3- Th2 frequencies were reduced only in UC compared to controls (7.6% vs 4.38%; p=0.007% and 14.84% vs 8.77%; p=0.02 respectively). Significantly increased frequencies of IL17 producing CD4 cells were observed in both PSC-UC and UC compared to controls (7.75% vs 4.7%; p<0.001% and 7.251% vs 4.70%; p=0.006 respectively). Although there were no differences in TNFα and IFNγ producing CD4 cells, patients with PSC-UC had a significantly higher frequency of IL17/IFNγ dual producing CD4 cells compared to controls (2.79% vs 1.76% respectively; p=0.03). Correlation analysis of PSC-UC and controls demonstrated that Th17 frequencies positively correlated with increasing frequencies of IL17 producing cells and negatively with Th1 (p<0.05).

Conclusions

Our study demonstrates for the first time that the colonic mucosal immune response in PSC-UC is characterised by significantly higher Th17 cells and lower Th1 cells compared to controls. Patients with PSC-UC have higher IL-17 and IL17/IFNγ dual producing CD4 cells. Our findings highlight the need to explore the role of key players such as the gut microbiome in mucosal T cell homeostasis and Th1/Th17 plasticity in PSC.

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