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P298. Dysregulation of the innate immune signalling in ulcerative colitis

A.C. Chew1, M.K. Tulic2, D. Mallon3, G.L. Radford-Smith4, S.L. Prescott2, I.C. Lawrance1

1University of Western Australia, Centre for Inflammatory Bowel Diseases, School of Medicine and Pharmacology, Fremantle, Australia; 2University of Western Australia, School of Paediatrics and Child Health, Perth, Australia; 3Fremantle Hospital, Department of Immunology, Fremantle, Australia; 4Royal Brisbane and Woman's Hospital, Brisbane, Australia

Background: Ulcerative colitis (UC) is a chronic inflammatory condition thought to result from inappropriate activation of the innate immune system. Dysregulation of intestinal mucosal immunity results in overproduction of inflammatory cytokines and trafficking of effector leukocytes into the bowel leading to inflammation. Toll-like receptors (TLRs) are key regulators of immune tolerance and promote tumour necrosis factor alpha (TNFα), and other inflammatory cytokines. The aim was to better understand the pathophysiology of UC, by investigating differences between UC patients who remitted and those who did not respond to anti-TNFα therapy.

Methods: Peripheral Blood Mononuclear Cells (PBMCs) were isolated from 10 controls (C), 10 UC responders (R) and 10 UC non-responders (NR) and the cell subtypes characterised by flow cytometry (FACS). PMBC cytokine expression levels were measured with and without specific TLR activation by Luminex® Xmap multiplexing technology. TLR2, ‑4, ‑9 and CD14 PBMC receptor levels were assessed and IRAK4, Iκβα and NFκB measured following specific TLR activation by FACS.

Results: Characterisation of PBMC cell populations demonstrated no significant differences in monocyte, natural killer cell, myeloid dendritic cell and T cell (naïve, helper, regulatory, cytotoxic and memory) numbers between Rs and NRs (p > 0.05), confirming that any differences in response to anti-TNFα treatment is not a result of the cell populations but due to dysregulation of TLR signalling. Basal PBMC expression in Rs was lower than NRs for TNFα (p = 0.002), IL‑1β (p = 0.003) and IL‑10 (p = 0.02). Rs production of TNFα, however, was significantly higher than in NRs following specific TLR2 (p = 0.02), ‑4 (p = 0.04) and ‑9 (p = 0.0002) stimulation. Similar findings were observed for IL‑1β and IL‑10 expression, but no differences were observed between Rs and NRs for IL‑6. No differences in TLR2, ‑4, ‑9 and CD14 PBMC receptor expression were detected, but NRs had less Iκβα and a reduced ability to phosphorylate NFκB compared to Rs which paralleled the cytokine production profile.

Conclusions: The findings suggest that immune dysregulation in UC patients mirror changes that have been observed in patients with and without allergic diseases. TLR function, in particular, plays a significant role in a patient's ability to respond to TNF therapy. This could be used to subtype UC patients and predict response to anti-TNFα medications allowing for more targeted and cost effective therapy.