IRISH SOCIETY OF GASTROENTEROLOGY
Oral Winners 2020 - First Prize
St. Vincent’s University Hospital School of Medicine
Crohn’s disease is associated with elevated levels of the proinflammatory CXCR3 ligands (CXCL9, 10 and 11) with an associated reduction in Paneth cell-derived antimicrobial peptides in ex-vivo ileal b
F Jones, C Egan, G Doherty, E McNamee
Centre for Colorectal Disease, St. Vincent’s University Hospital School of Medicine, University College Dublin Mucosal Immunology Research Laboratory, Institute of Immunology, Maynooth University, Maynooth
Despite an expanding array of treatment options, a significant proportion of Crohn’s disease (CD) patients fail to respond to currently available therapies, underpinning the importance of biological insights into disease pathogenesis. The proinflammatory chemokines CXCL9,10+11 bind to the CXCR3 receptor, highly expressed on effector T-cells. Mouse models of chronic ileitis have shown that CXCR3+ effector T cells drive the loss of paneth cells that play an important role in innate immunity and mucosal barrier function. In the TNFΔΔARE mouse ileitis-model, small molecule inhibition of the CXCR3 receptor reverses paneth cell loss and restores antimicrobial peptide levels.
The aim of this study was to evaluate the role of chemokines that bind to CXCR3+ effector T-cells in adult patients with ileal CD and to compare this to healthy controls.
13 CD patients and 16 controls attending for endoscopic evaluation were prospectively recruited at St.Vincent’s University Hospital and ileal biopsies were collected in media. RNA was extracted using the Quiagen kit, DNAse treated using DNAse I(Invitrogen) and reverse transcribed using M-MLV reverse transcriptase(Promega). Target cDNAs were quantified using an Applied BiosystemsTM QuantStudioTM 7 Flex Real-Time PCR System.
Our results show an increase in the relative mRNA expression of CXCR3 associated chemokines with significantly higher levels of CXCL9, CXCL10 and CXCL11 in ileal CD patients compared to healthy controls. This coincides with a reduction in paneth cell-derived antimicrobial peptides with significantly lower levels of alpha defensins (DEFA5,DEFA6) and lysozyme in CD patients compared to healthy controls.
This study supports data from animal models and provides a hypothesis for the loss of paneth cells in patients with ileal CD with important therapeutic potential utilizing CXCR3 receptor blockade.