Case Control Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 7, 2015; 21(1): 221-228
Published online Jan 7, 2015. doi: 10.3748/wjg.v21.i1.221
Reactivity against microsatellite instability-induced frameshift mutations in patients with inflammatory bowel disease
Florian Kuehn, Ernst Klar, Anja Bliemeister, Michael Linnebacher
Florian Kuehn, Ernst Klar, Anja Bliemeister, Michael Linnebacher, Department of General, Thoracic, Vascular and Transplantation Surgery, Molecular Oncology and Immunotherapy, University of Rostock, 18057 Rostock, Germany
Author contributions: Kuehn F acquired, analyzed and interpreted data, performed statistics and drafted the manuscript; Klar E delivered material support and critically revised the manuscript for important intellectual content; Bliemeister A acquired data and performed statistics; Linnebacher M designed and supervised the study, drafted and critically revised the manuscript.
Supported by University of Rostock (FORUN program)
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Michael Linnebacher, PhD, Department of General, Thoracic, Vascular and Transplantation Surgery, Molecular Oncology and Immunotherapy, University of Rostock, Schillingallee 35, 18057 Rostock, Germany. michael.linnebacher@med.uni-rostock.de
Telephone: +49-381-4946043 Fax: +49-381-4946002
Received: May 14, 2014
Peer-review started: May 14, 2014
First decision: June 27, 2014
Revised: July 20, 2014
Accepted: August 13, 2014
Article in press: August 28, 2014
Published online: January 7, 2015
Abstract

AIM: To analyze the cellular immune response towards microsatellite-instability (MSI)-induced frameshift-peptides (FSPs) in patients suffering from inflammatory bowel disease (IBD) with and without thiopurine-based immunosuppressive treatment.

METHODS: Frequencies of peripheral blood T cell responses of IBD patients (n = 75) against FSPs derived from 14 microsatellite-containing candidate genes were quantified by interferon-γ enzyme-linked immunospot. T cells derived from 20 healthy individuals served as controls.

RESULTS: Significant T cell reactivities against MSI-induced FSPs were observed in 59 of 75 IBD patients (78.7%). This was significantly more as we could observe in 20 healthy controls (P = 0.001). Overall, the reactivity was significantly influenced by thiopurine treatment (P = 0.032) and duration of disease (P = 0.002) but not by duration or cumulative amount of thiopurine therapy (P = 0.476). Unexpected, 15 of 24 (62.5%) IBD patients without prior thiopurine treatment also showed increased FSP-specific immune responses (P = 0.001).

CONCLUSION: These findings propose FSPs as potential novel class of inflammation-associated antigens and this in turn may have implications for screening, diagnosis as well as clinical management of patients suffering from IBD and other inflammatory conditions.

Keywords: Microsatellite-instability, Inflammatory bowel diseas, Frameshift peptides, Immune response, Thiopurine

Core tip: Oxidative stress resulting from chronic inflammation is likely to relax the mismatch repair (MMR) system and to cause DNA damage. On the other hand thiopurine treatment positively selects for cell variants with defective MMR system. inflammatory bowel disease (IBD) patients are often exposed to both factors, hypothetically resulting in an increased number of frameshift mutations. This study shows an increased immune response towards microsatellite-instability-induced frameshift-peptides (FSPs) in patients with IBD. It is the first report which provides functional evidence of FSP expression under non- but possible pre-neoplastic conditions. These findings have potential implications for screening, diagnosis as well as clinical management of IBD patients.