Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 28, 2016; 22(20): 4848-4859
Published online May 28, 2016. doi: 10.3748/wjg.v22.i20.4848
Immunological changes in different patient populations with chronic hepatitis C virus infection
Laszlo Szereday, Matyas Meggyes, Melinda Halasz, Julia Szekeres-Bartho, Alajos Par, Gabriella Par
Laszlo Szereday, Matyas Meggyes, Melinda Halasz, Julia Szekeres-Bartho, Department of Medical Microbiology and Immunology, University of Pecs, Clinical Centre, 7624 Pecs, Hungary
Laszlo Szereday, Matyas Meggyes, Melinda Halasz, Julia Szekeres-Bartho, Janos Szentagothai Research Centre, 7624 Pecs, Hungary
Alajos Par, Gabriella Par, First Department of Internal Medicine, University of Pecs, Clinical Centre, 7624 Pecs, Hungary
Author contributions: Szereday L, Meggyes M, Halasz M, Szekeres-Bartho J, Par A and Par G substantially contributed to the conception and design of the study, acquisition, analysis and interpretation of data; all authors drafted the article and made critical revisions related to the intellectual content of the manuscript, and approved final version of the article to be published.
Supported by Grants from Hungarian National Research Fund (OTKA K81454 and OTKA K104960); Liver Research Foundation (Pécs), United European Gastroenterology Federation; Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences to Szereday L.
Institutional review board statement: Written informed consent was obtained from all patients. The study protocol conforms to ethical guidelines of 1975 Declaration of Helsinki. Approval from the Regional Ethics Committee at the Medical School, University of Pécs, was obtained.
Conflict-of-interest statement: All authors do not have any conflict of interest.
Data sharing statement: No additional data are available.
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: Laszlo Szereday, MD, PhD, Associate Professor of Microbiology, Department of Medical Microbiology and Immunology, University of Pecs, Clinical Centre, 7624 Pecs, Hungary. szereday.laszlo@pte.hu
Telephone: +36-72-536001 Fax: +36-72-536253
Received: January 12, 2016
Peer-review started: January 15, 2016
First decision: February 18, 2016
Revised: March 5, 2016
Accepted: April 7, 2016
Article in press: April 7, 2016
Published online: May 28, 2016
Processing time: 127 Days and 15.8 Hours
Abstract

AIM: To investigate killer inhibitory and activating receptor expression by natural killer (NK), natural killer T-like (NKT-like) and CD8+ T lymphocytes in patients with chronic hepatitis C virus (HCV) infection with elevated and with persistently normal alanine aminotransferase (PNALT).

METHODS: The percentage of peripheral blood Treg cells, KIR2DL3, ILT-2, KIR3DL1, CD160, NKG2D, NKG2C expressing NK, T and NKT-like cells, cytokine production and NK cytotoxicity were determined by flow cytometry. Twenty-one patients with chronic HCV infection with elevated alanine aminotransferase, 11 HCV carriers with persistently normal alanine aminotransferase and 15 healthy volunteers were enrolled.

RESULTS: No significant differences were observed in the percentage of total T, NK or NKT-like cells between study groups. Comparing the activating and inhibitory receptor expression by NK cells obtained from HCV carriers with PNALT and chronic HCV hepatitis patients with elevated alanine aminotransferase, NKG2D activating receptor expression was the only receptor showing a significant difference. NKG2D expression of NK cells was significantly lower in patients with elevated alanine aminotransferase. The expression of CD160, NKG2D and NKG2C activating receptor by CD8+ T cells were significantly lower in patients with chronic HCV hepatitis than in healthy controls and in HCV carriers with PNALT. Plasma TGF-β1 levels inversely correlated with NKG2D expression by NK cells. In vitroTGF-β1 treatment inhibited NK cells cytotoxic activity and downregulated NKG2D expression. CD8+ T cells from HCV carriers with PNALT showed significantly elevated expression of CD160, NKG2D and NKG2C activating receptors compared to chronic HCV patients with elevated alanine aminotransferase. Enhanced expression of inhibitory KIR2DL3 receptor, and decreased ILT-2 expression on NK cells were also found in chronic hepatitis C patients compared to healthy controls.

CONCLUSION: Our study demonstrated a complex dysregulation of activating and inhibitory receptor expression, such as decreased NKG2D and CD160 activating receptor expression and increased KIR2DL3 inhibitory receptor expression by NK and cytotoxic T cells and may provide further mechanism contributing to defective cellular immune functions in chronic hepatitis C. Increased NKG2D receptor expression in HCV patients with persistently normal ALT suggests an important pathway for sustaining NK and CD8 T cell function and a protective role against disease progression.

Keywords: Hepatitis C; Natural killer cell; NKG2D; Cytotoxicity; Cytokine

Core tip: The host immune response to hepatitis C virus (HCV) involves both innate and adaptive arms of the immune system. Natural killer (NK) cells are key components of the innate antiviral immune response. To better characterize the immune defects underlying chronic viral persistence, we focus our analysis on killer inhibitory and activating receptor expression in patients with chronic HCV infection with elevated alanine aminotransferase (ALT) and also in patients with HCV carriers with persistently normal ALT. Decreased NKG2D and CD160 activating receptor expression and increased KIR2DL3 inhibitory receptor expression by NK and cytotoxic T cells in patients with chronic hepatitis C contributing to defective cellular immune functions.