Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 14, 2016; 22(22): 5173-5182
Published online Jun 14, 2016. doi: 10.3748/wjg.v22.i22.5173
Dominating expression of negative regulatory factors downmodulates major histocompatibility complex Class-II expression on dendritic cells in chronic hepatitis C infection
Shallu Tomer, Yogesh K Chawla, Ajay Duseja, Sunil K Arora
Shallu Tomer, Sunil K Arora, Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
Yogesh K Chawla, Ajay Duseja, Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
Author contributions: Tomer S and Arora SK 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 the final version of the article to be published.
Supported by Council of Scientific and Industrial Research, No. 27 (0262) 12/EMR-II.
Institutional review board statement: The study was reviewed and approved by Institute Ethics Committee, Post Graduate Institute of Medical Education and Research, Chandigarh. All blood samples from the patients were taken after informed consent and ethical permission was obtained for participation in the study.
Conflict-of-interest statement: Authors declare no conflict of interest.
Data sharing statement: Technical appendix, statistical code and dataset are available from corresponding author at Participants consent form was not taken for data sharing but the presented data are anonymized and risk of identification is low.
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:
Correspondence to: Sunil K Arora, MSc, PhD, MNAMS, Professor, Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh 160012, India.
Telephone: +91-172-2755192 Fax: +91-172-2744401
Received: February 17, 2016
Peer-review started: February 19, 2016
First decision: March 31, 2016
Revised: April 26, 2016
Accepted: May 4, 2016
Article in press: May 4, 2016
Published online: June 14, 2016

AIM: To elucidate the molecular mechanisms leading to development of functionally impaired dendritic cells (DCs) in chronic hepatitis C (CHC) patients infected with genotype 3 virus.

METHODS: This prospective study was conducted on the cohorts of CHC individuals identified as responders or non-responders to antiviral therapy. Myeloid DCs were isolated from the peripheral blood of each subject using CD1c (BDCA1)+ DC isolation Kit. Monocytes from healthy donor were cultured with DC growth factors such as IL-4 and GM-CSF either in the presence or absence of hepatitis C virus (HCV) viral proteins followed by LPS stimulation. Phenotyping was done by flowcytometry and gene expression profiling was evaluated by real-time PCR.

RESULTS: Non-responders [sustained virological response (SVR)-ve] to conventional antiviral therapy had significantly higher expression of genes associated with interferon responsive element such as IDO1 and PD-L1 (6-fold) and negative regulators of JAK-STAT pathway such as SOCS (6-fold) as compared to responders (SVR+ve) to antiviral therapy. The down-regulated genes in non-responders included factors involved in antigen processing and presentation mainly belonging to major histocompatibility complex (MHC) Class-II family as HLA-DP, HLA-DQ (2-fold) and superoxide dismutase (2-fold). Cells grown in the presence of HCV viral proteins had genes down-regulated for factors involved in innate response, interferon signaling, DC maturation and co-stimulatory signaling to T-cells, while the genes for cytokine signaling and Toll-like receptors (4-fold) were up-regulated as compared to cells grown in absence of viral proteins.

CONCLUSION: Underexpressed MHC class-II genes and upregulated negative regulators in non-responders indicate diminished capacity to present antigen and may constitute mechanism of functionally defective state of DCs.

Keywords: Dendritic cells, Hepatitis C, Non-responders, Negative regulators, Major histocompatibility complex Class-II genes

Core tip: The study was aimed to understand the mechanisms of dendritic cells dysfunction during chronic hepatitis C (CHC) infection. The findings highlight the association between different immune response genes and viral persistence in non-responders to antiviral therapy. Up regulation of negative regulators and down-regulation of molecules involved with antigen presentation seems to associate with non-responsiveness to antiviral therapy. Some novel pathways can be targeted to achieve better management of CHC patients.