The Presence of Autoantibodies to Cytoplasmic Rod and Ring Particles in the Serum of Patients with Chronic Hepatitis C Virus Infection

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Abstract

Background

Chronic hepatitis C virus (HCV) is associated with extra hepatic autoimmune disorders, while peg-IFNa-2a/RBV combination therapy may exacerbate these conditions. Autoantibodies to cytoplasmic structures, called rod and ring particles (RR), have strong associations with these patients and are identified by HEp-2 cells.

Objectives

Our purpose was to study the correlation of autoantibodies to cytoplasmic rod and ring particles in the serum of patients with chronic HCV infection with their response to standard therapy.

Methods

Serum samples were gathered from 120 patients with HCV infection (40 naive treatments, 40 with sustained virological response (SVR), and 40 with relapse response) during peg-IFNa-2a/RBV combination therapy and analyzed for the presence of RR antibodies by IIF on commercially available HEp-2 cell substrate slides from Euroimmun (Lu beck, Germany).

Results

Anti-rod and ring (anti-RR) autoantibodies were detected in only the serum of 1 out of 120 patients (0.8%), which belonged to a patient (out of 40) with relapse response (2.5%). No correlation was found between the types of response to peg-IFNa-2a/RBV combination therapy and the presence of anti-RR autoantibodies.

Conclusions

The only HCV patient with RR autoantibodies previously had received IFN/ribavirin antiviral therapy. The presence of these autoantibodies is extremely rare in Iranian HCV patients. Further studies are warranted to determine the role of genetic background and geographical pattern in the prevalence of these novel autoantibodies worldwide.

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Most cited references 30

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Binding of hepatitis C virus to CD81.

P Pileri, Y Uematsu, S Campagnoli … (1998)

Chronic hepatitis C virus (HCV) infection occurs in about 3 percent of the world's population and is a major cause of liver disease. HCV infection is also associated with cryoglobulinemia, a B lymphocyte proliferative disorder. Virus tropism is controversial, and the mechanisms of cell entry remain unknown. The HCV envelope protein E2 binds human CD81, a tetraspanin expressed on various cell types including hepatocytes and B lymphocytes. Binding of E2 was mapped to the major extracellular loop of CD81. Recombinant molecules containing this loop bound HCV and antibodies that neutralize HCV infection in vivo inhibited virus binding to CD81 in vitro.

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Innate and adaptive immune responses in HCV infections.

Markus Heim, Robert Thimme (2014)

Hepatitis C virus has been identified a quarter of a decade ago as a leading cause of chronic viral hepatitis that can lead to cirrhosis and hepatocellular carcinoma. Only a minority of patients can clear the virus spontaneously during acute infection. Elimination of HCV during acute infection correlates with a rapid induction of innate, especially interferon (IFN) induced genes, and a delayed induction of adaptive immune responses. However, the majority of patients is unable to clear the virus and develops viral persistence in face of an ongoing innate and adaptive immune response. The virus has developed several strategies to escape these immune responses. For example, to escape innate immunity, the HCV NS3/4A protease can efficiently cleave and inactivate two important signalling molecules in the sensory pathways that react to HCV pathogen-associated molecular patterns (PAMPs) to induce IFNs, i.e., the mitochondrial anti-viral signalling protein (MAVS) and the Toll-IL-1 receptor-domain-containing adaptor-inducing IFN-β (TRIF). Despite these escape mechanisms, IFN-stimulated genes (ISGs) are induced in a large proportion of patients with chronic infection. Of note, chronically HCV infected patients with constitutive IFN-stimulated gene (ISG) expression have a poor response to treatment with pegylated IFN-α (PegIFN-α) and ribavirin. The mechanisms that protect HCV from IFN-mediated innate immune reactions are not entirely understood, but might involve blockade of ISG protein translation at the ribosome, localization of viral replication to cell compartments that are not accessible to anti-viral IFN-stimulated effector systems, or direct antagonism of effector systems by viral proteins. Escape from adaptive immune responses can be achieved by emergence of viral escape mutations that avoid recognition by antibodies and T cells. In addition, chronic infection is characterized by the presence of functionally and phenotypically altered NK and T cell responses that are unable to clear the virus but most likely contribute to the ongoing liver disease. In this review, we will summarize current knowledge about the role of innate and adaptive immune responses in determining the outcome of HCV infection.

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Induction of Cytoplasmic Rods and Rings Structures by Inhibition of the CTP and GTP Synthetic Pathway in Mammalian Cells

Wendy Carcamo, Minoru Satoh, Hideko Kasahara … (2011)

Background Cytoplasmic filamentous rods and rings (RR) structures were identified using human autoantibodies as probes. In the present study, the formation of these conserved structures in mammalian cells and functions linked to these structures were examined. Methodology/Principal Findings Distinct cytoplasmic rods (∼3–10 µm in length) and rings (∼2–5 µm in diameter) in HEp-2 cells were initially observed in immunofluorescence using human autoantibodies. Co-localization studies revealed that, although RR had filament-like features, they were not enriched in actin, tubulin, or vimentin, and not associated with centrosomes or other known cytoplasmic structures. Further independent studies revealed that two key enzymes in the nucleotide synthetic pathway cytidine triphosphate synthase 1 (CTPS1) and inosine monophosphate dehydrogenase 2 (IMPDH2) were highly enriched in RR. CTPS1 enzyme inhibitors 6-diazo-5-oxo-L-norleucine and Acivicin as well as the IMPDH2 inhibitor Ribavirin exhibited dose-dependent induction of RR in >95% of cells in all cancer cell lines tested as well as mouse primary cells. RR formation by lower concentration of Ribavirin was enhanced in IMPDH2-knockdown HeLa cells whereas it was inhibited in GFP-IMPDH2 overexpressed HeLa cells. Interestingly, RR were detected readily in untreated mouse embryonic stem cells (>95%); upon retinoic acid differentiation, RR disassembled in these cells but reformed when treated with Acivicin. Conclusions/Significance RR formation represented response to disturbances in the CTP or GTP synthetic pathways in cancer cell lines and mouse primary cells and RR are the convergence physical structures in these pathways. The availability of specific markers for these conserved structures and the ability to induce formation in vitro will allow further investigations in structure and function of RR in many biological systems in health and diseases.

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Author and article information

Journal

Journal ID (nlm-ta): Hepat Mon

Journal ID (iso-abbrev): Hepat Mon

Journal ID (doi): 10.5812/hepatmon

Journal ID (publisher-id): Kowsar

Title: Hepatitis Monthly

Publisher: Kowsar

ISSN (Print): 1735-143X

ISSN (Electronic): 1735-3408

Publication date (Electronic): 11 December 2016

Publication date Collection: December 2016

Volume: 16

Issue: 12

Electronic Location Identifier: e42388

Affiliations

[1 ]Department of Virology, Iran University of Medical Sciences, Tehran, IR Iran

[2 ]HIV Laboratory of National Center, Deputy of Health, Iran University of Medical Sciences, Tehran, IR Iran

[3 ]Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, IR Iran

[4 ]Department of Community Medicine, Iran University of Medical Sciences, Tehran, IR Iran

Author notes

[* ]Corresponding Authors: Farah Bokharaei-Salim, Department of Virology, Iran University of Medical Sciences, Tehran, IR Iran. Tel/Fax: +98-2166047831, E-mail: bokharaei.f@ 123456iums.ac.ir ; Hossein Keyvani, Department of Virology, Iran University of Medical Sciences, Tehran, IR Iran. Tel/Fax: +98-2188706555, E-mail: Keyvanlab@ 123456yahoo.com

Article

DOI: 10.5812/hepatmon.42388

PMC ID: 5237575

SO-VID: 944989fb-a1aa-4729-ad26-c9ca1245a73b

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.

History

Date received : 19 September 2016

Date revision received : 20 October 2016

Date accepted : 29 November 2016

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The Presence of Autoantibodies to Cytoplasmic Rod and Ring Particles in the Serum of Patients with Chronic Hepatitis C Virus Infection

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Abstract

Background

Objectives

Methods

Results

Conclusions

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Point-Of-Care Testing for Hepatitis

Most cited references 30

Binding of hepatitis C virus to CD81.

Innate and adaptive immune responses in HCV infections.

Induction of Cytoplasmic Rods and Rings Structures by Inhibition of the CTP and GTP Synthetic Pathway in Mammalian Cells

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Cited by 2

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