Published online Feb 14, 2016. doi: 10.3748/wjg.v22.i6.1966
Peer-review started: May 15, 2015
First decision: October 14, 2015
Revised: November 4, 2015
Accepted: November 24, 2015
Article in press: November 24, 2015
Published online: February 14, 2016
Chronic inflammation associated with hepatitis C virus (HCV) infection can lead to disabling liver diseases with progression to liver cirrhosis and hepatocellular carcinoma. Despite the recent availability of more effective and less toxic therapeutic options, in most parts of the world the standard treatment consists of a weekly injection of pegylated interferon α (IFN-α) together with a daily dose of ribavirin. HCV patients frequently present circulating non-organ-specific autoantibodies demonstrating a variety of staining patterns in the indirect immunofluorescence assay for antinuclear antibodies (ANA). Between 20% to 40% of HCV patients treated with IFN-α and ribavirin develop autoantibodies showing a peculiar ANA pattern characterized as rods and rings (RR) structures. The aim of this article is to review the recent reports regarding RR structures and anti-rods/rings (anti-RR) autoantibody production by HCV patients after IFN-α/ribavirin treatment. Anti-RR autoantibodies first appear around the sixth month of treatment and reach a plateau around the twelfth month. After treatment completion, anti-RR titers decrease/disappear in half the patients and remain steady in the other half. Some studies have observed a higher frequency of anti-RR antibodies in relapsers, i.e., patients in which circulating virus reappears after initially successful therapy. The main target of anti-RR autoantibodies in HCV patients is inosine-5’-monophosphate dehydrogenase 2 (IMPDH2), the rate-limiting enzyme involved in the guanosine triphosphate biosynthesis pathway. Ribavirin is a direct IMPDH2 inhibitor and is able to induce the formation of RR structures in vitro and in vivo. In conclusion, these observations led to the hypothesis that anti-RR autoantibody production is a human model of immunologic tolerance breakdown that allows us to explore the humoral autoimmune response from the beginning of the putative triggering event: exposure to ribavirin and interferon.
Core tip: Between 20% and 40% of hepatitis C virus patients treated with interferon-α and ribavirin develop autoantibodies showing a peculiar antinuclear antibodies pattern characterized as rods and rings (RR) structures. In those patients, the first appearance of anti-RR autoantibodies occurs around the sixth month of treatment and reaches a plateau around the twelfth month. The main target of anti-RR autoantibodies is the inosine-5’-monophosphate dehydrogenase 2 (IMPDH2) enzyme, critical in de novo GTP biosynthesis. In cell culture, IMPDH2 inhibition by ribavirin promotes its aggregation into RR structures. These observations led to the hypothesis that anti-RR autoantibody production represents a human model of immunologic tolerance breakdown that allows us to explore interesting aspects of the humoral autoimmune response from the beginning of the putative triggering event.