Interferon–ribavirin therapy induces serum antibodies determining ‘rods and rings’ pattern in hepatitis C patients

Abstract

A cytoplasmic antigen associated to inosine-5'-monophosphatedehydrogenase 2 eliciting specific antibodies (antirods and rings, RR) has been identified in patients with chronic hepatitis C who were exposed to pegylated interferon (PI) and ribavirin (RBV). The significance of anti-RR in these patients merits to be investigated. Sera from 88 chronic hepatitis C virus (HCV)-infected patients undergoing PI-RBV therapy were analysed for the presence of RR pattern by indirect immunofluorescence on HEp-2 substrate (Inova Diagnostics, San Diego, CA, USA). Anti-RR antibodies developed de novo in 32 patients independently of any demographic and virological feature, but with a significant association with cumulative exposure to PI-RBV (P = 0.0089; chi-square test). RR pattern was significantly more frequent in relapsers than in patients achieving sustained virological response (56% vs 30%; P = 0.0282, chi-square test). Anti-RR titre ranged from 1:80 to 1:1280, but significantly declined following treatment cessation. Anti-RR develop de novo in a substantial proportion of patients exposed to PI-RBV in relation to the duration of treatment exposure. Further investigations are necessary to unravel the mechanisms leading to the formation of these autoantibodies.

Assembly of IMPDH2-Based, CTPS-Based, and Mixed Rod/Ring Structures Is Dependent on Cell Type and Conditions of Induction

“…Anti-RR positive sera from HCV patients recognized only IMPDH2-based RR structures HCV patients that have undergone ribavirin/interferon-a therapy develop autoantibodies that recognize RR structures in a standard ANA-HEp-2 test (Covini et al, 2012;Keppeke et al, 2012;Carcamo et al, 2013;Stinton et al, 2013;Novembrino et al, 2014). It has been consistently shown that these autoantibodies recognize the IMPDH2 enzyme in roughly 70% of anti-RR positive samples (Seelig et RR components remains unknown.…”

“…Ribavirin is used as an adjuvant to interferon-a therapy in chronic hepatitis C virus (HCV) infection. Curiously, it has been shown that 20%-40% of HCV patients treated with interferon-a plus ribavirin present autoantibodies against RR structures after six months of treatment, with titers increasing throughout treatment and eventually decreasing after interruption of treatment (Covini et al, 2012;Keppeke et al, 2012;Novembrino et al, 2014). These autoantibodies seem to be, in most cases, directed against IMPDH2, which is the very target of ribavirin used in the anti-HCV treatment (Carcamo et al, 2011(Carcamo et al, , 2013Seelig et al, 2011;Probst et al, 2013).…”

The Cytoophidium and Its Kind: Filamentation and Compartmentation of Metabolic Enzymes

“…Curiously, several groups have observed autoantibodies against IMPDH cytoophidium in patients infected with hepatitis C and under treatment with interferon-α and ribavirin, an IMPDH inhibitor , Carcamo et al 2014, Climent et al 2016, Keppeke et al 2012, Novembrino et al 2014. The autoantibodies usually appear after 6 months of treatment begins and disappear in at least half the patients after treatment is completed, suggesting that ribavirin may play a role in autoantibody production against the IMPDH cytoophidium (Keppeke et al 2014).…”

Anti-rods/rings autoantibody seropositivity does not affect response to telaprevir treatment for chronic hepatitis C infection

“…We speculate that long-lived plasma cells might be responsible for the long-term presence of anti-RR antibody in these patients. Previous studies have suggested that anti-RR titer increases throughout the duration of therapy, but declines upon cessation of treatment [11, 12, 15, 31]. To our knowledge, this is the first report of long-lived anti-RR autoantibody.…”

“…Many patients with anti-RR react with IMPDH, which is inhibited by direct binding to RBV and appears to be the major autoantigen in RRs [9, 26, 27]. Although no mechanistic evidence suggesting that anti-RR autoantibody contributes to resistance to IFN/RBV therapy has yet been reported, previous studies showed that anti-RR antibodies were more prevalent in patients who did not respond to therapy or relapsed, when compared to sustained responders [10, 15]. Additionally, non-responsive or relapsing patients had higher anti-RR titers, suggesting that anti-RR positivity may be indicative of poor treatment outcomes [28].…”