Differential Reactivity to IMPDH2 by Anti-rods/rings Autoantibodies and Unresponsiveness to Pegylated Interferon-alpha/Ribavirin Therapy in US and Italian HCV Patients

Abstract

In the two cohorts analyzed, the anti-IMPDH2 response as a component of the anti-RR response is much more prominent in the Italian cohort. The reason for the difference between the US and Italian cohorts is unclear but it possibly illustrates the heterogeneity in response and the overall negative correlation between the production of these autoantibodies and response to IFN/R therapy. Patients with high titer anti-RR antibodies are either relapsers (Italian) or non-responders/relapsers (US).

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.…”

“…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).…”

‘Rod and ring’ formation from IMP dehydrogenase is regulated through the one-carbon metabolic pathway

“…the Methotrexate Leucovorin Rescue protocol) and during immunosuppression for rheumatoid arthritis. We and others have demonstrated an autoantibody response against RR structures (IMPDH as a major autoantigen) in a subset of hepatitis C patients that have undergone interferon-α and ribavirin therapy (Carcamo et al, 2013;Covini et al, 2012;Keppeke et al, 2012). Prolonged exposure to interferon-α and ribavirin increases the prevalence of this autoantibody response (Keppeke et al, 2014), and in rare cases anti-RR antibody can be detected in non-hepatitis patients (Calise et al, 2014a.…”

Report on the second International Consensus on ANA Pattern (ICAP) workshop in Dresden 2015

“…The nuclear dense fine speckled pattern (AC-2) is considered particularly important given its strong association with anti-DFS70/LEDGF antibodies and the fact that many investigators either have not heard of it or do not know the relevance of its negative correlation to systemic autoimmune rheumatic diseases. 8,9 There was some concern over the apparent lack of clinical relevance of Golgi-like pattern (AC-22) [10][11][12] or the rods and rings pattern (AC-23), [13][14][15][16] and yet they represent distinctive and consistent patterns that belong to the competentlevel group. It has been proposed that the competent level and expert level are equivalent to the more simple description of ''basic'' and ''advanced'' levels and should not depend strictly on the clinical relevance of the pattern.…”