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Cytoplasmic rods/rings autoantibodies in chronic hepatitis C patients undergone peginterferon and ribavirin therapy target inosine-5´-monophosphate dehydrogenase 2 (IMPDH2)
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Speaker:
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Giovanni Covini
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Author:
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G. Covini1*, W. Carcamo2, E. Bredi1, E. Grassi3, M. Colombo3, E.K.L. Chan2
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Affiliation:
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1Department of Gastroenterology, Istituto Clinico Humanitas, Rozzano, Italy, 2Department of Oral Biology, University of Florida, Gainesville, FL, USA, 3Department of Gastroenterology, Ospedale Maggiore Policlinico, Milan, Italy. *giovanni.covini@humanitas.it
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In the present study, we describe a novel cytoplasmic autoantibody developing in patients with chronic hepatitis C during antiviral therapy. Antibodies react with cytoplasmic structures that appear like rods and rings (RR). The aim of this study was to determine the nature of this autoantigen and its prevalence in HCV treated patients.
Methods: Sera from 75 naive HCV+ patients treated with peginterferon alfa-2a (IFN) coupled with oral ribavirin (rbv) were investigated for autoimmunity by indirect immunofluorescence (IIF) using HEp-2 cells as substrate before and during the anti-viral therapy. Double IIF, immunoprecipitation (IP), and Western blotting (WB) were performed using a rabbit anti-inosine monophosphate dehydrogenase 2 (IMPDH2) as a positive control. Biological and clinical variables were studied for statistical analysis.
Results: In 15 out of 75 (20%) patients, the IIF study revealed the presence of antibodies reacting with cytoplasmic structures like rods ranging about ~3-10 µm in length and rings ranging about 2-5 µm diameter. Rods may align either close to the nuclear envelope or extend perpendicularly to the nucleus. Interestingly, this novel autoantibody was found in sera collected during IFN/rbv treatment only, whereas it was never detected before antiviral therapy. Anti-RR positive sera co-localized and recognized the same proteins identified from rabbit anti-IMPDH2 positive control. The prevalence of anti-RR antibody was significantly higher in non-responders/relapsers than in responder patients. In fact, 10 out of 15 (67%) anti-RR positive non-responder/relapser patients were significantly higher than 20 out of 60 (33%) anti-RR negative non-responder patients (P value = 0.037). The identity of one of the RR antigens was shown to be IMPDH2 using IP-Western.
Conclusions: In this study we describe a new cytoplasmic autoantigen in HCV patients treated with IFN/rbv observed in HEp-2 cell slides during screening for ANA test. Interestingly anti-RR antibodies were not present in HCV sera at baseline. Because rbv is a sensitive inhibitor of IMPDH our data suggest an important role of rbv to trigger their appearance. The overall prevalence of anti-RR antibodies was found in 20% of HCV treated patients. Importantly, our study suggests that positivity for anti-RR alters response to antiviral therapy.
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