Immunologic Research

, Volume 60, Issue 1, pp 38–49 | Cite as

Temporal evolution of human autoantibody response to cytoplasmic rods and rings structure during anti-HCV therapy with ribavirin and interferon-α

  • Gerson Dierley Keppeke
  • Minoru Satoh
  • Maria Lucia Gomes Ferraz
  • Edward K. L. Chan
  • Luís Eduardo C. Andrade


Autoantibodies to inosine monophosphate dehydrogenase-2 (IMPDH2), an enzyme involved in de novo biosynthesis of guanine nucleotides, are observed in a subset of hepatitis C virus (HCV) patients receiving interferon alpha (IFN-α) plus ribavirin. Anti-IMPDH2 antibodies display a peculiar cytoplasmic “rod/ring” (RR) pattern in IIF-HEp-2. We examined the dynamics of anti-RR autoimmune response with respect to immunoglobulin isotypes, titer, avidity, and protein targets in 80 sequential samples from 15 HCV patients (plus 12 randomly selected anti-RR-positive, totalizing 92 samples) collected over an 18-month period, including samples collected before, during, and after IFN-α + ribavirin treatment. Immunoprecipitation showed reactivity with the 55 kDa IMPDH2 protein in 12/15 patients (80 %) and 11/15 (73 %) reacted with IMPDH2 in a sandwich ELISA. During treatment, anti-IMPDH2 autoantibodies hit their highest levels after 6–12 months of treatment and decreased post-treatment, while anti-HCV antibodies levels were stable over time. Anti-IMPDH2 IgM levels increased up until the sixth month of treatment and remained stable thereafter, while IgG levels increased steadily up to the twelfth month. Both IgG and IgM decreased during the post-treatment period. IgG avidity increased steadily up to the twelfth month of treatment. In conclusion, this study showed that the temporal kinetics of IFN-α + ribavirin-induced humoral autoimmune response to IMPDH2 exhibited a considerably delayed pace of increase in antibody levels and avidity as well as in isotype class switch in comparison with a conventional humoral response to infectious agents. These unique findings uncover intriguing differences between the autoimmune response and the immune response to exogenous agents in humans.


Autoantibodies IMPDH2 Hepatitis C Ribavirin Interferon-α 



Inosine-5′-monophosphate dehydrogenase 2


Interferon alpha


Anti-nuclear antibodies


Indirect immunofluorescence using HEp-2 cell substrate


Hepatitis C virus


Enzyme-linked immunosorbent assay


Standard error of the mean



This study and G.D.K. were financially supported by Grants 2010/50710-6 and 2011/12448-0, São Paulo Research Foundation (FAPESP). G.D.K.’s time as a visiting scholar at the University of Florida was supported by Grant 9028-11-0 from Brazilian government agency CAPES. L.E.C.A. receives a research grant from Brazilian government agency CNPq 305064/2011-8. Special thanks to Dr. Wendy Carcamo, who helped with the sandwich ELISA technique and cell culture, and to John Calise for careful review of English syntax and grammar.

Conflict of interest

The authors declare no commercial or financial conflict of interest.


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Gerson Dierley Keppeke
    • 1
    • 2
  • Minoru Satoh
    • 3
    • 4
  • Maria Lucia Gomes Ferraz
    • 5
  • Edward K. L. Chan
    • 2
  • Luís Eduardo C. Andrade
    • 1
    • 6
  1. 1.Rheumatology DivisionUniversidade Federal de São PauloSão PauloBrazil
  2. 2.Department of Oral BiologyUniversity of FloridaGainesvilleUSA
  3. 3.Department of Clinical Nursing, School of Health SciencesUniversity of Occupational and Environmental HealthKitakyushuJapan
  4. 4.Division of Rheumatology and Clinical Immunology, Department of MedicineUniversity of FloridaGainesvilleUSA
  5. 5.Gastroenterology DivisionUniversidade Federal de São PauloSão PauloBrazil
  6. 6.Immunology DivisionFleury Medicine and Health LaboratoriesSão PauloBrazil

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