Skip to main content

Advertisement

SpringerLink
Log in

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

  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

IMPDH2:

Inosine-5′-monophosphate dehydrogenase 2

IFN-α:

Interferon alpha

ANA:

Anti-nuclear antibodies

IIF-HEp-2:

Indirect immunofluorescence using HEp-2 cell substrate

HCV:

Hepatitis C virus

ELISA:

Enzyme-linked immunosorbent assay

SEM:

Standard error of the mean

References

  1. Elkon K, Casali P. Nature and functions of autoantibodies. Nat Clin Pract Rheumatol. 2008;4(9):491–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Selmi C. Autoimmunity in 2011. Clin Rev Allergy Immunol. 2012;43(1–2):194–206.

    Article  CAS  PubMed  Google Scholar 

  3. Costenbader KH, Gay S, Alarcon-Riquelme ME, Iaccarino L, Doria A. Genes, epigenetic regulation and environmental factors: which is the most relevant in developing autoimmune diseases? Autoimmun Rev. 2012;11(8):604–9.

    Article  PubMed  Google Scholar 

  4. Kofler R, Dixon FJ, Theofilopoulos AN. Genetic basis for autoantibody-production in murine models of systemic autoimmunity. Contrib Microbiol Immunol. 1989;11:206–30.

    CAS  PubMed  Google Scholar 

  5. Kono DH, Theofilopoulos AN. Genetics of systemic autoimmunity in mouse models of lupus. Int Rev Immunol. 2000;19(4–5):367–87.

    Article  CAS  PubMed  Google Scholar 

  6. Seery JP, Carroll JM, Cattell V, Watt FM. Antinuclear autoantibodies and lupus nephritis in transgenic mice expressing interferon gamma in the epidermis. J Exp Med. 1997;186(9):1451–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Yoshida H, Satoh M, Behney KM, Lee CG, Richards HB, Shaheen VM, et al. Effect of an exogenous trigger on the pathogenesis of lupus in (NZB × NZW)F1 mice. Arthritis Rheum. 2002;46(8):2235–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Gelpi C, Rodriguez-Sanchez JL, Martinez MA, Craft J, Hardin JA. Murine graft vs host disease. A model for study of mechanisms that generate autoantibodies to ribonucleoproteins. J Immunol. 1988;140(12):4160–6.

    CAS  PubMed  Google Scholar 

  9. Pollard KM. Perspectives. Autoantibodies and autoimmunity. Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA; 2005.

    Book  Google Scholar 

  10. Peitsch MC, Tschopp J. Assembly of macromolecular pores by immune defense systems. Curr Opin Cell Biol. 1991;3(4):710–6.

    Article  CAS  PubMed  Google Scholar 

  11. Cohen S. Antibodies. Mod Trends Immunol. 1963;55:25–52.

    CAS  PubMed  Google Scholar 

  12. Beveridge WI. Acquired immunity: viral infections. Mod Trends Immunol. 1963;102:130–44.

    CAS  PubMed  Google Scholar 

  13. Saegusa J, Kiuchi Y, Itoh T. Antinucleolar autoantibody induced in mice by mercuric chloride—strain difference in susceptibility. Jikken Dobutsu. 1990;39(4):597–9.

    CAS  PubMed  Google Scholar 

  14. Druet P, Ayed K, Bariety J, Bernaudin JF, Druet E, Girard JF, et al. Experimental immune glomerulonephritis induced in the rat by mercuric chloride. Adv Nephrol Necker Hosp. 1979;8:321–42.

    CAS  PubMed  Google Scholar 

  15. Pusey CD, Bowman C, Morgan A, Weetman AP, Hartley B, Lockwood CM. Kinetics and pathogenicity of autoantibodies induced by mercuric chloride in the brown Norway rat. Clin Exp Immunol. 1990;81(1):76–82.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Saegusa J, Yamamoto S, Iwai H, Ueda K. Antinucleolar autoantibody induced in mice by mercuric chloride. Ind Health. 1990;28(1):21–30.

    Article  CAS  PubMed  Google Scholar 

  17. Ochel M, Vohr HW, Pfeiffer C, Gleichmann E. IL-4 is required for the IgE and IgG1 increase and IgG1 autoantibody formation in mice treated with mercuric chloride. J Immunol. 1991;146(9):3006–11.

    CAS  PubMed  Google Scholar 

  18. Keppeke GD, Nunes E, Ferraz ML, Silva EA, Granato C, Chan EK, et al. Longitudinal study of a human drug-induced model of autoantibody to cytoplasmic rods/rings following HCV therapy with ribavirin and interferon-alpha. PLoS One. 2012;7(9):e45392.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Carcamo WC, Satoh M, Kasahara H, Terada N, Hamazaki T, Chan JY, et al. Induction of cytoplasmic rods and rings structures by inhibition of the CTP and GTP synthetic pathway in mammalian cells. PLoS One. 2011;6(12):e29690.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Carcamo WC, Ceribelli A, Calise SJ, Krueger C, Liu C, Daves M, et al. Differential reactivity to IMPDH2 by anti-rods/rings autoantibodies and unresponsiveness to pegylated interferon-alpha/ribavirin therapy in US and Italian HCV patients. J Clin Immunol. 2012;33(2):420–6.

    Article  PubMed  Google Scholar 

  21. Seelig HP, Appelhans H, Bauer O, Bluthner M, Hartung K, Schranz P, et al. Autoantibodies against inosine-5′-monophosphate dehydrogenase 2—characteristics and prevalence in patients with HCV-infection. Clin Lab. 2011;57(9–10):753–65.

    CAS  PubMed  Google Scholar 

  22. Probst C, Radzimski C, Blocker IM, Teegen B, Bogdanos DP, Stocker W, et al. Development of a recombinant cell-based indirect immunofluorescence assay (RC-IFA) for the determination of autoantibodies against “rings and rods”-associated inosine-5′-monophosphate dehydrogenase 2 in viral hepatitis C. Clin Chim Acta. 2013;418:91–6.

    Article  CAS  PubMed  Google Scholar 

  23. Bairagya HR, Mukhopadhyay BP, Bera AK. Role of salt bridge dynamics in inter domain recognition of human IMPDH isoforms: an insight to inhibitor topology for isoform-II. J Biomol Struct Dyn. 2011;29(3):441–62.

    Article  CAS  PubMed  Google Scholar 

  24. Natsumeda Y, Ohno S, Kawasaki H, Konno Y, Weber G, Suzuki K. Two distinct cDNAs for human IMP dehydrogenase. J Biol Chem. 1990;265(9):5292–5.

    CAS  PubMed  Google Scholar 

  25. Covini G, Carcamo WC, Bredi E, von Muhlen CA, Colombo M, Chan EK. Cytoplasmic rods and rings autoantibodies developed during pegylated interferon and ribavirin therapy in patients with chronic hepatitis C. Antivir Ther. 2011;17(5):805–11.

    Article  PubMed  Google Scholar 

  26. Thomas EC, Gunter JH, Webster JA, Schieber NL, Oorschot V, Parton RG, et al. Different characteristics and nucleotide binding properties of inosine monophosphate dehydrogenase (IMPDH) isoforms. PLoS One. 2012;7(12):e51096.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Wettey FR, Jackson AP. Indirect immunofluorescence microscopy. Subcell Biochem. 2006;40:427–9.

    PubMed  Google Scholar 

  28. Satoh M, Langdon JJ, Hamilton KJ, Richards HB, Panka D, Eisenberg RA, et al. Distinctive immune response patterns of human and murine autoimmune sera to U1 small nuclear ribonucleoprotein C protein. J Clin Invest. 1996;97(11):2619–26.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Satoh M, Treadwell EL, Reeves WH. Pristane induces high titers of anti-Su and anti-nRNP/Sm autoantibodies in BALB/c mice. Quantitation by antigen capture ELISAs based on monospecific human autoimmune sera. J Immunol Methods. 1995;182(1):51–62.

    Article  CAS  PubMed  Google Scholar 

  30. Satoh M, Langdon JJ, Reeves WH. Clinical applications of an anti-ku antigen-capture ELISA. Clin Immunol Newsl. 1993;13(2–3):23–31.

    Article  Google Scholar 

  31. Trieu EP, Targoff IN. SDS-PAGE for (3)(5)S immunoprecipitation and immunoprecipitation western blotting. Methods Mol Biol. 2012;869:215–33.

    Article  CAS  PubMed  Google Scholar 

  32. Dotzauer G. Effects of environment on an antigen–antibody reaction; reactions dependent on the electrolyte concentration and Hofmeister series. Dtsch Z Gesamte Gerichtl Med. 1958;47(4):573–9.

    CAS  PubMed  Google Scholar 

  33. Weinbach R. Mechanism of antigen–antibody reactions. Nature. 1964;202:409–10.

    Article  CAS  PubMed  Google Scholar 

  34. Schmitz H, Haas R. Determination of different cytomegalovirus immunoglobulins (IgG, IgA, IgM) by immunofluorescence. Arch Gesamte Virusforsch. 1972;37(1):131–40.

    Article  CAS  PubMed  Google Scholar 

  35. Hayward AR. Development of the immune response. Clin Allergy. 1973;3(Suppl):559–70.

    Article  PubMed  Google Scholar 

  36. Averbeck M, Gebhardt C, Emmrich F, Treudler R, Simon JC. Immunologic principles of allergic disease. J Dtsch Dermatol Ges. 2007;5(11):1015–28.

    Article  PubMed  Google Scholar 

  37. Enders G, Knotek F. Rubella IgG total antibody avidity and IgG subclass-specific antibody avidity assay and their role in the differentiation between primary rubella and rubella reinfection. Infection. 1989;17(4):218–26.

    Article  CAS  PubMed  Google Scholar 

  38. Schroeder HW Jr, Cavacini L. Structure and function of immunoglobulins. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S41–52.

    Article  PubMed Central  PubMed  Google Scholar 

  39. Goodnow CC, Vinuesa CG, Randall KL, Mackay F, Brink R. Control systems and decision making for antibody production. Nat Immunol. 2010;11(8):681–8.

    Article  CAS  PubMed  Google Scholar 

  40. Guzman MG, Halstead SB, Artsob H, Buchy P, Farrar J, Gubler DJ, et al. Dengue: a continuing global threat. Nat Rev Microbiol. 2010;8(12 Suppl):S7–16.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Chanama S, Anantapreecha S, A-nuegoonpipat A, Sa-gnasang A, Kurane I, Sawanpanyalert P. Analysis of specific IgM responses in secondary dengue virus infections: levels and positive rates in comparison with primary infections. J Clin Virol. 2004;31(3):185–9.

    Article  CAS  PubMed  Google Scholar 

  42. Iwakata S, Rhodes AJ, Labzoffsky NA. The significance of specific IgM antibody in the diagnosis of rubella employing the immunofluorescence technique. Can Med Assoc J. 1972;106(4):327–30.

    PubMed Central  CAS  PubMed  Google Scholar 

  43. Frisch-Niggemeyer W. Rapid separation of immunoglobulin M from immunoglobulin G antibodies for reliable diagnosis of recent rubella infections. J Clin Microbiol. 1975;2(5):377–81.

    PubMed Central  CAS  PubMed  Google Scholar 

  44. Vaz CA, Mackenzie DW, Hearn VM, Camargo ZP, Singer-Vermes LM, Burger E, et al. Specific recognition pattern of IgM and IgG antibodies produced in the course of experimental paracoccidioidomycosis. Clin Exp Immunol. 1992;88(1):119–23.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Arvin AM, Koropchak CM. Immunoglobulins M and G to varicella-zoster virus measured by solid-phase radioimmunoassay: antibody responses to varicella and herpes zoster infections. J Clin Microbiol. 1980;12(3):367–74.

    PubMed Central  CAS  PubMed  Google Scholar 

  46. Schaade L, Kleines M, Hausler M. Application of virus-specific immunoglobulin M (IgM), IgG, and IgA antibody detection with a polyantigenic enzyme-linked immunosorbent assay for diagnosis of Epstein–Barr virus infections in childhood. J Clin Microbiol. 2001;39(11):3902–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Bjorkman C, Naslund K, Stenlund S, Maley SW, Buxton D, Uggla A. An IgG avidity ELISA to discriminate between recent and chronic Neospora caninum infection. J Vet Diagn Invest. 1999;11(1):41–4.

    Article  CAS  PubMed  Google Scholar 

  48. Aguado-Martinez A, Alvarez-Garcia G, Arnaiz-Seco I, Innes E, Ortega-Mora LM. Use of avidity enzyme-linked immunosorbent assay and avidity Western blot to discriminate between acute and chronic Neospora caninum infection in cattle. J Vet Diagn Invest. 2005;17(5):442–50.

    Article  CAS  PubMed  Google Scholar 

  49. Bowen DG, Walker CM. Adaptive immune responses in acute and chronic hepatitis C virus infection. Nature. 2005;436(7053):946–52.

    Article  CAS  PubMed  Google Scholar 

  50. Strasak AM, Kim AY, Lauer GM, de Sousa PS, Ginuino CF, Fernandes CA, et al. Antibody dynamics and spontaneous viral clearance in patients with acute hepatitis C infection in Rio de Janeiro, Brazil. BMC Infect Dis. 2011;11:15.

    Article  PubMed Central  PubMed  Google Scholar 

  51. Vergani D, Mieli-Vergani G. Autoimmune manifestations in viral hepatitis. Semin Immunopathol. 2013;35(1):73–85.

    Article  CAS  PubMed  Google Scholar 

  52. Ferri S, Muratori L, Lenzi M, Granito A, Bianchi FB, Vergani D. HCV and autoimmunity. Curr Pharm Des. 2008;14(17):1678–85.

    Article  CAS  PubMed  Google Scholar 

  53. Toubi E, Gordon S, Kessel A, Rosner I, Rozenbaum M, Shoenfeld Y, et al. Elevated serum B-lymphocyte activating factor (BAFF) in chronic hepatitis C virus infection: association with autoimmunity. J Autoimmun. 2006;27(2):134–9.

    Article  CAS  PubMed  Google Scholar 

  54. Landau DA, Rosenzwajg M, Saadoun D, Klatzmann D, Cacoub P. The B lymphocyte stimulator receptor–ligand system in hepatitis C virus-induced B cell clonal disorders. Ann Rheum Dis. 2009;68(3):337–44.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

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.

Author information

Authors and Affiliations

  1. Rheumatology Division, Universidade Federal de São Paulo, Rua Botucatu 740, São Paulo, SP, 04023-062, Brazil

    Gerson Dierley Keppeke & Luís Eduardo C. Andrade

  2. Department of Oral Biology, University of Florida, 1600 SW Archer Rd, Gainesville, FL, 32610-0424, USA

    Gerson Dierley Keppeke & Edward K. L. Chan

  3. Department of Clinical Nursing, School of Health Sciences, University of Occupational and Environmental Health, 1-1 Isei-ga-oka, Yahata-nishi-ku, Kitakyushu, Fukuoka, 807-8555, Japan

    Minoru Satoh

  4. Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Florida, Gainesville, FL, 32610-0221, USA

    Minoru Satoh

  5. Gastroenterology Division, Universidade Federal de São Paulo, Rua Botucatu 740, São Paulo, SP, 04023-062, Brazil

    Maria Lucia Gomes Ferraz

  6. Immunology Division, Fleury Medicine and Health Laboratories, Avenida Gal Waldomiro Lima 508, São Paulo, SP, 04102-050, Brazil

    Luís Eduardo C. Andrade

Authors
  1. Gerson Dierley Keppeke
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Minoru Satoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria Lucia Gomes Ferraz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Edward K. L. Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Luís Eduardo C. Andrade
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gerson Dierley Keppeke.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Keppeke, G.D., Satoh, M., Ferraz, M.L.G. et al. Temporal evolution of human autoantibody response to cytoplasmic rods and rings structure during anti-HCV therapy with ribavirin and interferon-α. Immunol Res 60, 38–49 (2014). https://doi.org/10.1007/s12026-014-8515-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-014-8515-2

Keywords

Search

Navigation