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

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Abstract

Purpose

Autoantibodies to cytoplasmic structures called rods and rings (RR) are primarily specific to patients with hepatitis C virus (HCV) infection treated with pegylated interferon-alpha/ribavirin (IFN/R). Our aim is to examine anti-RR antibodies specificity and correlation with the response to IFN/R therapy in two independent cohorts (US and Italy) of HCV patients.

Methods

Sera from the US cohort (n = 47) and the Italian cohort (n = 46) pre-selected for anti-RR antibodies were analyzed by immunofluorescence and radioimmunoprecipitation. The prevalence and titers of anti-RR were analyzed for correlation with the response to IFN/R therapy.

Results

In the US cohort, anti-RR antibodies were more frequently non-responders to IFN/R (71 % vs 29 % responders). Titers in responder patients (n = 11) were ≤1:3200, whereas titers in non-responder patients (n = 27) reached 1:819,200 (p = 0.0016). In the Italian cohort, anti-RR titers ranged from 1:200 to >1:819,200 and only relapsers had the highest anti-RR titers. Radioimmunoprecipitation demonstrated that anti-RR autoantibodies were mainly anti-inosine monophosphate dehydrogenase 2 (IMPDH2) - 96 % in the Italian cohort vs. 53 % in the US cohort.

Conclusions

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).

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Abbreviations

ANA:

Anti-nuclear antibody

CTPS1:

Cytidine triphosphate synthetase 1

DON:

6-diazo-5-oxo-L-norleucine

HCV:

Hepatitis C virus

IFN/R:

Pegylated interferon-alpha/ribavirin

IFN-α:

Pegylated interferon-alpha

IIF:

Indirect immunofluorescence

IMPDH2:

Inosine monophosphate dehydrogenase 2

IP:

Immunoprecipitation

NR:

Non-responders

RBV:

Ribavirin

RR:

Rods and rings

SVR:

Sustained virological response

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Acknowledgements

Natasha Deming, Pabina Dhawan, and Jennifer R. Bess are acknowledged for the early work helping in the screening of HCV patient sera for anti-RR positive samples.

Disclosures

The authors declare that they have no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Oral Biology, University of Florida, 1395 Center Drive, Gainesville, FL, 32610-0424, USA

    Wendy C. Carcamo, Angela Ceribelli, S. John Calise, Claire Krueger & Edward K. L. Chan

  2. Pathology, Immunology, and Laboratory Medicine, University of Florida, 1600 SW Archer Rd., Gainesville, FL, 32610-0275, USA

    Chen Liu & Minoru Satoh

  3. Clinical Biochemistry, General Hospital, 39100, Bolzano, Italy

    Massimo Daves

  4. Allergology and Clinical Immunology, A.O. S. Maria degli Angeli, 33170, Pordenone, Italy

    Danilo Villalta

  5. Laboratory of Clinical Pathology, San Antonio Hospital, 33028, Tolmezzo, Italy

    Nicola Bizzaro

  6. Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Florida, 1600 SW Archer Rd., Gainesville, FL, 32610-0221, USA

    Minoru Satoh

Authors
  1. Wendy C. Carcamo
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  2. Angela Ceribelli
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  3. S. John Calise
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  4. Claire Krueger
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  5. Chen Liu
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  7. Danilo Villalta
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  9. Minoru Satoh
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  10. Edward K. L. Chan
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Corresponding author

Correspondence to Edward K. L. Chan.

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Carcamo, W.C., Ceribelli, A., Calise, S.J. 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 33, 420–426 (2013). https://doi.org/10.1007/s10875-012-9827-4

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  • DOI: https://doi.org/10.1007/s10875-012-9827-4

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