Skip to main content

Advertisement

SpringerLink
Log in

Graves’ orbitopathy, idiopathic orbital inflammatory pseudotumor and Epstein–Barr virus infection: a serological and molecular study

  • Original Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Objective

One of the hypotheses on the pathogenesis of autoimmune diseases, including Graves’ disease (GD) and Graves’ orbitopathy (GO), involves bacterial or viral infections. Recently, Epstein–Barr virus (EBV) has been proposed to play a role in the pathogenesis of idiopathic orbital inflammatory pseudotumor (IOIP) in Asians. The aim of the present study was to investigate the possible association of GO with EBV infection/exposure, as compared with IOIP, using serum and tissue samples, as well as primary cultures of orbital fibroblasts.

Methods

Thirty-one patients were studied, including four with IOIP, ten with GO, nine with GD without GO and eight control patients without IOIP, GD and GO. All patients with IOIP and GO underwent orbital decompression. Control patients underwent palpebral surgery. Fibroadipose orbital tissue samples were collected. Serum anti-EBV antibodies were measured in all patients. EBV-DNA was measured in blood samples, orbital tissue samples and primary cultures of orbital fibroblasts.

Results

Serum assays showed that the vast majority of patients have had a previous exposure to EBV, but no one had an acute infection. EBV-DNA was detected in ~40% of blood samples from GO, GD and control patients, but in none of the IOIP samples. EBV-DNA was not detected in any of the orbital tissue samples tested or in primary cultures of orbital fibroblasts.

Conclusions

EBV infection does not seem to be associated with GD, GO and IOIP in Caucasians. Whether EBV is involved in IOIP in Asians or other populations remains to be confirmed.

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

Similar content being viewed by others

References

  1. Davies TF (2008) Infection and autoimmune thyroid disease. J Clin Endocrinol Metab 93:674–676

    Article  CAS  PubMed  Google Scholar 

  2. Marinò M, Latrofa F, Menconi F, Chiovato L, Vitti P (2015) Role of genetic and non-genetic factors in the etiology of Graves’ disease. J Endocrinol Invest 38:283–294

    Article  PubMed  Google Scholar 

  3. Brix TH, Hansen PS, Hegedüs L, Wenzel BE (2008) Too early to dismiss Yersinia enterocolitica infection in the aetiology of Graves’ disease. Evidence from a twin case-control study. Clin Endocrinol 69:491–496

    Article  Google Scholar 

  4. Larizza D, Calcaterra V, Martinetti M, Negrini R, De Silvestri A, Cisternino M, Iannone AM, Solcia E (2006) Helicobacter pylori infection and autoimmune thyroid disease in young patients: the disadvantage of carrying the human leukocyte antigen-DRB1*0301 allele. J Clin Endocrinol Metab 91:176–179

    Article  CAS  PubMed  Google Scholar 

  5. Bassi V, Marino G, Iengo A, Fattoruso O, Santinelli C (2012) Autoimmune thyroid diseases and Helicobacter pylori: the correlation is present only in Graves’ disease. World J Gastroenterol 18:1093–1097

    Article  PubMed  PubMed Central  Google Scholar 

  6. Ciampolillo A, Mirakian R, Schulz T, Buscema M, Schulz T, Pujol-Borrell R, Bottazzo GF (1989) Retrovirus-like sequences in Graves’ disease: implications for human autoimmunity. Lancet 1:1096–1099

    Article  CAS  PubMed  Google Scholar 

  7. Humphrey M, Baker JJ, Carr FE, Drabick JJ, Carr FE, Burke DS, Wartofsky L, Djuh YY, Burman KD (1991) Absence of retroviral sequences in Graves’ disease. Lancet 337:17–18

    Article  CAS  PubMed  Google Scholar 

  8. Fierabracci A, Upton CP, Hajibagheri N, Bottazzo GF (2001) Lack of detection of retroviral particles (HIAP-1) in the H9 T cell line co-cultured with thyrocytes of Graves’ disease. J Autoimmun 16:457–462

    Article  CAS  PubMed  Google Scholar 

  9. Jaspan JB, Luo H, Ahmed B, Tenenbaum S, Voss T, Sander DM, Bollinger K, Baquet T, Garry RF (1995) Evidence for a retroviral trigger in Graves’ disease. Autoimmunity 20:135–142

    Article  CAS  PubMed  Google Scholar 

  10. Wick G, Grubeck-Loebenstein B, Trieb K, Trieb K, Kalischnig G, Aguzzi A (1992) Human foamy virus antigens in thyroid tissue of Graves’ disease patients. Int Arch Allergy Immunol 99:153–156

    Article  CAS  PubMed  Google Scholar 

  11. Schweizer M, Turek R, Reinhardt M, Neumann HD (1994) Absence of foamy virus DNA in Graves’ disease. AIDS Res Hum Retrovir 10:601–605

    Article  CAS  PubMed  Google Scholar 

  12. Schweizer M, Turek R, Hahn H, Schliephake A, Netzer KO, Eder G, Reinhardt M, Rethwilm A, Neumann-Haefelin D (1995) Markers of foamy virus infections in monkeys, apes, and accidentally infected humans: appropriate testing fails to confirm suspected foamy virus prevalence in humans. AIDS Res Hum Retrovir 11:161–170

    Article  CAS  PubMed  Google Scholar 

  13. Jin R, Zhao P, Ma X, Ma J, Wu Y, Yang X, Zhang J, Zhong R, Zeng Y (2013) Quantification of Epstein–Barr virus DNA in patients with idiopathic orbital inflammatory pseudotumor. PLoS ONE 8:e50812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Patnana M, Sevrukov AB, Elsayes KM, Viswanathan C, Lubner M, Menias CO (2012) Inflammatory pseudotumor: the great mimicker. AJR Am J Roentgenol 198:W217–W227

    Article  PubMed  Google Scholar 

  15. Wiersinga WM, Perros P, Kahaly GJ, Mourits MP, Baldeschi L, Boboridis K, Boschi A, Dickinson AJ, Kendall-Taylor P, Krassas GE, Lane CM, Lazarus JH, Marcocci C, Marinò M, Nardi M, Neoh C, Orgiazzi J, Pinchera A, Pitz S, Prummel MF, Sartini MS, Stahl M, von Arx G (2006) Clinical assessment of patients with Graves’ orbitopathy: the European group on Graves’ orbitopathy recommendations to generalists, specialists and clinical researchers. Eur J Endocrinol 155:387–389

    Article  CAS  PubMed  Google Scholar 

  16. Bartalena L, Baldeschi L, Dickinson A, Eckstein A, Kendall-Taylor P, Marcocci C, Mourits M, Perros P, Boboridis K, Boschi A, Currò N, Daumerie C, Kahaly GJ, Krassas GE, Lane CM, Lazarus JH, Marinò M, Nardi M, Neoh C, Orgiazzi J, Pearce S, Pinchera A, Pitz S, Salvi M, Sivelli P, Stahl M, von Arx G, Wiersinga WM, European Group on Graves’ Orbitopathy (EUGOGO) (2008) Consensus statement of the European Group on Graves’ orbitopathy (EUGOGO) on management of GO. Eur J Endocrinol 158:273–285

    Article  CAS  PubMed  Google Scholar 

  17. Bartalena L, Baldeschi L, Boboridis K, Eckstein A, Kahaly GJ, Marcocci C, Perros P, Salvi M, Wiersinga WM, European Group on Graves’ Orbitopathy (EUGOGO) (2016) The 2016 European Thyroid Association/European Group on Graves’ Orbitopathy Guidelines for the Management of Graves’ Orbitopathy. Eur Thyroid J 5:9–26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bartalena L, Masiello E, Magri F, Veronesi G, Bianconi E, Zerbini F, Gaiti M, Spreafico E, Gallo D, Premoli P, Piantanida E, Tanda ML, Ferrario M, Vitti P, Chiovato L (2016) The phenotype of newly diagnosed Graves’ disease in Italy in recent years is milder than in the past: results of a large observational longitudinal study. J Endocrinol Invest 39:1445–1451

    Article  CAS  PubMed  Google Scholar 

  19. Menconi F, Marcocci C, Marinò M (2014) Diagnosis and classification of Graves’ disease. Autoimmun Rev 13:398–402

    Article  PubMed  Google Scholar 

  20. Marinò M, Latrofa F, Menconi F, Chiovato L, Vitti P (2014) An update on the medical treatment of Graves’ hyperthyroidism. J Endocrinol Invest 37:1041–1048

    Article  PubMed  Google Scholar 

  21. Bartalena L, Chiovato L, Vitti P (2016) Management of hyperthyroidism due to Graves’ disease: frequently asked questions and answers (if any). J Endocrinol Invest 39:1105–1114

    Article  CAS  PubMed  Google Scholar 

  22. Botta R, Lisi S, Marcocci C, Sellari-Franceschini S, Rocchi R, Latrofa F, Menconi F, Altea MA, Leo M, Sisti E, Casini G, Nardi M, Pinchera A, Vitti P, Marinò M (2013) Enalapril reduces proliferation and hyaluronic acid release in orbital fibroblasts. Thyroid 23:92–96

    Article  CAS  PubMed  Google Scholar 

  23. Lisi S, Botta R, Lemmi M, Sellari-Franceschini S, Altea MA, Sisti E, Casini G, Nardi M, Marcocci C, Pinchera A, Marinò M (2011) Quercetin decreases proliferation of orbital fibroblasts and their release of hyaluronic acid. J Endocrinol Invest 34:521–527

    CAS  PubMed  Google Scholar 

  24. Rotondo Dottore G, Leo M, Casini G, Latrofa F, Cestari L, Sellari-Franceschini S, Nardi M, Vitti P, Marcocci C, Marinò M (2016) Anti-oxidant actions of selenium in orbital fibroblasts: a basis for the effects of selenium in Graves’ orbitopathy. Thyroid. doi:10.1089/thy.2016.0397

    PubMed  Google Scholar 

  25. Middeldorp JM (2015) Epstein–Barr virus-specific humoral immune responses in health and disease. Curr Top Microbiol Immunol 391:289–323

    CAS  PubMed  Google Scholar 

  26. Möhl S, Chen J, Sathiyamoorthy K, Jardetzky TS, Longnecker S (2016) Structural and mechanistic insights into the tropism of Epstein–Barr virus. Mol Cells 39:286–291

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical and Experimental Medicine, Endocrinology Unit I, University of Pisa and University Hospital of Pisa, Via Paradisa 2, 56124, Pisa, Italy

    M. Leo, G. R. Dottore, P. Vitti, C. Marcocci & M. Marinò

  2. Division of Virology, University Hospital of Pisa, Via Paradisa 2, 56124, Pisa, Italy

    F. Maggi, P. Mazzetti & M. Pistello

  3. Department of Surgical, Medical and Molecular Pathology, Ophthalmopathy Unit I, University of Pisa and University Hospital of Pisa, Via Paradisa 2, 56124, Pisa, Italy

    G. Casini & M. Nardi

  4. Department of Surgical, Medical and Molecular Pathology, ENT Unit I, University of Pisa and University Hospital of Pisa, Via Paradisa 2, 56124, Pisa, Italy

    S. Sellari-Franceschini

Authors
  1. M. Leo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F. Maggi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G. R. Dottore
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G. Casini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P. Mazzetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. Pistello
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S. Sellari-Franceschini
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M. Nardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. P. Vitti
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. C. Marcocci
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. M. Marinò
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Marinò.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in the study were in accordance with the ethical standards of the Institutional and/or National Research Committee and with the 1964 Helsinki declaration and its later amendments or comparable ethics standards. All applicable international, national and institutional guidelines were followed. The study does not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Leo, M., Maggi, F., Dottore, G.R. et al. Graves’ orbitopathy, idiopathic orbital inflammatory pseudotumor and Epstein–Barr virus infection: a serological and molecular study. J Endocrinol Invest 40, 499–503 (2017). https://doi.org/10.1007/s40618-016-0587-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-016-0587-5

Keywords

Search

Navigation