Virologica Sinica

, Volume 32, Issue 5, pp 423–430 | Cite as

Elevated expression of EBV and TLRs in the brain is associated with Rasmussen’s encephalitis

  • Xin Wang
  • Yisong Wang
  • Dong Liu
  • Peigang Wang
  • Dongying Fan
  • Yuguang Guan
  • Tianfu Li
  • Guoming LuanEmail author
  • Jing AnEmail author
Research Article


Rasmussen’s encephalitis (RE) is a rare pediatric neurological disorder, the etiology of which remains unclear. It has been speculated that the immunopathogenesis of RE involves damage to neurons, which eventually leads to the occurrence of RE. Viral infection may be a critical factor in triggering RE immunopathogenesis. In this study, we analyzed the expression of Epstein-Barr virus (EBV) antigens as well as of Toll-like receptor 3 (TLR3), TLR9, and downstream adapter TIR-domain-containing adapter-inducing interferon-β (TRIF) in the brain tissues of 26 patients with RE and 16 control individuals using immunohistochemistry (IHC). In the RE group, EBV antigens were detected in 53% of individuals at various expression levels. In contrast, there was no detectable EBV antigen expression in control brain tissues. Moreover, we found marked increases in the expression of TLR3, TLR9, and TRIF in the brain tissues of RE patients compared with levels in the control group. Furthermore, among RE cases, EBV expression and high TLR3 expression were associated with more severe brain atrophy. Our results suggest that the elevated expression of EBV and TLRs may be involved in RE occurrence through the activation of downstream molecules.


Rasmussen’s encephalitis (RE) Epstein-Barr virus (EBV) Toll-Like receptor (TLR) TIR-domain-containing adapter-inducing interferon-β (TRIF) epilepsy 



This work was supported by the following funds: the National Natural Science Foundation of China (81471957, 81571275, 81671971, and 81701992), the Beijing Municipal Natural Science Foundation (7144217), and the Scientific Research Common Program of Beijing Municipal Commission of Education (KM201610025001).

Author Contributions

JA, GML and YSW conceived and designed the experiments. XW and DL performed the experiments and analyzed the data. PGW, YGG, TFL and DYF contributed reagents/materials/analysis tools. XW and DL wrote the manuscript and prepared the figures and/or tables. JA and GML revised the manuscript, organized the collaboration and directed the project. All authors read and approved the final manuscript.

Compliance with Ethics Guidelines

The authors declare that they have no conflict of interest. This study was approved by the Ethics Committee of Sanbo Brain Hospital, Capital Medical University (2013 061801), and written informed consent was obtained from all participants or their guardians prior to the study.


  1. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. 2001. Recognition of double-stranded rna and activation of nf-kappab by toll-like receptor 3. Nature, 413: 732–738.CrossRefGoogle Scholar
  2. Allred DC, Harvey JM, Berardo M, Clark GM. 1998. Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol, 11: 155–168.PubMedGoogle Scholar
  3. Bauer J, Bien CG, Lassmann H. 2002. Rasmussen’s encephalitis: A role for autoimmune cytotoxic t lymphocytes. Curr Opin Neurol, 15: 197–200.CrossRefGoogle Scholar
  4. Bien CG, Bauer J, Deckwerth TL, Wiendl H, Deckert M, Wiestler OD, Schramm J, Elger CE, Lassmann H. 2002. Destruction of neurons by cytotoxic t cells: A new pathogenic mechanism in rasmussen’s encephalitis. Ann Neurol, 51: 311–318.CrossRefGoogle Scholar
  5. Bien CG, Granata T, Antozzi C, Cross JH, Dulac O, Kurthen M, Lassmann H, Mantegazza R, Villemure JG, Spreafico R, Elger CE. 2005. Pathogenesis, diagnosis and treatment of rasmussen encephalitis: A european consensus statement. Brain, 128: 454–471.CrossRefGoogle Scholar
  6. Bsibsi M, Ravid R, Gveric D, van Noort JM. 2002. Broad expression of toll-like receptors in the human central nervous system. J Neuropathol Exp Neurol, 61: 1013–1021.CrossRefGoogle Scholar
  7. Chen S, Guan Y, Zhang Y, Qi X, An J, Wang Y, Luan G. 2016. Elevated expression of human papillomavirus antigen in brain tissue of patients with rasmussen’s encephalitis. Epilepsy Res, 126: 119–125.CrossRefGoogle Scholar
  8. Eeg-Olofsson O, Bergström T, Andermann F, Andermann E, Olivier A, Rydenhag B. 2004. Herpesviral DNA in brain tissue from patients with temporal lobe epilepsy. Acta Neurol Scand, 109: 169–174.CrossRefGoogle Scholar
  9. Farrell MA, Cheng L, Cornford ME, Grody WW, Vinters HV. 1991. Cytomegalovirus and rasmussen’s encephalitis. Lancet, 337: 1551–1552.CrossRefGoogle Scholar
  10. Friedman H, Ch’ien L, Parham D. 1977. Virus in brain of child with hemiplegia, hemiconvulsions, and epilepsy. Lancet, 2: 666.CrossRefGoogle Scholar
  11. Guan Y, Zhou J, Luan G, Liu X. 2014. Surgical treatment of patients with rasmussen encephalitis. Stereotact Funct Neurosurg, 92: 86–93.CrossRefGoogle Scholar
  12. Jay V, Becker LE, Otsubo H, Cortez M, Hwang P, Hoffman HJ, Zielenska M. 1995. Chronic encephalitis and epilepsy (rasmussen’s encephalitis): Detection of cytomegalovirus and herpes simplex virus 1 by the polymerase chain reaction and in situ hybridization. Neurology, 45: 108–117.CrossRefGoogle Scholar
  13. Mantegazza R, Bernasconi P, Baggi F, Spreafico R, Ragona F, Antozzi C, Bernardi G, Granata T. 2002. Antibodies against glur3 peptides are not specific for rasmussen’s encephalitis but are also present in epilepsy patients with severe, early onset disease and intractable seizures. J Neuroimmunol, 131: 179–185.CrossRefGoogle Scholar
  14. Matin N, Tabatabaie O, Falsaperla R, Lubrano R, Pavone P, Mahmood F, Gullotta M, Serra A, Di Mauro P, Cocuzza S, Vitaliti G. 2015. Epilepsy and innate immune system: A possible immunogenic predisposition and related therapeutic implications. Hum Vaccin Immunother, 11: 2021–2029.CrossRefGoogle Scholar
  15. Pardo CA, Vining EP, Guo L, Skolasky RL, Carson BS, Freeman JM. 2004. The pathology of rasmussen syndrome: Stages of cortical involvement and neuropathological studies in 45 hemispherectomies. Epilepsia, 45: 516–526.CrossRefGoogle Scholar
  16. Power C, Poland SD, Blume WT, Girvin JP, Rice GP. 1990. Cytomegalovirus and rasmussen’s encephalitis. Lancet, 336: 1282–1284.CrossRefGoogle Scholar
  17. Rasmussen T, Olszewski J, Lloydsmith D. 1958. Focal seizures due to chronic localized encephalitis. Neurology, 8: 435–445.CrossRefGoogle Scholar
  18. Rogers SW, Andrews PI, Gahring LC, Whisenand T, Cauley K, Crain B, Hughes TE, Heinemann SF, McNamara JO. 1994. Autoantibodies to glutamate receptor glur3 in rasmussen’s encephalitis. Science, 265: 648–651.CrossRefGoogle Scholar
  19. Takahashi Y, Matsuda K, Kubota Y, Shimomura J, Yamasaki E, Kudo T, Fukushima K, Osaka H, Akasaka N, Imamura A, Yamada S, Kondo N, Fujiwara T. 2006. Vaccination and infection as causative factors in japanese patients with rasmussen syndrome: Molecular mimicry and hla class i. Clin Dev Immunol, 13: 381–387.CrossRefGoogle Scholar
  20. Varadkar S, Bien CG, Kruse CA, Jensen FE, Bauer J, Pardo CA, Vincent A, Mathern GW, Cross JH. 2014. Rasmussen’s encephalitis: Clinical features, pathobiology, and treatment advances. Lancet Neurol, 13: 195–205.CrossRefGoogle Scholar
  21. Verma R, Bharti K. 2017. Toll like receptor 3 and viral infections of nervous system. J Neurol Sci, 372: 40–48.CrossRefGoogle Scholar
  22. Walter GF, Renella RR. 1989. Epstein-barr virus in brain and rasmussen’s encephalitis. Lancet, 1: 279–280.CrossRefGoogle Scholar
  23. Wang L, Wei D, Huang S, Peng Z, Le X, Wu TT, Yao J, Ajani J, Xie K. 2003. Transcription factor sp1 expression is a significant predictor of survival in human gastric cancer. Clin Cancer Res, 9: 6371–6380.PubMedGoogle Scholar
  24. Wiendl H, Bien CG, Bernasconi P, Fleckenstein B, Elger CE, Dichgans J, Mantegazza R, Melms A. 2001. Glur3 antibodies: Prevalence in focal epilepsy but no specificity for rasmussen’s encephalitis. Neurology, 57: 1511–1514.CrossRefGoogle Scholar
  25. Zhang Y, Wang Y, Chen S, Guan Y, Liu C, Li T, Luan G, An J. 2017. Expression of human cytomegalovirus components in the brain tissues of patients with rasmussen’s encephalitis. Virol Sin, 32: 115–121.CrossRefGoogle Scholar

Copyright information

© Wuhan Institute of Virology, CAS and Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  1. 1.Department of Microbiology, School of Basic Medical SciencesCapital Medical UniversityBeijingChina
  2. 2.Department of Neurosurgery, Sanbo Brain HospitalCapital Medical UniversityBeijingChina
  3. 3.Beijing Key Laboratory of EpilepsyBeijingChina
  4. 4.Center of EpilepsyBeijing Institute for Brain DisordersBeijingChina

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