GET THE APP

Could Multiple Sclerosis Develop due to Epstein Barr Virus Infect
Advanced Techniques in Biology & Medicine

Advanced Techniques in Biology & Medicine
Open Access

ISSN: 2379-1764

+44 1223 790975

Opinion Article - (2016) Volume 4, Issue 4

Could Multiple Sclerosis Develop due to Epstein Barr Virus Infections Causing a Time-Delayed Transcriptional-Activation of Human Endogenous Retroviruses?

Jacob Z Dalgaard*
The University of Warwick, Coventry, England, UK
*Corresponding Author: Jacob Z Dalgaard, The University of Warwick, Coventry, Farmer Ward Road Kenilworth, Warwickshire CV82DJ, United Kingdom, Tel: 44( 0)1926851170/44(0)7939692966 Email:

Abstract

The underlying cause of multiple sclerosis (MS) is not fully understood. However, it is known that Epstein Barr virus (EBV) infections pre-date the development of the disease. Here I explore whether the underlying cause of Multiple Sclerosis can be explained by an inappropriate intra-cellular transcriptional response to the integration of the EBV in the genome of neural cells. Such a re-programming is proposed to lead to the transcriptional activation of other dormant viruses, human endogenous retroviruses (HERVs), followed by the “auto-immune” response and inflammation observed in the brain of MS patients?

Keywords: Multiple sclerosis, Epstein barr virus, HERVs, Human endogenous retroviruses, Vitamin D, Transcription regulation, Epigenetics

Multiple sclerosis (MS) is a chronic inflammatory disease leading to demyelination (loss of oligodendrocytes) and axon injury within the central nervous system. Both genetic and environmental factors have been attributed to MS risk. The major risk factor for MS is EBV [1- 12]. EBV belongs to the herpes virus family, known to infect the central nervous system (CNS). Approximately 90% of the population carries antibodies to EBV; most people are exposed to the virus in childhoodwhere the disease pattern is asymptomatic, while virus infections in teenage years or later in life, leads to a more severe disease referred to as mononucleosis. People that have not been exposed to the virus have a very low risk of developing MS; however, if they are exposed to EBV during childhood they will have a significant risk of developing the disease later in life (less than a 0.2% chance). This risk increases further 2-3 fold if the EBV infection leads to mononucleosis [13]. Under normal EBV infections, the virus will at some point migrate through the peripheral neural axons to the CNS, enter the cells nucleus and integrate itself into the genome. Here the virus enters a latent stage with very low levels of viral gene-expression. This silenced stage is dependent on host factors.

Here I propose that: A) due to the maintenance of this latent/ dormant EBV stage is defective in MS patients, or B) due to the lowlevel expression of the latent virus; the EBV causes changes in the transcription programme of the neural host cell, leading to an activation of other dormant viruses (HERVs; see below). In this model, MS is the direct result of the immunological and inflammatory response to this “inappropriate” expression of viral proteins and genomes in the CNS.

Herpes viruses are not the only family of viruses that integrate themselves into the host genome. Retroviruses are also able to enter an integrated latent stage and have earlier been proposed to be involved in MS [14-16]. Indeed, towards 8% of our genomic DNA consists of DNA of retroviral origin [17]. The majority of such DNA is LTR (Long Terminal Repeat) sequences lacking open reading frames. However, some elements (Human Endogenous Retroviruses; HERV) possess functional open reading frames. There are several clinical observations that have been proposed to support a role for HERVs in MS:

I) MS patients are characterized by the presences of immunoglobulins in the cerebrospinal fluid. In general, viral CNS infections in non-MS patients can lead to the appearance of antibodies in the cerebrospinal fluid specifically targeted towards the pathogen, however, in MS patients the cerebrospinal fluid antibodies are diverse, recognizing several viral antigens including EBV and HERVs [18].

II) It has been shown that most, but not all, MS patient’s lymphocytes express reverse-transcriptase positive retrovirallike HERV particles [19-21].

III) The adaptive immune response to certain HERVs is elevated in most MS patients, especially when MS is active [22-24].

IV) HERV antigens exhibit elevated expression levels in peripheral mono-nuclear blood cells from MS patients [25-27].

V) In a Sardinian cohort of MS patients a correlation between levels of retroviral related RNAs in the cerebrospinal fluid and disease prognosis has been established [28].

VI) A study looking at transcriptional levels found that transcription levels of HERVs (HERV-H, HERV-K and HERV-W) are higher in MS CSN cells [29].

How would it be possible that an initial EBV infection, low-level latent EBV expression or defective silencing of integrated EBVs, subsequently could lead to a time-delayed expression of HERVs? Although the mechanism is not known, such an effect has already been described in another system: A very interesting set of experiments, looking at cocaine addiction in rats, showed that approximately 20% of the animals having had a single exposure to the drug developed changes in the CNS gene expression and DNA methylation profiles [30]. Importantly these changes did not occur at the time of cocaine exposure, but in a delayed manner during extended periods after the initial exposure. The rats, where the changes occurred, were the ones that subsequently became addicted when they were re-exposed to cocaine. Similarly, in MS patients, EBV infection and virus integration in the neurons could, in a similar sub-population, lead to time delayed changes in the gene-expression program in the CNS, including to the reactivation of HERVs. Such a re-activation would then provoke an “auto”-immune response, as they potentially would not have been expressed during B-cell and T-cell maturation and clonal elimination.

How would this a model fit the genetic linkage studies? Interestingly, while Genome Wide Association Studies have identified a large number (more than 100) of single nucleotide polymorphisms (SNPs) that show linkage dis-equibrilium with regards to MS risk [31-38]. However, each SNP linked marker only slightly increases the risk of developing MS, adding up to a 54% genetic cause of the disease. Importantly, the SNP linked to the MHC allele HLA-DR2 (DRB1*1501)/DQ6 (DQB1*0602) shows the strongest genetic association with MS risk, increasing the odds 3.08 fold [31,39,40]. MHC molecules are involved in displaying peptides, generated within the cell, to the immune-system, and this MHC mediated display acted to establish an immune-response to viral infections.

Another SNP that has been linked to increased MS risk is associated with NF-kβ, a factor that plays a central role in the inflammatory response [37,41].

Similarly, as expected, other SNPs associated with minor increased MS risks, are in the vicinity of other gene involved in the immune and inflammatory responses [32,35,41-43].

However, in support of the proposed model, a subsequent study has established that there is a significant over-representation, among the MS-risk associated SNPs, of SNPs that are in the vicinity of HERVs [44]. This observation adds direct support for the importance of these elements in the MS disease development.

An additional observation that supports the proposed model for the establishment MS is the observation that retroviral drugs inhibit the MS development; HIV-positive patients that receive anti-retroviral drug treatment show a decreased risk of developing MS [45,46]. Indeed, one HIV-positive patient with MS recovered completely when she was put on anti-retroviral drugs [47] and it was indeed proposed in this study that it could be due to the drugs effect on HERVs.

Finally, the in the public most well-known risk factor for MS is the patients’ geographical latitude in regards to residence [48,49]. This effect on MS disease risk has been proposed to be due to different vitamin D levels in patients due to differences in sun exposure [50]. In support of this, recent studies have established linkage between four alleles significantly affecting (decreased) levels of the vitamin D precursor 25-hydroxy vitamin D, and MS risk. However, the increased risk was only two-fold greater [51]. Vitamin D deficiency has been shown to lead to excessive B-cell response in MS patients [52]. Alternatively, both vitamin D and the geographical latitude of the patients' residence could also have a more direct effect on the establishment of the disease through an effect on the transcriptional programme in neurons. In this context, it is noteworthy that another patient, Dr. Wahls, has shown an astonishing recovery from this otherwise chronic disease, after making significant changes to her diet [53]. Importantly, the diet she is following is very rich in brassica, known to have anti-inflammatory effects, and which are a source of isothiocyanates. These compounds inhibit both histone deacetylase transferases and DNA-methyltransferases [54]. Although histone de-acetylase and DNA-methyltransferases inhibitors could seem counter-intuitive in causing silencing of integrated EBV/ HERVs, it is well known that activation of one subset of genes by desilencing, can lead to repression of another sub-set of genes.

In conclusion, I would like to add that if this model is correct, MS patients should be treated with a combination of drugs; including retrovirals (currently being tested for treatment of MS), antiinflammatory and immune-suppressing drugs, potentially combined with the brassica rich diet. Importantly, since the MS symptoms only express themselves once inflammation and de-myelination have occurred, any treatment has to be maintained for extended periods of time to allow persistent inactivation of the inflammatory and immunological responses, and for the re-myelination of the neurons by the oligodendrocytes.

References

  1. Sumaya CV, Myers LW, Ellison GW (1980) Epstein-Barr virus antibodies in multiple sclerosis. Arch Neurol 37: 94-96.
  2. Santiago O, Gutierrez J, Sorlozano A, de Dios Luna J, Villegas E, et al. (2010) Relation between Epstein-Barr virus and multiple sclerosis: Analytic study of scientific production. Eur J ClinMicrobiol Infect Dis 29: 857-866.
  3. Ascherio A, Munger KL, Lennette ET, Spiegelman D, Hernan MA, et al. (2001) Epstein-Barr virus antibodies and risk of multiple sclerosis: A prospective study. JAMA 286: 3083-3088.
  4. Levin LI, Munger KL, Rubertone MV, Peck CA, Lennette ET, et al. (2005) Temporal relationship between elevation of Epstein-Barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis. JAMA 293: 2496-2500.
  5. Jilek S, Schluep M, Meylan P, Vingerhoets F, Guignard L, et al. (2008) Strong EBV-specific CD8+ T-cell response in patients with early multiple sclerosis. Brain 131: 1712-1721.
  6. Lunemann JD, Edwards N, Muraro PA, Hayashi S, Cohen JI, et al. (2006) Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis. Brain 129: 1493-1506.
  7. Angelini DF, Serafini B, Piras E, Severa M, Coccia EM, et al. (2013) Increased CD8+ T cell response to Epstein-Barr virus lytic antigens in the active phase of multiple sclerosis. PLoSPathog 9: e1003220.
  8. Serafini B, Rosicarelli B, Franciotta D, Magliozzi R, Reynolds R, et al. (2007) Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J Exp Med 204: 2899-2912.
  9. Magliozzi R, Serafini B, Rosicarelli B, Chiappetta G, Veroni C, et al. (2013) B-cell enrichment and Epstein-Barr virus infection in inflammatory cortical lesions in secondary progressive multiple sclerosis. J NeuropatholExpNeurol 72: 29-41.
  10. Lunemann JD, Tintore M, Messmer B, Strowig T, Rovira A, et al. (2010) Elevated Epstein-Barr virus-encoded nuclear antigen-1 immune responses predict conversion to multiple sclerosis. Ann Neurol 67: 159-169.
  11. McKay KA, Jahanfar S, Duggan T, Tkachuk S, Tremlett H (2016) Factors associated with onset, relapses or progression in multiple sclerosis: A systematic review. Neurotoxicology.
  12. Correale J, Gaitan MI (2015) Multiple sclerosis and environmental factors: The role of vitamin D, parasites, and Epstein-Barr virus infection. ActaNeurolScand 132: 46-55.
  13. Nielsen TR, Rostgaard K, Nielsen NM, Koch-Henriksen N, Haahr S, et al. (2007) Multiple sclerosis after infectious mononucleosis. Arch Neurol 64: 72-75.
  14. Christensen T (2005) Association of human endogenous retroviruses with multiple sclerosis and possible interactions with herpes viruses. Rev Med Virol 15: 179-211.
  15. Christensen T (2010) HERVs in neuropathogenesis. J NeuroimmunePharmacol 5: 326-335.
  16. Christensen T (2016) Human endogenous retroviruses in neurologic disease. APMIS 124: 116-126.
  17. Griffiths DJ (2001) Endogenous retroviruses in the human genome sequence. Genome Biol 2: REVIEWS1017.
  18. Reiber H, Ungefehr S, Jacobi C (1998) The intrathecal, polyspecific and oligoclonal immune response in multiple sclerosis. Mult Scler 4: 111-117.
  19. Perron H, Firouzi R, Tuke P, Garson JA, Michel M, et al. (1997) Cell cultures and associated retroviruses in multiple sclerosis. Collaborative Research Group on MS. ActaNeurolScandSuppl 169: 22-31.
  20. Christensen T, Jensen AW, Munch M, Haahr S, Sorensen PD, et al. (1997) Characterization of retroviruses from patients with multiple sclerosis. ActaNeurolScandSuppl 169: 49-58.
  21. Christensen T, Dissing Sorensen P, Riemann H, Hansen HJ, Moller-Larsen A (1998) Expression of sequence variants of endogenous retrovirus RGH in particle form in multiple sclerosis. Lancet 352: 1033.
  22. Brudek T, Christensen T, Hansen HJ, Bobecka J, Moller-Larsen A (2004) Simultaneous presence of endogenous retrovirus and herpes virus antigens has profound effect on cell-mediated immune responses: Implications for multiple sclerosis. AIDS Res Hum Retroviruses 20: 415-423.
  23. Mameli G, Cossu D, Cocco E, Frau J, Marrosu MG, et al. (2015) Epitopes of HERV-Wenv induce antigen-specific humoral immunity in multiple sclerosis patients. J Neuroimmunol 280: 66-68.
  24. Perron H, Jouvin-Marche E, Michel M, Ounanian-Paraz A, Camelo S, et al. (2001) Multiple sclerosis retrovirus particles and recombinant envelope trigger an abnormal immune response in vitro, by inducing polyclonal Vbeta16 T-lymphocyte activation. Virology 287: 321-332.
  25. Brudek T, Christensen T, Aagaard L, Petersen T, Hansen HJ, et al. (2009) B cells and monocytes from patients with active multiple sclerosis exhibit increased surface expression of both HERV-H Env and HERV-W Env, accompanied by increased seroreactivity. Retrovirology 6: 104.
  26. Laska MJ, Brudek T, Nissen KK, Christensen T, Moller-Larsen A, et al. (2012) Expression of HERV-Fc1, a human endogenous retrovirus, is increased in patients with active multiple sclerosis. J Virol 86: 3713-3722.
  27. Mameli G, Poddighe L, Mei A, Uleri E, Sotgiu S, et al. (2012) Expression and activation by Epstein Barr virus of human endogenous retroviruses-W in blood cells and astrocytes: inference for multiple sclerosis. PLoS One 7: e44991.
  28. Sotgiu S, Serra C, Mameli G, Pugliatti M, Rosati G, et al. (2002) Multiple sclerosis-associated retrovirus and MS prognosis: An observational study. Neurology 59: 1071-1073.
  29. Johnston JB, Silva C, Holden J, Warren KG, Clark AW, et al. (2001) Monocyte activation and differentiation augment human endogenous retrovirus expression: implications for inflammatory brain diseases. Ann Neurol 50: 434-442.
  30. Massart R, Barnea R, Dikshtein Y, Suderman M, Meir O, et al. (2015) Role of DNA methylation in the nucleus accumbens in incubation of cocaine craving. J Neurosci 35: 8042-8058.
  31. Patsopoulos NA, Bayer Pharma MSGWG, Steering Committees of Studies Evaluating I-b, a CCRA, Consortium AN, et al. (2011) Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci. Ann Neurol 70: 897-912.
  32. International Multiple Sclerosis Genetics C;Hafler DA, Compston A, Sawcer S, Lander ES, et al. (2007) Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 357: 851-862.
  33. International Multiple Sclerosis Genetics C (2010) Comprehensive follow-up of the first genome-wide association study of multiple sclerosis identifies KIF21B and TMEM39A as susceptibility loci. Hum Mol Genet 19: 953-962.
  34. De Jager PL, Jia X, Wang J, de Bakker PI, Ottoboni L, et al. (2009) Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nat Genet 41: 776-782.
  35. International Multiple Sclerosis Genetics C;Wellcome Trust Case Control C;Sawcer S, Hellenthal G, Pirinen M, et al. (2011) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476: 214-219.
  36. International Multiple Sclerosis Genetics C;Lill CM, Schjeide BM, Graetz C, Ban M, et al. (2013) MANBA, CXCR5, SOX8, RPS6KB1 and ZBTB46 are genetic risk loci for multiple sclerosis. Brain 136: 1778-1782.
  37. Hussman JP, Beecham AH, Schmidt M, Martin ER, McCauley JL, et al. (2016) GWAS analysis implicates NF-kappaB-mediated induction of inflammatory T cells in multiple sclerosis. Genes Immun 17: 305-312.
  38. Bos SD, Berge T, Celius EG, Harbo HF (2016) From genetic associations to functional studies in multiple sclerosis. Eur J Neurol 23: 847-853.
  39. Olerup O, Hillert J (1991) HLA class II-associated genetic susceptibility in multiple sclerosis: A critical evaluation. Tissue Antigens 38: 1-15.
  40. Barcellos LF, Sawcer S, Ramsay PP, Baranzini SE, Thomson G, et al. (2006) Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis. Hum Mol Genet 15: 2813-2824.
  41. International Multiple Sclerosis Genetics C, Beecham AH, Patsopoulos NA, Xifara DK, Davis MF, et al. (2013) Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet 45: 1353-1360.
  42. Gregory SG, Schmidt S, Seth P, Oksenberg JR, Hart J, et al. (2007) Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat Genet 39: 1083-1091.
  43. Damotte V, Guillot-Noel L, Patsopoulos NA, Madireddy L, El Behi M, et al. (2014) A gene pathway analysis highlights the role of cellular adhesion molecules in multiple sclerosis susceptibility. Genes Immun 15: 126-132.
  44. Brutting C, Emmer A, Kornhuber M, Staege MS (2016) A survey of endogenous retrovirus (ERV) sequences in the vicinity of multiple sclerosis (MS)-associated single nucleotide polymorphisms (SNPs). MolBiol Rep 43: 827-836.
  45. Nexo BA, Pedersen L, Sorensen HT, Koch-Henriksen N (2013) Treatment of HIV and risk of multiple sclerosis. Epidemiology 24: 331-332.
  46. Gold J, Goldacre R, Maruszak H, Giovannoni G, Yeates D, et al. (2015) HIV and lower risk of multiple sclerosis: Beginning to unravel a mystery using a record-linked database study. J NeurolNeurosurg Psychiatry 86: 9-12.
  47. Maruszak H, Brew BJ, Giovannoni G, Gold J (2011) Could antiretroviral drugs be effective in multiple sclerosis? A case report. Eur J Neurol 18: e110-111.
  48. Simpson S, Jr., Blizzard L, Otahal P, Van der Mei I, Taylor B (2011) Latitude is significantly associated with the prevalence of multiple sclerosis: A meta-analysis. J NeurolNeurosurg Psychiatry 82: 1132-1141.
  49. Hernan MA, Olek MJ, Ascherio A (1999) Geographic variation of MS incidence in two prospective studies of US women. Neurology 53: 1711-1718.
  50. Ebers GC (2008) Environmental factors and multiple sclerosis. Lancet Neurol 7: 268-277.
  51. Mokry LE, Ross S, Ahmad OS, Forgetta V, Smith GD, et al. (2015) Vitamin D and risk of multiple sclerosis: A mendelian randomization study. PLoS Med 12: e1001866.
  52. Fyfe I (2016) Multiple sclerosis: Vitamin D deficiency leads to excessive B-cell responses in multiple sclerosis. Nat Rev Neurol 12: 252.
  53. Wahls T, Adamson E (2014) The Wahlsprotocol; Howi beat MS using paleo principles and functional medicine. Avery, New York.
  54. Wagner AE, Terschluesen AM, Rimbach G (2013) Health promoting effects of brassica-derived phytochemicals: From chemopreventive and anti-inflammatory activities to epigenetic regulation. Oxid Med Cell Longev 2013: 964539.
Citation: Dalgaard JZ (2016) Could Multiple Sclerosis Develop due to Epstein Barr Virus Infections Causing a Time-Delayed Transcriptional-Activation of Human Endogenous Retroviruses? Adv Tech Biol Med 4: 191.

Copyright: © 2016 Dalgaard JZ. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Top