Young, L. S. & Rickinson, A. B. Epstein-Barr virus: 40 years on. Nat. Rev. Cancer 4, 757–768 (2004).CAS PubMed Article Google Scholar Young, L. S., Yap, L. F. & Murray, P. G. Epstein-Barr virus: more than 50 years old and still providing surprises. Nat. Rev. Cancer 16, 789–802 (2016).CAS PubMed Article Google Scholar Wong, Y.,…
Young, L. S. & Rickinson, A. B. Epstein-Barr virus: 40 years on. Nat. Rev. Cancer 4, 757–768 (2004).
Young, L. S., Yap, L. F. & Murray, P. G. Epstein-Barr virus: more than 50 years old and still providing surprises. Nat. Rev. Cancer 16, 789–802 (2016).
Wong, Y., Meehan, M. T., Burrows, S. R., Doolan, D. L. & Miles, J. J. Estimating the global burden of Epstein-Barr virus-related cancers. J. Cancer Res. Clin. Oncol. https://doi.org/10.1007/s00432-021-03824-y (2021).
Shannon-Lowe, C. & Rickinson, A. The global landscape of EBV-associated tumors. Front. Oncol. 9, 713 (2019).
Dunmire, S. K., Verghese, P. S. & Balfour, H. H. Jr. Primary Epstein-Barr virus infection. J. Clin. Virol. 102, 84–92 (2018).
Fournier, B. & Latour, S. Immunity to EBV as revealed by immunedeficiencies. Curr. Opin. Immunol. 72, 107–115 (2021).
Ascherio, A. & Munger, K. L. Epidemiology of multiple sclerosis: from risk factors to prevention-an update. Semin. Neurol. 36, 103–114 (2016).
Laderach, F. & Munz, C. Epstein Barr virus exploits genetic susceptibility to increase multiple sclerosis risk. Microorganisms https://doi.org/10.3390/microorganisms9112191 (2021).
Walton, C. et al. Rising prevalence of multiple sclerosis worldwide: insights from the Atlas of MS, third edition. Mult. Scler. 26, 1816–1821 (2020).
Alroughani, R. & Boyko, A. Pediatric multiple sclerosis: a review. BMC Neurol. 18, 27 (2018).
Rodgers, M. M. et al. Gait characteristics of individuals with multiple sclerosis before and after a 6-month aerobic training program. J. Rehabil. Res. Dev. 36, 183–188 (1999).
Confavreux, C. & Vukusic, S. The clinical course of multiple sclerosis. Handb. Clin. Neurol. 122, 343–369 (2014).
Thompson, A. J. et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 17, 162–173 (2018).
Brodin, P. et al. Variation in the human immune system is largely driven by non-heritable influences. Cell 160, 37–47 (2015).
Soldan, S. S. & Jacobson, S. in Neurotropic Viral Infections (ed. Reiss, C.) 175–220 (Springer, 2016).
Ruprecht, K. The role of Epstein-Barr virus in the etiology of multiple sclerosis: a current review. Expert Rev. Clin. Immunol. 16, 1143–1157 (2020).
Lanz, T. V. et al. Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature 603, 321–327 (2022).
Bjornevik, K. et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science 375, 296–301 (2022).
Bar-Or, A., Banwell, B., Berger, J. R. & Lieberman, P. M. Guilty by association: Epstein-Barr virus in multiple sclerosis. Nat. Med. 28, 904–906 (2022).
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513, 202–209 (2014).
Baer, R. et al. DNA sequence and expression of the B95-8 Epstein-Barr virus genome. Nature 310, 207–211 (1984).
Kanda, T., Yajima, M. & Ikuta, K. Epstein-Barr virus strain variation and cancer. Cancer Sci. 110, 1132–1139 (2019).
Thorley-Lawson, D. A. EBV persistence–introducing the virus. Curr. Top. Microbiol. Immunol. 390, 151–209 (2015).
Farrell, P. J. Epstein-Barr virus strain variation. Curr. Top. Microbiol. Immunol. 390, 45–69 (2015).
Santpere, G. et al. Genome-wide analysis of wild-type Epstein-Barr virus genomes derived from healthy individuals of the 1000 Genomes Project. Genome Biol. Evol. 6, 846–860 (2014).
Lay, M. L. et al. Epstein-Barr virus genotypes and strains in central nervous system demyelinating disease and Epstein-Barr virus-related illnesses in Australia. Intervirology 55, 372–379 (2012).
Brennan, R. M. et al. Strains of Epstein-Barr virus infecting multiple sclerosis patients. Mult. Scler. 16, 643–651 (2010).
de-Thé, G. et al. Sero-epidemiology of the Epstein-Barr virus: preliminary analysis of an international study- a review 3–16 (IARC Science Publications, 1975).
Balfour, H. H. Jr. et al. Age-specific prevalence of Epstein-Barr virus infection among individuals aged 6-19 years in the United States and factors affecting its acquisition. J. Infect. Dis. 208, 1286–1293 (2013).
Chandran, B. & Hutt-Fletcher, L. in Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis (eds Arvin, A. et al.) (Cambridge Univ. Press, 2007).
Thorley-Lawson, D. A. Epstein-Barr virus: exploiting the immune system. Nat. Rev. Immunol. 1, 75–82 (2001).
Thompson, M. P. & Kurzrock, R. Epstein-Barr virus and cancer. Clin. Cancer Res. 10, 803–821 (2004).
Hassani, A., Corboy, J. R., Al-Salam, S. & Khan, G. Epstein-Barr virus is present in the brain of most cases of multiple sclerosis and may engage more than just B cells. PLoS ONE 13, e0192109 (2018).
Gianella, S. et al. Effect of cytomegalovirus and Epstein-Barr virus replication on intestinal mucosal gene expression and microbiome composition of HIV-infected and uninfected individuals. AIDS 31, 2059–2067 (2017).
Speck, P., Haan, K. M. & Longnecker, R. Epstein-Barr virus entry into cells. Virology 277, 1–5 (2000).
Xiao, J., Palefsky, J. M., Herrera, R. & Tugizov, S. M. Characterization of the Epstein-Barr virus glycoprotein BMRF-2. Virology 359, 382–396 (2007).
Xiao, J., Palefsky, J. M., Herrera, R., Berline, J. & Tugizov, S. M. EBV BMRF-2 facilitates cell-to-cell spread of virus within polarized oral epithelial cells. Virology 388, 335–343 (2009).
Zhang, H. et al. Ephrin receptor A2 is an epithelial cell receptor for Epstein-Barr virus entry. Nat. Microbiol. 3, 1–8 (2018).
Stubbins, R. J. et al. Epstein-Barr virus associated smooth muscle tumors in solid organ transplant recipients: incidence over 31 years at a single institution and review of the literature. Transpl. Infect. Dis. 21, e13010 (2019).
Kimura, H. & Cohen, J. I. Chronic active Epstein-Barr virus disease. Front. Immunol. 8, 1867 (2017).
Jha, H. C. et al. Gammaherpesvirus infection of human neuronal cells. mBio 6, e01844–e01815 (2015).
Menet, A. et al. Epstein-Barr virus infection of human astrocyte cell lines. J. Virol. 73, 7722–7733 (1999).
Kanda, T. EBV-encoded latent genes. Adv. Exp. Med. Biol. 1045, 377–394 (2018).
Kieff, E. & Rickinson, A. B. in Fields Virology (eds Knipe, D. M. & Howley, P. M.) 2603–2654 (Lippincott Williams and Wilkins, 2007).
Shinozaki-Ushiku, A., Kunita, A. & Fukayama, M. Update on Epstein-Barr virus and gastric cancer (review). Int. J. Oncol. 46, 1421–1434 (2015).
Greenspan, J. S., Greenspan, D. & Webster-Cyriaque, J. Hairy leukoplakia; lessons learned: 30-plus years. Oral Dis. 22, 120–127 (2016).
Murata, T. et al. Molecular basis of Epstein-Barr virus latency establishment and lytic reactivation. Viruses https://doi.org/10.3390/v13122344 (2021).
McKenzie, J. & El-Guindy, A. Epstein-Barr virus lytic cycle reactivation. Curr. Top. Microbiol. Immunol. 391, 237–261 (2015).
Chan, C. K. et al. Epstein-Barr virus antibody patterns preceding the diagnosis of nasopharyngeal carcinoma. Cancer Causes Control. 2, 125–131 (1991).
Mueller, N. et al. Epstein-Barr virus antibody patterns preceding the diagnosis of non-Hodgkin’s lymphoma. Int. J. Cancer 49, 387–393 (1991).
Lu, F. et al. Defective Epstein-Barr virus genomes and atypical viral gene expression in B-cell lines derived from multiple myeloma patients. J. Virol. 95, e0008821 (2021).
Rosemarie, Q. & Sugden, B. Epstein-Barr virus: how its lytic phase contributes to oncogenesis. Microorganisms https://doi.org/10.3390/microorganisms8111824 (2020).
Maple, P. A. C., Gran, B., Tanasescu, R., Pritchard, D. I. & Constantinescu, C. S. An absence of Epstein-Barr virus reactivation and associations with disease activity in people with multiple sclerosis undergoing therapeutic hookworm vaccination. Vaccines https://doi.org/10.3390/vaccines8030487 (2020).
Torkildsen, O., Nyland, H., Myrmel, H. & Myhr, K. M. Epstein-Barr virus reactivation and multiple sclerosis. Eur. J. Neurol. 15, 106–108 (2008).
Yea, C. et al. Epstein-Barr virus in oral shedding of children with multiple sclerosis. Neurology 81, 1392–1399 (2013).
Soldan, S. S. & Lieberman, P. M. Epstein-Barr virus infection in the development of neurological disorders. Drug Discov. Today Dis. Model. 32, 35–52 (2020).
Munz, C. Latency and lytic replication in Epstein-Barr virus-associated oncogenesis. Nat. Rev. Microbiol. 17, 691–700 (2019).
Leen, A. et al. Differential immunogenicity of Epstein-Barr virus latent-cycle proteins for human CD4+ T-helper 1 responses. J. Virol. 75, 8649–8659 (2001).
Bickham, K. et al. EBNA1-specific CD4+ T cells in healthy carriers of Epstein-Barr virus are primarily Th1 in function. J. Clin. Invest. 107, 121–130 (2001).
Munz, C. et al. Human CD4+ T lymphocytes consistently respond to the latent Epstein-Barr virus nuclear antigen EBNA1. J. Exp. Med. 191, 1649–1660 (2000).
Azzi, T. et al. Role for early-differentiated natural killer cells in infectious mononucleosis. Blood 124, 2533–2543 (2014).
Dunmire, S. K., Grimm, J. M., Schmeling, D. O., Balfour, H. H. Jr & Hogquist, K. A. The incubation period of primary Epstein-Barr virus infection: viral dynamics and immunologic events. PLoS Pathog. 11, e1005286 (2015).
Williams, H. et al. The immune response to primary EBV infection: a role for natural killer cells. Br. J. Haematol. 129, 266–274 (2005).
Strowig, T. et al. Priming of protective T cell responses against virus-induced tumors in mice with human immune system components. J. Exp. Med. 206, 1423–1434 (2009).
Chijioke, O. et al. Human natural killer cells prevent infectious mononucleosis features by targeting lytic Epstein-Barr virus infection. Cell Rep. 5, 1489–1498 (2013).
Zumwalde, N. A. et al. Adoptively transferred Vγ9Vδ2 T cells show potent antitumor effects in a preclinical B cell lymphomagenesis model. JCI Insight https://doi.org/10.1172/jci.insight.93179 (2017).
Lino, C. N. R. & Ghosh, S. Epstein-Barr virus in inborn immunodeficiency-more than infection. Cancers https://doi.org/10.3390/cancers13194752 (2021).
Cohen, J. I. Primary immunodeficiencies associated with EBV disease. Curr. Top. Microbiol. Immunol. 390, 241–265 (2015).
Huo, S. et al. EBV-EBNA1 constructs an immunosuppressive microenvironment for nasopharyngeal carcinoma by promoting the chemoattraction of Treg cells. J. Immunother. Cancer https://doi.org/10.1136/jitc-2020-001588 (2020).
Westhoff Smith, D., Chakravorty, A., Hayes, M., Hammerschmidt, W. & Sugden, B. The Epstein-Barr virus oncogene EBNA1 suppresses natural killer cell responses and apoptosis early after infection of peripheral B cells. mBio 12, e0224321 (2021).
Keane, J. T. et al. The interaction of Epstein-Barr virus encoded transcription factor EBNA2 with multiple sclerosis risk loci is dependent on the risk genotype. EBioMedicine 71, 103572 (2021).
Spender, L. C. et al. Cell target genes of Epstein-Barr virus transcription factor EBNA-2: induction of the p55alpha regulatory subunit of PI3-kinase and its role in survival of EREB2.5 cells. J. Gen. Virol. 87, 2859–2867 (2006).
Pages, F. et al. Epstein-Barr virus nuclear antigen 2 induces interleukin-18 receptor expression in B cells. Blood 105, 1632–1639 (2005).
Anastasiadou, E. et al. Epstein-Barr virus-encoded EBNA2 alters immune checkpoint PD-L1 expression by downregulating miR-34a in B-cell lymphomas. Leukemia 33, 132–147 (2019).
Yanagi, Y. et al. RNAseq analysis identifies involvement of EBNA2 in PD-L1 induction during Epstein-Barr virus infection of primary B cells. Virology 557, 44–54 (2021).
Kanda, K. et al. The EBNA2-related resistance towards alpha interferon (IFN-alpha) in Burkitt’s lymphoma cells effects induction of IFN-induced genes but not the activation of transcription factor ISGF-3. Mol. Cell Biol. 12, 4930–4936 (1992).
Su, C. et al. EBNA2 driven enhancer switching at the CIITA-DEXI locus suppresses HLA class II gene expression during EBV infection of B-lymphocytes. PLoS Pathog. 17, e1009834 (2021).
Jochum, S., Moosmann, A., Lang, S., Hammerschmidt, W. & Zeidler, R. The EBV immunoevasins vIL-10 and BNLF2a protect newly infected B cells from immune recognition and elimination. PLoS Pathog. 8, e1002704 (2012).
Bouvet, M. et al. Multiple viral microRNAs regulate interferon release and signaling early during infection with Epstein-Barr virus. mBio https://doi.org/10.1128/mBio.03440-20 (2021).
Murer, A. et al. MicroRNAs of Epstein-Barr virus attenuate T-cell-mediated immune control in vivo. mBio https://doi.org/10.1128/mBio.01941-18 (2019).
Joshi, N., Usuku, K. & Hauser, S. L. The T-cell response to myelin basic protein in familial multiple sclerosis: diversity of fine specificity, restricting elements, and T-cell receptor usage. Ann. Neurol. 34, 385–393 (1993).
Martin, C. et al. Absence of seven human herpesviruses, including HHV-6, by polymerase chain reaction in CSF and blood from patients with multiple sclerosis and optic neuritis. Acta Neurol. Scand. 95, 280–283 (1997).
Sindic, C. J., Monteyne, P. & Laterre, E. C. The intrathecal synthesis of virus-specific oligoclonal IgG in multiple sclerosis. J. Neuroimmunol. 54, 75–80 (1994).
Sriram, S. et al. Chlamydia pneumoniae infection of the central nervous system in multiple sclerosis. Ann. Neurol. 46, 6–14 (1999).
Virtanen, J. O., Wohler, J., Fenton, K., Reich, D. S. & Jacobson, S. Oligoclonal bands in multiple sclerosis reactive against two herpesviruses and association with magnetic resonance imaging findings. Mult. Scler. 20, 27–34 (2014).
Franciotta, D. et al. Cerebrospinal BAFF and Epstein-Barr virus-specific oligoclonal bands in multiple sclerosis and other inflammatory demyelinating neurological diseases. J. Neuroimmunol. 230, 160–163 (2011).
Wang, Z. et al. Antibodies from multiple sclerosis brain identified Epstein-Barr virus nuclear antigen 1 & 2 epitopes which are recognized by oligoclonal bands. J. Neuroimmune Pharmacol. 16, 567–580 (2021).
van Nierop, G. P., Mautner, J., Mitterreiter, J. G., Hintzen, R. Q. & Verjans, G. M. Intrathecal CD8 T-cells of multiple sclerosis patients recognize lytic Epstein-Barr virus proteins. Mult. Scler. 22, 279–291 (2016).
Chabas, D. et al. The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 294, 1731–1735 (2001).
Cencioni, M. T., Mattoscio, M., Magliozzi, R., Bar-Or, A. & Muraro, P. A. B cells in multiple sclerosis – from targeted depletion to immune reconstitution therapies. Nat. Rev. Neurol. 17, 399–414 (2021).
Lisak, R. P. et al. B cells from patients with multiple sclerosis induce cell death via apoptosis in neurons in vitro. J. Neuroimmunol. 309, 88–99 (2017).
Li, R. et al. Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy. Sci. Transl. Med. 7, 310ra166 (2015).
Panitch, H. S., Hirsch, R. L., Schindler, J. & Johnson, K. P. Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system. Neurology 37, 1097–1102 (1987).
Feng, X. et al. Low expression of interferon-stimulated genes in active multiple sclerosis is linked to subnormal phosphorylation of STAT1. J. Neuroimmunol. 129, 205–215 (2002).
Lucchinetti, C. et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann. Neurol. 47, 707–717 (2000).
Lassmann, H. Multiple sclerosis pathology. Cold Spring Harb. Perspect. Med. https://doi.org/10.1101/cshperspect.a028936 (2018).
Barnett, M. H. & Prineas, J. W. Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann. Neurol. 55, 458–468 (2004).
Salou, M., Nicol, B., Garcia, A. & Laplaud, D. A. Involvement of CD8+ T cells in multiple sclerosis. Front. Immunol. 6, 604 (2015).
Salou, M. et al. Expanded CD8 T-cell sharing between periphery and CNS in multiple sclerosis. Ann. Clin. Transl. Neurol. 2, 609–622 (2015).
Cagol, A. et al. Association of brain atrophy with disease progression independent of relapse activity in patients with relapsing multiple sclerosis. JAMA Neurol. https://doi.org/10.1001/jamaneurol.2022.1025 (2022).
Kim, W. & Patsopoulos, N. A. Genetics and functional genomics of multiple sclerosis. Semin. Immunopathol. 4, 63–79 (2022).
Yuan, S., Xiong, Y. & Larsson, S. C. An atlas on risk factors for multiple sclerosis: a Mendelian randomization study. J. Neurol. 268, 114–124 (2021).
Jersild, C., Dupont, B., Fog, T., Platz, P. J. & Svejgaard, A. Histocompatibility determinants in multiple sclerosis. Transplant. Rev. 22, 148–163 (1975).
Cook, S. D. Multiple sclerosis and viruses. Mult. Scler. 3, 388–389 (1997).
Australia & New Zealand Multiple Sclerosis Genetics Consortium. Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20. Nat. Genet. 41, 824–828 (2009).
De Jager, P. L. et al. Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nat. Genet. 41, 776–782 (2009).
International Multiple Sclerosis Genetics Consortium. Risk alleles for multiple sclerosis identified by a genomewide study. N. Engl. J. Med. 357, 851–862 (2007).
Cree, B. A. Multiple sclerosis genetics. Handb. Clin. Neurol. 122, 193–209 (2014).
Lin, X., Deng, F. Y., Lu, X. & Lei, S. F. Susceptibility genes for multiple sclerosis identified in a gene-based genome-wide association study. J. Clin. Neurol. (2015).
He, B., Yang, B., Lundahl, J., Fredrikson, S. & Hillert, J. The myelin basic protein gene in multiple sclerosis: identification of discrete alleles of a 1.3 kb tetranucleotide repeat sequence. Acta Neurol. Scand. 97, 46–51 (1998).
Kellar-Wood, H., Robertson, N., Govan, G. G., Compston, D. A. & Harding, A. E. Leber’s hereditary optic neuropathy mitochondrial DNA mutations in multiple sclerosis. Ann. Neurol. 36, 109–112 (1994).
Reynier, P. et al. mtDNA haplogroup J: a contributing factor of optic neuritis. Eur. J. Hum. Genet. 7, 404–406 (1999).
Thompson, R. J. et al. Analysis of polymorphisms of the 2’,3’-cyclic nucleotide-3’-phosphodiesterase gene in patients with multiple sclerosis. Mult. Scler. 2, 215–221 (1996).
Sollid, L. M. Epstein-Barr virus as a driver of multiple sclerosis. Sci. Immunol. 7, eabo7799 (2022).
Wucherpfennig, K. W. & Strominger, J. L. Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell 80, 695–705 (1995).
Lunemann, J. D. et al. EBNA1-specific T cells from patients with multiple sclerosis cross react with myelin antigens and co-produce IFN-gamma and IL-2. J. Exp. Med. 205, 1763–1773 (2008).
Tengvall, K. et al. Molecular mimicry between Anoctamin 2 and Epstein-Barr virus nuclear antigen 1 associates with multiple sclerosis risk. Proc. Natl Acad. Sci. USA 116, 16955–16960 (2019).
van Sechel, A. C. et al. EBV-induced expression and HLA-DR-restricted presentation by human B cells of alpha B-crystallin, a candidate autoantigen in multiple sclerosis. J. Immunol. 162, 129–135 (1999).
Jelcic, I. et al. Memory B cells activate brain-homing, autoreactive CD4(+) T cells in multiple sclerosis. Cell 175, 85–100 e123 (2018).
Nociti, V. et al. Epstein-Barr virus antibodies in serum and cerebrospinal fluid from multiple sclerosis, chronic inflammatory demyelinating polyradiculoneuropathy and amyotrophic lateral sclerosis. J. Neuroimmunol. 225, 149–152 (2010).
Ascherio, A., Munger, K. L. & Lunemann, J. D. The initiation and prevention of multiple sclerosis. Nat. Rev. Neurol. 8, 602–612 (2012).
Lunemann, J. D. & Ascherio, A. Immune responses to EBNA1: biomarkers in MS. Neurology 73, 13–14 (2009).
Mescheriakova, J. Y., van Nierop, G. P., van der Eijk, A. A., Kreft, K. L. & Hintzen, R. Q. EBNA-1 titer gradient in families with multiple sclerosis indicates a genetic contribution. Neurol. Neuroimmunol. Neuroinflamm. https://doi.org/10.1212/NXI.0000000000000872 (2020).
Hedström, A. K. et al. High levels of Epstein-Barr virus nuclear antigen-1-specific antibodies and infectious mononucleosis act both independently and synergistically to increase multiple sclerosis risk. Front. Neurol. 10, 1368 (2019).
van Noort, J. M., Bajramovic, J. J., Plomp, A. C. & van Stipdonk, M. J. Mistaken self, a novel model that links microbial infections with myelin-directed autoimmunity in multiple sclerosis. J. Neuroimmunol. 105, 46–57 (2000).
Hecker, M. et al. High-density peptide microarray analysis of IgG autoantibody reactivities in serum and cerebrospinal fluid of multiple sclerosis patients. Mol. Cell Proteom. 15, 1360–1380 (2016).
Capone, G. et al. Peptide matching between Epstein-Barr virus and human proteins. Pathog. Dis. 69, 205–212 (2013).
Meier, U. C., Cipian, R. C., Karimi, A., Ramasamy, R. & Middeldorp, J. M. Cumulative roles for Epstein-Barr virus, human endogenous retroviruses, and human herpes virus-6 in driving an inflammatory cascade underlying MS pathogenesis. Front. Immunol. 12, 757302 (2021).
Dantuma, N. P., Sharipo, A. & Masucci, M. G. Avoiding proteasomal processing: the case of EBNA1. Curr. Top. Microbiol. Immunol. 269, 23–36 (2002).
Levitskaya, J., Sharipo, A., Leonchiks, A., Ciechanover, A. & Masucci, M. G. Inhibition of ubiquitin/proteasome-dependent protein degradation by the Gly-Ala repeat domain of the Epstein-Barr virus nuclear antigen 1. Proc. Natl Acad. Sci. USA 94, 12616–12621 (1997).
Levitskaya, J. et al. Inhibition of antigen processing by the internal repeat region of the Epstein-Barr virus nuclear antigen-1. Nature 375, 685–688 (1995).
Tovar Fernandez, M. C. et al. Substrate-specific presentation of MHC class I-restricted antigens via autophagy pathway. Cell Immunol. 374, 104484 (2022).
Apcher, S., Daskalogianni, C., Manoury, B. & Fahraeus, R. Epstein Barr virus-encoded EBNA1 interference with MHC class I antigen presentation reveals a close correlation between mRNA translation initiation and antigen presentation. PLoS Pathog. 6, e1001151 (2010).
Tellam, J. T. et al. mRNA Structural constraints on EBNA1 synthesis impact on in vivo antigen presentation and early priming of CD8+ T cells. PLoS Pathog. 10, e1004423 (2014).
Murat, P. et al. G-quadruplexes regulate Epstein-Barr virus-encoded nuclear antigen 1 mRNA translation. Nat. Chem. Biol. 10, 358–364 (2014).
Tellam, J. T., Lekieffre, L., Zhong, J., Lynn, D. J. & Khanna, R. Messenger RNA sequence rather than protein sequence determines the level of self-synthesis and antigen presentation of the EBV-encoded antigen, EBNA1. PLoS Pathog. 8, e1003112 (2012).
Pender, M. P. The essential role of Epstein-Barr virus in the pathogenesis of multiple sclerosis. Neuroscientist 17, 351–367 (2011).
Melchers, F. & Rolink, A. R. B cell tolerance–how to make it and how to break it. Curr. Top. Microbiol. Immunol. 305, 1–23 (2006).
Weniger, M. A. & Kuppers, R. Molecular biology of Hodgkin lymphoma. Leukemia 35, 968–981 (2021).
Sommermann, T. et al. Functional interplay of Epstein-Barr virus oncoproteins in a mouse model of B cell lymphomagenesis. Proc. Natl Acad. Sci. USA 117, 14421–14432 (2020).
Laurence, M. & Benito-Leon, J. Epstein-Barr virus and multiple sclerosis: updating Pender’s hypothesis. Mult. Scler. Relat. Disord. 16, 8–14 (2017).
Choi, I. K. et al. Mechanism of EBV inducing anti-tumour immunity and its therapeutic use. Nature 590, 157–162 (2021).
Deng, Y. et al. CD27 is required for protective lytic EBV antigen-specific CD8+ T-cell expansion. Blood 137, 3225–3236 (2021).
Veroni, C., Serafini, B., Rosicarelli, B., Fagnani, C. & Aloisi, F. Transcriptional profile and Epstein-Barr virus infection status of laser-cut immune infiltrates from the brain of patients with progressive multiple sclerosis. J. Neuroinflamm. 15, 18 (2018).
Magliozzi, R. et al. B-cell enrichment and Epstein-Barr virus infection in inflammatory cortical lesions in secondary progressive multiple sclerosis. J. Neuropathol. Exp. Neurol. 72, 29–41 (2013).
Serafini, B. et al. Epstein-Barr virus latent infection and BAFF expression in B cells in the multiple sclerosis brain: implications for viral persistence and intrathecal B-cell activation. J. Neuropathol. Exp. Neurol. 69, 677–693 (2010).
Tzartos, J. S. et al. Association of innate immune activation with latent Epstein-Barr virus in active MS lesions. Neurology 78, 15–23 (2012).
Moreno, M. A. et al. Molecular signature of Epstein-Barr virus infection in MS brain lesions. Neurol. Neuroimmunol. Neuroinflamm 5, e466 (2018).
Serafini, B., Rosicarelli, B., Veroni, C., Mazzola, G. A. & Aloisi, F. Epstein-Barr virus-specific CD8 T cells selectively infiltrate the brain in multiple sclerosis and interact locally with virus-infected cells: clue for a virus-driven immunopathological mechanism. J. Virol. https://doi.org/10.1128/JVI.00980-19 (2019).
Recher, M. et al. Extralymphatic virus sanctuaries as a consequence of potent T-cell activation. Nat. Med. 13, 1316–1323 (2007).
Hochberg, D. et al. Acute infection with Epstein-Barr virus targets and overwhelms the peripheral memory B-cell compartment with resting, latently infected cells. J. Virol. 78, 5194–5204 (2004).
Veroni, C. et al. Immune and Epstein-Barr virus gene expression in cerebrospinal fluid and peripheral blood mononuclear cells from patients with relapsing-remitting multiple sclerosis. J. Neuroinflamm. 12, 132 (2015).
Kiriyama, T., Kataoka, H., Kasai, T., Nonomura, A. & Ueno, S. Negative association of Epstein-Barr virus or herpes simplex virus-1 with tumefactive central nervous system inflammatory demyelinating disease. J. Neurovirol. 16, 466–471 (2010).
Sargsyan, S. A. et al. Absence of Epstein-Barr virus in the brain and CSF of patients with multiple sclerosis. Neurology 74, 1127–1135 (2010).
Willis, S. N. et al. Epstein-Barr virus infection is not a characteristic feature of multiple sclerosis brain. Brain 132, 3318–3328 (2009).
Peferoen, L. A. et al. Epstein Barr virus is not a characteristic feature in the central nervous system in established multiple sclerosis. Brain 133, e137 (2010).
Torkildsen, O. et al. Upregulation of immunoglobulin-related genes in cortical sections from multiple sclerosis patients. Brain Pathol. 20, 720–729 (2010).
Lassmann, H., Niedobitek, G., Aloisi, F., Middeldorp, J. M. & NeuroproMiSe EBV Working Group. Epstein-Barr virus in the multiple sclerosis brain: a controversial issue–report on a focused workshop held in the Centre for Brain Research of the Medical University of Vienna, Austria. Brain 134, 2772–2786 (2011).
Hislop, A. D. & Taylor, G. S. T-cell responses to EBV. Curr. Top. Microbiol. Immunol. 391, 325–353 (2015).
Hislop, A. D., Taylor, G. S., Sauce, D. & Rickinson, A. B. Cellular responses to viral infection in humans: lessons from Epstein-Barr virus. Annu. Rev. Immunol. 25, 587–617 (2007).
Munger, K. L., Levin, L. I., O’Reilly, E. J., Falk, K. I. & Ascherio, A. Anti-Epstein-Barr virus antibodies as serological markers of multiple sclerosis: a prospective study among United States military personnel. Mult. Scler. 17, 1185–1193 (2011).
Levin, L. I. et al. Temporal relationship between elevation of Epstein-Barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis. JAMA 293, 2496–2500 (2005).
Lunemann, J. D. et al. Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis. Brain 129, 1493–1506 (2006).
International Multiple Sclerosis Genetics Consortium. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476, 214–219 (2011).
Jilek, S. et al. Strong EBV-specific CD8+ T-cell response in patients with early multiple sclerosis. Brain 131, 1712–1721 (2008).
Angelini, D. F. et al. Increased CD8+ T cell response to Epstein-Barr virus lytic antigens in the active phase of multiple sclerosis. PLoS Pathog. 9, e1003220 (2013).
Pender, M. P., Csurhes, P. A., Pfluger, C. M. & Burrows, S. R. Deficiency of CD8+ effector memory T cells is an early and persistent feature of multiple sclerosis. Mult. Scler. 20, 1825–1832 (2014).
Pender, M. P., Csurhes, P. A., Pfluger, C. M. & Burrows, S. R. Decreased CD8+ T cell response to Epstein-Barr virus infected B cells in multiple sclerosis is not due to decreased HLA class I expression on B cells or monocytes. BMC Neurol. 11, 95 (2011).
Pender, M. P., Csurhes, P. A., Pfluger, C. M. & Burrows, S. R. CD8 T cell deficiency impairs control of Epstein–Barr virus and worsens with age in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 83, 353–354 (2012).
Veroni, C. & Aloisi, F. The CD8 T cell-Epstein-Barr virus-B cell trialogue: a central issue in multiple sclerosis pathogenesis. Front. Immunol. 12, 665718 (2021).
van Langelaar, J. et al. The association of Epstein-Barr virus infection with CXCR3+ B-cell development in multiple sclerosis: impact of immunotherapies. Eur. J. Immunol. 51, 626–633 (2021).
Baglio, S. R. et al. Sensing of latent EBV infection through exosomal transfer of 5’pppRNA. Proc. Natl Acad. Sci. USA 113, E587–E596 (2016).
Afrasiabi, A. et al. The interaction of human and Epstein-Barr virus miRNAs with multiple sclerosis risk loci. Int. J. Mol. Sci. https://doi.org/10.3390/ijms22062927 (2021).
Chen, C. C. et al. Elucidation of exosome migration across the blood–brain barrier model in vitro. Cell. Mol. Bioeng. 9, 509–529 (2016).
Jiang, S. et al. The Epstein-Barr virus regulome in lymphoblastoid cells. Cell Host Microbe 22, 561–573.e4 (2017).
Harley, J. B. et al. Transcription factors operate across disease loci, with EBNA2 implicated in autoimmunity. Nat. Genet. 50, 699–707 (2018).
Hong, T. et al. Epstein-Barr virus nuclear antigen 2 extensively rewires the human chromatin landscape at autoimmune risk loci. Genome Res. https://doi.org/10.1101/gr.264705.120 (2021).
Afrasiabi, A. et al. Evidence from genome wide association studies implicates reduced control of Epstein-Barr virus infection in multiple sclerosis susceptibility. Genome Med. 11, 26 (2019).
Ricigliano, V. A. et al. EBNA2 binds to genomic intervals associated with multiple sclerosis and overlaps with vitamin D receptor occupancy. PLoS ONE 10, e0119605 (2015).
Mechelli, R. et al. Epstein-Barr virus genetic variants are associated with multiple sclerosis. Neurology 84, 1362–1368 (2015).
Zhou, Y. et al. Utilising multi-large omics data to elucidate biological mechanisms within multiple sclerosis genetic susceptibility loci. Mult. Scler. 27, 2141–2149 (2021).
Ruhrmann, S., Stridh, P., Kular, L. & Jagodic, M. Genomic imprinting: a missing piece of the multiple sclerosis puzzle? Int. J. Biochem. Cell Biol. 67, 49–57 (2015).
Kular, L. & Jagodic, M. Epigenetic insights into multiple sclerosis disease progression. J. Intern. Med. 288, 82–102 (2020).
Kular, L. et al. DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis. Nat. Commun. 9, 2397 (2018).
He, Y., Huang, L., Tang, Y., Yang, Z. & Han, Z. Genome-wide identification and analysis of splicing QTLs in multiple sclerosis by RNA-seq data. Front. Genet. 12, 769804 (2021).
Wanke, F. et al. EBI2 is highly expressed in multiple sclerosis lesions and promotes early CNS migration of encephalitogenic CD4 T cells. Cell Rep. 18, 1270–1284 (2017).
Guo, R. & Gewurz, B. E. Epigenetic control of the Epstein-Barr lifecycle. Curr. Opin. Virol. 52, 78–88 (2022).
Tempera, I. & Lieberman, P. M. Epigenetic regulation of EBV persistence and oncogenesis. Semin. Cancer Biol. 26, 22–29 (2014).
Kucukali, C. I., Kurtuncu, M., Coban, A., Cebi, M. & Tuzun, E. Epigenetics of multiple sclerosis: an updated review. Neuromol. Med. 17, 83–96 (2015).
Soldan, S. S. et al. Epigenetic plasticity enables CNS-trafficking of EBV-infected B lymphocytes. PLoS Pathog. 17, e1009618 (2021).
Greer, J. M. et al. Immunogenic and encephalitogenic epitope clusters of myelin proteolipid protein. J. Immunol. 156, 371–379 (1996).
Zdimerova, H. et al. Attenuated immune control of Epstein-Barr virus in humanized mice is associated with the multiple sclerosis risk factor HLA-DR15. Eur. J. Immunol. 51, 64–75 (2021).
Agostini, S. et al. HLA alleles modulate EBV viral load in multiple sclerosis. J. Transl. Med. 16, 80 (2018).
Wandinger, K. et al. Association between clinical disease activity and Epstein-Barr virus reactivation in MS. Neurology 55, 178–184 (2000).
Cocuzza, C. E. et al. Quantitative detection of Epstein-Barr virus DNA in cerebrospinal fluid and blood samples of patients with relapsing-remitting multiple sclerosis. PLoS ONE 9, e94497 (2014).
Lindsey, J. W., Hatfield, L. M., Crawford, M. P. & Patel, S. Quantitative PCR for Epstein-Barr virus DNA and RNA in multiple sclerosis. Mult. Scler. 15, 153–158 (2009).
Buljevac, D. et al. Epstein-Barr virus and disease activity in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 76, 1377–1381 (2005).
Hollenbach, J. A. & Oksenberg, J. R. The immunogenetics of multiple sclerosis: a comprehensive review. J. Autoimmun. 64, 13–25 (2015).
Enz, L. S. et al. Increased HLA-DR expression and cortical demyelination in MS links with HLA-DR15. Neurol. Neuroimmunol. Neuroinflamm. https://doi.org/10.1212/NXI.0000000000000656 (2020).
Martin, R., Sospedra, M., Eiermann, T. & Olsson, T. Multiple sclerosis: doubling down on MHC. Trends Genet. 37, 784–797 (2021).
Menegatti, J., Schub, D., Schafer, M., Grasser, F. A. & Ruprecht, K. HLA-DRB1*15:01 is a co-receptor for Epstein-Barr virus, linking genetic and environmental risk factors for multiple sclerosis. Eur. J. Immunol. 51, 2348–2350 (2021).
Burnham, J. A., Wright, R. R., Dreisbach, J. & Murray, R. S. The effect of high-dose steroids on MRI gadolinium enhancement in acute demyelinating lesions. Neurology 41, 1349–1354 (1991).
Baker, D., Marta, M., Pryce, G., Giovannoni, G. & Schmierer, K. Memory B cells are major targets for effective immunotherapy in relapsing multiple sclerosis. EBioMedicine 16, 41–50 (2017).
Ceronie, B. et al. Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells. J. Neurol. 265, 1199–1209 (2018).
Hauser, S. L. et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N. Engl. J. Med. 358, 676–688 (2008).
Kappos, L. et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet 378, 1779–1787 (2011).
Segal, B. M. et al. Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol. 7, 796–804 (2008).
Kappos, L. et al. Atacicept in multiple sclerosis (ATAMS): a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Neurol. 13, 353–363 (2014).
Bilger, A. et al. Leflunomide/teriflunomide inhibit Epstein-Barr virus (EBV)- induced lymphoproliferative disease and lytic viral replication. Oncotarget 8, 44266–44280 (2017).
Doubrovina, E. et al. Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation. Blood 119, 2644–2656 (2012).
Heslop, H. E. et al. Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood 115, 925–935 (2010).
Savoldo, B. et al. Treatment of solid organ transplant recipients with autologous Epstein Barr virus-specific cytotoxic T lymphocytes (CTLs). Blood 108, 2942–2949 (2006).
Pender, M. P. et al. Epstein-Barr virus-specific adoptive immunotherapy for progressive multiple sclerosis. Mult. Scler. 20, 1541–1544 (2014).
Pender, M. P. et al. Epstein-Barr virus-specific T cell therapy for progressive multiple sclerosis. JCI Insight https://doi.org/10.1172/jci.insight.124714 (2018).
Pender, M. P. et al. Epstein-Barr virus-specific T cell therapy for progressive multiple sclerosis. JCI Insight https://doi.org/10.1172/jci.insight.144624 (2020).
Pender, M. P., Csurhes, P. A., Burrows, J. M. & Burrows, S. R. Defective T-cell control of Epstein-Barr virus infection in multiple sclerosis. Clin. Transl. Immunol. 6, e126 (2017).
Bar-Or, A. et al. Updated open-label extension clinical data and new magnetization transfer ratio imaging data from a phase I study of ATA188, an off-the-shelf, allogeneic Epstein-Barr virus-targeted T-cell immunotherapy for progressive multiple sclerosis [ECTRIMS 2021 poster]. Multiple Sclerosis J. 27 (2_suppl.), P638 (2021).
Lycke, J. et al. Acyclovir treatment of relapsing-remitting multiple sclerosis. A randomized, placebo-controlled, double-blind study. J. Neurol. 243, 214–224 (1996).
Bech, E. et al. A randomized, double-blind, placebo-controlled MRI study of anti-herpes virus therapy in MS. Neurology 58, 31–36 (2002).
Friedman, J. E. et al. A randomized clinical trial of valacyclovir in multiple sclerosis. Mult. Scler. 11, 286–295 (2005).
Annibali, V. et al. IFN-beta and multiple sclerosis: from etiology to therapy and back. Cytokine Growth Factor. Rev. 26, 221–228 (2015).
Bentz, G. L., Liu, R., Hahn, A. M., Shackelford, J. & Pagano, J. S. Epstein-Barr virus BRLF1 inhibits transcription of IRF3 and IRF7 and suppresses induction of interferon-beta. Virology 402, 121–128 (2010).
Hahn, A. M., Huye, L. E., Ning, S., Webster-Cyriaque, J. & Pagano, J. S. Interferon regulatory factor 7 is negatively regulated by the Epstein-Barr virus immediate-early gene, BZLF-1. J. Virol. 79, 10040–10052 (2005).
De Clercq, E. Potential of acyclic nucleoside phosphonates in the treatment of DNA virus and retrovirus infections. Expert Rev. Anti Infect. Ther. 1, 21–43 (2003).
Drosu, N. C., Edelman, E. R. & Housman, D. E. Tenofovir prodrugs potently inhibit Epstein-Barr virus lytic DNA replication by targeting the viral DNA polymerase. Proc. Natl Acad. Sci. USA 117, 12368–12374 (2020).
Torkildsen, O., Myhr, K. M., Skogen, V., Steffensen, L. H. & Bjornevik, K. Tenofovir as a treatment option for multiple sclerosis. Mult. Scler. Relat. Disord. 46, 102569 (2020).
Elliott, S. L. et al. Phase I trial of a CD8+ T-cell peptide epitope-based vaccine for infectious mononucleosis. J. Virol. 82, 1448–1457 (2008).
Sokal, E. M. et al. Recombinant gp350 vaccine for infectious mononucleosis: a phase 2, randomized, double-blind, placebo-controlled trial to evaluate the safety, immunogenicity, and efficacy of an Epstein-Barr virus vaccine in healthy young adults. J. Infect. Dis. 196, 1749–1753 (2007).
Moutschen, M. et al. Phase I/II studies to evaluate safety and immunogenicity of a recombinant gp350 Epstein-Barr virus vaccine healthy adults. Vaccine 25, 4697–4705 (2007).
Bach, J. F. The effect of infections on susceptibility to autoimmune and allergic diseases. N. Engl. J. Med. 347, 911–920 (2002).
Sheik-Ali, S. Infectious mononucleosis and multiple sclerosis – updated review on associated risk. Mult. Scler. Relat. Disord. 14, 56–59 (2017).
Dirmeier, U. et al. Latent membrane protein 1 of Epstein-Barr virus coordinately regulates proliferation with control of apoptosis. Oncogene 24, 1711–1717 (2005).
Hussain, M., Gatherer, D. & Wilson, J. B. Modelling the structure of full-length Epstein-Barr virus nuclear antigen 1. Virus Genes 49, 358–372 (2014).
Leave a Comment
Your email address will not be published. Required fields are marked with *