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Published in: Journal of Translational Medicine 1/2018

Open Access 01-12-2018 | Research

HLA alleles modulate EBV viral load in multiple sclerosis

Authors: Simone Agostini, Roberta Mancuso, Franca R. Guerini, Sandra D’Alfonso, Cristina Agliardi, Ambra Hernis, Milena Zanzottera, Nadia Barizzone, Maurizio A. Leone, Domenico Caputo, Marco Rovaris, Mario Clerici

Published in: Journal of Translational Medicine | Issue 1/2018

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Abstract

Background

The etiopathology of multiple sclerosis (MS) is believed to include genetic and environmental factors. Human leukocyte antigen (HLA) alleles, in particular,  are associated with disease susceptibility, whereas Epstein Barr Virus (EBV) infection has long been suspected to play a role in disease pathogenesis. The aim of the present study is to evaluate correlations between HLA alleles and EBV infection in MS.

Methods

HLA alleles, EBV viral load (VL) and serum anti-EBV antibody titers were evaluated in EBV-seropositive MS patients (N = 117) and age- and sex-matched healthy controls (HC; N = 89).

Results

Significantly higher DNA viral loads (p = 0.048) and EBNA-1 antibody titer (p = 0.0004) were seen in MS compared to HC. EBV VL was higher in HLA-B*07+ (p = 0.02) and HLA-DRB1*15+ (p = 0.02) MS patients, whereas it was lower in HLA-A*02+ (p = 0.04) subjects. EBV VL was highest in HLA-A*02−/B*07+/DRB1*15+ patients and lowest in HLA-A*A02+/B*07−/DRB1*15− individuals (p < 0.0001). HLA-B*07 resulted the most associated allele to EBV VL after multiple regression analysis considering altogether the three alleles, (p = 0.0001). No differences were observed in anti-EBV antibody titers in relationship with HLA distribution.

Conclusions

Host HLA-B*07 allele influence EBV VL in MS. As HLA-class I molecules present antigens to T lymphocytes and initiate immune response against viruses, these results could support a role for EBV in MS.
Appendix
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Literature
2.
go back to reference GAMES; Transatlantic multiple sclerosis genetics cooperative. A meta-analysis of whole genome linkage screens in multiple sclerosis. J Neuroimmunol. 2003;143:39–46.CrossRef GAMES; Transatlantic multiple sclerosis genetics cooperative. A meta-analysis of whole genome linkage screens in multiple sclerosis. J Neuroimmunol. 2003;143:39–46.CrossRef
3.
4.
go back to reference Nolan D, Castley M, Tschochner M, James I, Qiu W, Sayer D, et al. Contributions of vitamin D response elements and HLA promoters to multiple sclerosis risk. Neurology. 2012;79:538–46.CrossRefPubMed Nolan D, Castley M, Tschochner M, James I, Qiu W, Sayer D, et al. Contributions of vitamin D response elements and HLA promoters to multiple sclerosis risk. Neurology. 2012;79:538–46.CrossRefPubMed
5.
go back to reference Zivadinov R, Uxa L, Zacchi T, Nasuelli D, Ukmar M, Furlan C, et al. HLA genotypes and disease severity assessed by magnetic resonance imaging findings in patients with multiple sclerosis. J Neurol. 2003;250:1099–106.CrossRefPubMed Zivadinov R, Uxa L, Zacchi T, Nasuelli D, Ukmar M, Furlan C, et al. HLA genotypes and disease severity assessed by magnetic resonance imaging findings in patients with multiple sclerosis. J Neurol. 2003;250:1099–106.CrossRefPubMed
6.
go back to reference Moutsianas L, Jostins L, Beecham AH, Dilthey AT, Xifar DK, Ban M, et al. Class II HLA interactions modulate genetic risk for multiple sclerosis. Nat Genet. 2015;47:1107–13.CrossRefPubMedPubMedCentral Moutsianas L, Jostins L, Beecham AH, Dilthey AT, Xifar DK, Ban M, et al. Class II HLA interactions modulate genetic risk for multiple sclerosis. Nat Genet. 2015;47:1107–13.CrossRefPubMedPubMedCentral
7.
go back to reference Brynedal B, Duvefelt K, Jonasdottir G, Roos IM, Akesson E, Palmgren J, et al. HLA-A confers an HLA-DRB1 independent influence on the risk of multiple sclerosis. PLoS ONE. 2007;2:e664.CrossRefPubMedPubMedCentral Brynedal B, Duvefelt K, Jonasdottir G, Roos IM, Akesson E, Palmgren J, et al. HLA-A confers an HLA-DRB1 independent influence on the risk of multiple sclerosis. PLoS ONE. 2007;2:e664.CrossRefPubMedPubMedCentral
8.
go back to reference Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol. 2007;61:288–99.CrossRefPubMed Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol. 2007;61:288–99.CrossRefPubMed
9.
10.
go back to reference Serafini B, Severa M, Columba-Cabezas S, Rosicarelli B, Veroni C, Chiappetta C, 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. 2010;69:677–93.CrossRefPubMed Serafini B, Severa M, Columba-Cabezas S, Rosicarelli B, Veroni C, Chiappetta C, 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. 2010;69:677–93.CrossRefPubMed
11.
go back to reference Hollsberg P, Hansen HJ, Haahr S. Altered CD8+ T cell responses to selected Epstein-Barr virus immunodominant epitopes in patients with multiple sclerosis. Clin Exp Immunol. 2003;132:137–43.CrossRefPubMedPubMedCentral Hollsberg P, Hansen HJ, Haahr S. Altered CD8+ T cell responses to selected Epstein-Barr virus immunodominant epitopes in patients with multiple sclerosis. Clin Exp Immunol. 2003;132:137–43.CrossRefPubMedPubMedCentral
12.
go back to reference Jilek S, Schluep M, Harari A, Canales M, Lysandropoulos A, Zekeridou A, et al. HLA-B7-restricted EBV-specific CD8+ T cells are dysregulated in multiple sclerosis. J Immunol. 2012;188:4671–80.CrossRefPubMed Jilek S, Schluep M, Harari A, Canales M, Lysandropoulos A, Zekeridou A, et al. HLA-B7-restricted EBV-specific CD8+ T cells are dysregulated in multiple sclerosis. J Immunol. 2012;188:4671–80.CrossRefPubMed
13.
go back to reference Lassmann H, Niedobitek G, Aloisi F, Middeldorp JM, 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. 2011;134:2772–86.CrossRefPubMedPubMedCentral Lassmann H, Niedobitek G, Aloisi F, Middeldorp JM, 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. 2011;134:2772–86.CrossRefPubMedPubMedCentral
14.
go back to reference Serafini B, Rosicarelli B, Franciotta D, Magliozzi R, Reynolds R, Cinque P, et al. Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J Exp Med. 2007;204:2899–912.CrossRefPubMedPubMedCentral Serafini B, Rosicarelli B, Franciotta D, Magliozzi R, Reynolds R, Cinque P, et al. Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J Exp Med. 2007;204:2899–912.CrossRefPubMedPubMedCentral
15.
go back to reference Alvarez-Lafuente R, Garcia-Montojo M, De Las Heras V, Dominguez-Mozo MI, Bartolome M, Benito-Martin MS, et al. Herpesviruses and human endogenous retroviral sequences in the cerebrospinal fluid of multiple sclerosis patients. Mult Scler. 2008;14:595–601.CrossRefPubMed Alvarez-Lafuente R, Garcia-Montojo M, De Las Heras V, Dominguez-Mozo MI, Bartolome M, Benito-Martin MS, et al. Herpesviruses and human endogenous retroviral sequences in the cerebrospinal fluid of multiple sclerosis patients. Mult Scler. 2008;14:595–601.CrossRefPubMed
16.
go back to reference Willis SN, Stadelmann C, Rodig SJ, Caron T, Gattenloehner S, Mallozzi SS, et al. Epstein-Barr virus infection is not a characteristic feature of multiple sclerosis brain. Brain. 2009;132:3318–28.CrossRefPubMedPubMedCentral Willis SN, Stadelmann C, Rodig SJ, Caron T, Gattenloehner S, Mallozzi SS, et al. Epstein-Barr virus infection is not a characteristic feature of multiple sclerosis brain. Brain. 2009;132:3318–28.CrossRefPubMedPubMedCentral
17.
go back to reference Sargsyan SA, Shearer AJ, Ritchie AM, Burgoon MP, Anderson S, Hemmer B, et al. Absence of Epstein-Barr virus in the brain and CSF of patients with multiple sclerosis. Neurology. 2010;74:1127–35.CrossRefPubMedPubMedCentral Sargsyan SA, Shearer AJ, Ritchie AM, Burgoon MP, Anderson S, Hemmer B, et al. Absence of Epstein-Barr virus in the brain and CSF of patients with multiple sclerosis. Neurology. 2010;74:1127–35.CrossRefPubMedPubMedCentral
18.
go back to reference Xiao D, Ye X, Zhang N, Ou M, Guo C, Zhang B, et al. A meta-analysis of interaction between Epstein-Barr virus and HLA-DRB1*1501 on risk of multiple sclerosis. Sci Rep. 2015;5:18083.CrossRefPubMedPubMedCentral Xiao D, Ye X, Zhang N, Ou M, Guo C, Zhang B, et al. A meta-analysis of interaction between Epstein-Barr virus and HLA-DRB1*1501 on risk of multiple sclerosis. Sci Rep. 2015;5:18083.CrossRefPubMedPubMedCentral
19.
go back to reference De Jager PL, Simon KC, Munger KL, Rioux JD, Hafler DA, Ascherio A. Integrating risk factors: HLA-DRB1*1501 and Epstein-Barr virus in multiple sclerosis. Neurology. 2008;70:1113–8.CrossRefPubMed De Jager PL, Simon KC, Munger KL, Rioux JD, Hafler DA, Ascherio A. Integrating risk factors: HLA-DRB1*1501 and Epstein-Barr virus in multiple sclerosis. Neurology. 2008;70:1113–8.CrossRefPubMed
20.
go back to reference Sundqvist E, Sundstrom P, Linden M, Hedstrom AK, Aloisi F, Hillert J, et al. Epstein-Barr virus and multiple sclerosis: interaction with HLA. Genes Immun. 2012;13:14–20.CrossRefPubMed Sundqvist E, Sundstrom P, Linden M, Hedstrom AK, Aloisi F, Hillert J, et al. Epstein-Barr virus and multiple sclerosis: interaction with HLA. Genes Immun. 2012;13:14–20.CrossRefPubMed
21.
go back to reference Zivadinov R, Weinstock-Guttman B, Zorzon M, Uxa L, Serafin M, Bosco A, et al. Gene-environment interactions between HLA B7/A2, EBV antibodies are associated with MRI injury in multiple sclerosis. J Neuroimmunol. 2009;209:123–30.CrossRefPubMed Zivadinov R, Weinstock-Guttman B, Zorzon M, Uxa L, Serafin M, Bosco A, et al. Gene-environment interactions between HLA B7/A2, EBV antibodies are associated with MRI injury in multiple sclerosis. J Neuroimmunol. 2009;209:123–30.CrossRefPubMed
22.
go back to reference Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69:292–302.CrossRefPubMedPubMedCentral Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69:292–302.CrossRefPubMedPubMedCentral
23.
go back to reference Agliardi C, Guerini FR, Saresella M, Caputo D, Leone MA, Zanzottera M, et al. Vitamin D receptor (VDR) gene SNPs influence VDR expression and modulate protection from multiple sclerosis in HLA-DRB1*15-positive individuals. Brain Behav Immun. 2011;25:1460–7.CrossRefPubMed Agliardi C, Guerini FR, Saresella M, Caputo D, Leone MA, Zanzottera M, et al. Vitamin D receptor (VDR) gene SNPs influence VDR expression and modulate protection from multiple sclerosis in HLA-DRB1*15-positive individuals. Brain Behav Immun. 2011;25:1460–7.CrossRefPubMed
24.
go back to reference Barizzone N, Zara I, Sorosina M, Lupoli S, Porcu E, Pitzalis M, et al. The burden of multiple sclerosis variants in continental Italians and Sardinians. Mult Scler J. 2015;21:1385–95.CrossRef Barizzone N, Zara I, Sorosina M, Lupoli S, Porcu E, Pitzalis M, et al. The burden of multiple sclerosis variants in continental Italians and Sardinians. Mult Scler J. 2015;21:1385–95.CrossRef
25.
go back to reference Mancuso R, Hernis A, Cavarretta R, Caputo D, Calabrese E, Nemni R, et al. Detection of vital DNA sequence in the cerebrospinal fluid of patients with multiple sclerosis. J Med Virol. 2010;82:1051–7.CrossRefPubMed Mancuso R, Hernis A, Cavarretta R, Caputo D, Calabrese E, Nemni R, et al. Detection of vital DNA sequence in the cerebrospinal fluid of patients with multiple sclerosis. J Med Virol. 2010;82:1051–7.CrossRefPubMed
26.
go back to reference Farrell RA, Antony D, Wall GR, Clark DA, Fisniku L, Swanton J, et al. Humoral immune response to EBV in multiple sclerosis is associated with disease activity on MRI. Neurology. 2009;73:32–8.CrossRefPubMedPubMedCentral Farrell RA, Antony D, Wall GR, Clark DA, Fisniku L, Swanton J, et al. Humoral immune response to EBV in multiple sclerosis is associated with disease activity on MRI. Neurology. 2009;73:32–8.CrossRefPubMedPubMedCentral
27.
go back to reference Hohaus S, Santnagelo R, Giachelia M, Massini G, Cuccaro A, Martini M, et al. The viral load of Epstein-Barr virus (EBV) DNA in peripheral blood predicts for biological and clinical characteristics in Hodgkin lymphoma. Clin Cancer Res. 2011;17:2885–92.CrossRefPubMed Hohaus S, Santnagelo R, Giachelia M, Massini G, Cuccaro A, Martini M, et al. The viral load of Epstein-Barr virus (EBV) DNA in peripheral blood predicts for biological and clinical characteristics in Hodgkin lymphoma. Clin Cancer Res. 2011;17:2885–92.CrossRefPubMed
28.
go back to reference Ben Fredj N, Rotola A, Nefz F, Chebei S, Rizzo R, Caselli E, et al. Identification of human herpesviruses 1–8 in Tunisian multiple sclerosis patients and healthy blood donors. J Neurovirol. 2012;18:12–9.CrossRefPubMed Ben Fredj N, Rotola A, Nefz F, Chebei S, Rizzo R, Caselli E, et al. Identification of human herpesviruses 1–8 in Tunisian multiple sclerosis patients and healthy blood donors. J Neurovirol. 2012;18:12–9.CrossRefPubMed
29.
go back to reference Lucas RM, Taylor BV. Epstein-Barr virus infection: a smoking gun for multiple sclerosis? Neurology. 2012;79:1310–1.CrossRefPubMed Lucas RM, Taylor BV. Epstein-Barr virus infection: a smoking gun for multiple sclerosis? Neurology. 2012;79:1310–1.CrossRefPubMed
30.
go back to reference Lindsey JW, Hatfield LM, Crawford MP, Patel S. Quantitative PCR for Epstein-Barr virus DNA and RNA in multiple sclerosis. Mult Scler. 2009;15:153–8.CrossRefPubMed Lindsey JW, Hatfield LM, Crawford MP, Patel S. Quantitative PCR for Epstein-Barr virus DNA and RNA in multiple sclerosis. Mult Scler. 2009;15:153–8.CrossRefPubMed
31.
go back to reference Cocuzza CE, Piazza F, Musumeci R, Oggioni D, Andreoni S, Gardinetti M, et al. Quantitative detection of Epstein-Barr virus DNA in cerebrospinal fluid and blood samples of patients with relapsing-remitting multiple sclerosis. PLoS ONE. 2014;9:e94497.CrossRefPubMedPubMedCentral Cocuzza CE, Piazza F, Musumeci R, Oggioni D, Andreoni S, Gardinetti M, et al. Quantitative detection of Epstein-Barr virus DNA in cerebrospinal fluid and blood samples of patients with relapsing-remitting multiple sclerosis. PLoS ONE. 2014;9:e94497.CrossRefPubMedPubMedCentral
32.
go back to reference Maurmann S, Fricke L, Wagner HJ, Schlenke P, Hennig H, Steinhoff J, et al. Molecular parameters for precise diagnosis of asymptomatic Epstein-Barr virus reactivation in healthy carriers. J Clin Microbiol. 2003;41:5419–28.CrossRefPubMedPubMedCentral Maurmann S, Fricke L, Wagner HJ, Schlenke P, Hennig H, Steinhoff J, et al. Molecular parameters for precise diagnosis of asymptomatic Epstein-Barr virus reactivation in healthy carriers. J Clin Microbiol. 2003;41:5419–28.CrossRefPubMedPubMedCentral
33.
go back to reference Pender MP, Csurhes PA, Burrows JM, Burrows SR. Defective T-cell control of Epstein-Barr virus infection in multiple sclerosis. Clin Transl Immunology. 2017;6:e126.CrossRefPubMedPubMedCentral Pender MP, Csurhes PA, Burrows JM, Burrows SR. Defective T-cell control of Epstein-Barr virus infection in multiple sclerosis. Clin Transl Immunology. 2017;6:e126.CrossRefPubMedPubMedCentral
34.
go back to reference International Multiple Sclerosis Genetics C, Wellcome Trust Case Control C, Sawcer S, Hellenthal G, Pirinen M, Spencer CC, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011;476:214–9.CrossRef International Multiple Sclerosis Genetics C, Wellcome Trust Case Control C, Sawcer S, Hellenthal G, Pirinen M, Spencer CC, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011;476:214–9.CrossRef
35.
go back to reference Nielsen TR, Rostgaard K, Askling J, Steffensen R, Oturai A, Jersild C, et al. Effects of infectious mononucleosis and HLA-DRB1*15 in multiple sclerosis. Mult Scler. 2009;15:431–6.CrossRefPubMed Nielsen TR, Rostgaard K, Askling J, Steffensen R, Oturai A, Jersild C, et al. Effects of infectious mononucleosis and HLA-DRB1*15 in multiple sclerosis. Mult Scler. 2009;15:431–6.CrossRefPubMed
36.
go back to reference Sundstrom P, Nystrom L, Jidell E, Hallmans G. EBNA-1 reactivity and HLA DRB1*1501 as statistically independent risk factors for multiple sclerosis: a case-control study. Mult Scler. 2008;14:1120–2.CrossRefPubMed Sundstrom P, Nystrom L, Jidell E, Hallmans G. EBNA-1 reactivity and HLA DRB1*1501 as statistically independent risk factors for multiple sclerosis: a case-control study. Mult Scler. 2008;14:1120–2.CrossRefPubMed
37.
go back to reference Hjalgrim H, Rostgaard K, Johnson PC, Lake A, Shield L, Little AM, et al. HLA-A alleles and infectious mononucleosis suggest a critical role for cytotoxic T-cell response in EBV-related Hodgkin lymphoma. Proc Natl Acad Sci USA. 2010;107:6400–5.CrossRefPubMedPubMedCentral Hjalgrim H, Rostgaard K, Johnson PC, Lake A, Shield L, Little AM, et al. HLA-A alleles and infectious mononucleosis suggest a critical role for cytotoxic T-cell response in EBV-related Hodgkin lymphoma. Proc Natl Acad Sci USA. 2010;107:6400–5.CrossRefPubMedPubMedCentral
38.
go back to reference Huang X, Kushekhar K, Nolte I, Kooistra W, Visser L, Bouwman I, et al. HLA associations in classical Hodgkin lymphoma: EBV status matters. PLoS ONE. 2012;7:e39986.CrossRefPubMedPubMedCentral Huang X, Kushekhar K, Nolte I, Kooistra W, Visser L, Bouwman I, et al. HLA associations in classical Hodgkin lymphoma: EBV status matters. PLoS ONE. 2012;7:e39986.CrossRefPubMedPubMedCentral
Metadata
Title
HLA alleles modulate EBV viral load in multiple sclerosis
Authors
Simone Agostini
Roberta Mancuso
Franca R. Guerini
Sandra D’Alfonso
Cristina Agliardi
Ambra Hernis
Milena Zanzottera
Nadia Barizzone
Maurizio A. Leone
Domenico Caputo
Marco Rovaris
Mario Clerici
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2018
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-018-1450-6

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