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Published in: Journal of Neurology 2/2018

01-02-2018 | Review

Low intrathecal antibody production despite high seroprevalence of Epstein–Barr virus in multiple sclerosis: a review of the literature

Authors: Klemens Ruprecht, Brigitte Wildemann, Sven Jarius

Published in: Journal of Neurology | Issue 2/2018

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Abstract

Background

Patients with multiple sclerosis (MS) frequently have an intrathecal production of antibodies to different common viruses, which can be detected by elevated antiviral antibody indices (AIs). There is a strong and consistent association of MS and Epstein–Barr virus (EBV) infection.

Objective

To systematically compare the frequencies of intrathecal antibody production to EBV, measles virus, rubella virus, varicella zoster virus (VZV) and herpes simplex virus (HSV) in patients with MS.

Methods

Review of the English and German literature on the frequencies of intrathecal immunoglobulin (Ig)G antibody production, as defined by an elevated AI, to EBV, measles virus, rubella virus, VZV and HSV in adult and pediatric patients with MS.

Results

In nine original studies identified, the frequencies of an intrathecal production of antibodies to Epstein–Barr nuclear antigen-1 (33/340, 9.7%), EBV viral capsid antigen (12/279, 4.3%) and antigens from EBV-infected cell lines (14/90, 15.6%) in adult patients with MS were clearly lower (p ≤ 0.03 for all pairwise comparisons) than the frequencies of an intrathecal production of antibodies to measles virus (612/922, 66.4%), rubella virus (521/922, 56.5%), VZV (470/922, 51%; data from 17 original studies) and HSV (78/291, 26.8%; data from 6 original studies). Though based on a lower number of original studies and patients, findings in children with MS were essentially similar. As in adults and children with MS the seroprevalence of EBV is higher than the seroprevalences of the other investigated viruses, the lower frequency of elevated EBV AIs became even more pronounced after correction of the frequencies of elevated antiviral AIs for the seroprevalences of the respective viruses.

Conclusions

Given the very high seroprevalence of EBV in MS, the frequency of intrathecally produced antibodies to EBV in patients with MS is paradoxically low compared to that of other common viruses. These findings are compatible with the recently proposed hypothesis that in individuals going on to develop MS antiviral antibody-producing cells may invade the brain predominantly at the time of and triggered by acute primary EBV infection, before anti-EBV IgG producing cells have yet occurred.
Literature
1.
go back to reference Almohmeed YH, Avenell A, Aucott L, Vickers MA (2013) Systematic review and meta-analysis of the sero-epidemiological association between Epstein Barr virus and multiple sclerosis. PLoS One 8:e61110CrossRefPubMedPubMedCentral Almohmeed YH, Avenell A, Aucott L, Vickers MA (2013) Systematic review and meta-analysis of the sero-epidemiological association between Epstein Barr virus and multiple sclerosis. PLoS One 8:e61110CrossRefPubMedPubMedCentral
2.
go back to reference Alotaibi S, Kennedy J, Tellier R, Stephens D, Banwell B (2004) Epstein–Barr virus in pediatric multiple sclerosis. JAMA 291:1875–1879CrossRefPubMed Alotaibi S, Kennedy J, Tellier R, Stephens D, Banwell B (2004) Epstein–Barr virus in pediatric multiple sclerosis. JAMA 291:1875–1879CrossRefPubMed
3.
go back to reference Ascherio A, Munger KL (2007) Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol 61:288–299CrossRefPubMed Ascherio A, Munger KL (2007) Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol 61:288–299CrossRefPubMed
4.
go back to reference Ascherio A, Munger KL (2016) Epidemiology of multiple sclerosis: from risk factors to prevention—an update. Semin Neurol 36:103–114CrossRefPubMed Ascherio A, Munger KL (2016) Epidemiology of multiple sclerosis: from risk factors to prevention—an update. Semin Neurol 36:103–114CrossRefPubMed
5.
go back to reference Ascherio A, Munger KL, Lennette ET, Spiegelman D, Hernan MA, Olek MJ, Hankinson SE, Hunter DJ (2001) Epstein–Barr virus antibodies and risk of multiple sclerosis: a prospective study. JAMA 286:3083–3088CrossRefPubMed Ascherio A, Munger KL, Lennette ET, Spiegelman D, Hernan MA, Olek MJ, Hankinson SE, Hunter DJ (2001) Epstein–Barr virus antibodies and risk of multiple sclerosis: a prospective study. JAMA 286:3083–3088CrossRefPubMed
7.
go back to reference Balfour HH Jr, Odumade OA, Schmeling DO, Mullan BD, Ed JA, Knight JA, Vezina HE, Thomas W, Hogquist KA (2013) Behavioral, virologic, and immunologic factors associated with acquisition and severity of primary Epstein-Barr virus infection in university students. J Infect Dis 207:80–88CrossRefPubMed Balfour HH Jr, Odumade OA, Schmeling DO, Mullan BD, Ed JA, Knight JA, Vezina HE, Thomas W, Hogquist KA (2013) Behavioral, virologic, and immunologic factors associated with acquisition and severity of primary Epstein-Barr virus infection in university students. J Infect Dis 207:80–88CrossRefPubMed
8.
go back to reference Banwell B, Krupp L, Kennedy J, Tellier R, Tenembaum S, Ness J, Belman A, Boiko A, Bykova O, Waubant E, Mah JK, Stoian C, Kremenchutzky M, Bardini MR, Ruggieri M, Rensel M, Hahn J, Weinstock-Guttman B, Yeh EA, Farrell K, Freedman M, Iivanainen M, Sevon M, Bhan V, Dilenge ME, Stephens D, Bar-Or A (2007) Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study. Lancet Neurol 6:773–781CrossRefPubMed Banwell B, Krupp L, Kennedy J, Tellier R, Tenembaum S, Ness J, Belman A, Boiko A, Bykova O, Waubant E, Mah JK, Stoian C, Kremenchutzky M, Bardini MR, Ruggieri M, Rensel M, Hahn J, Weinstock-Guttman B, Yeh EA, Farrell K, Freedman M, Iivanainen M, Sevon M, Bhan V, Dilenge ME, Stephens D, Bar-Or A (2007) Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study. Lancet Neurol 6:773–781CrossRefPubMed
9.
go back to reference Bednarova J, Stourac P, Adam P (2005) Relevance of immunological variables in neuroborreliosis and multiple sclerosis. Acta Neurol Scand 112:97–102CrossRefPubMed Bednarova J, Stourac P, Adam P (2005) Relevance of immunological variables in neuroborreliosis and multiple sclerosis. Acta Neurol Scand 112:97–102CrossRefPubMed
10.
go back to reference Belbasis L, Bellou V, Evangelou E, Ioannidis JP, Tzoulaki I (2015) Environmental risk factors and multiple sclerosis: an umbrella review of systematic reviews and meta-analyses. Lancet Neurol 14:263–273CrossRefPubMed Belbasis L, Bellou V, Evangelou E, Ioannidis JP, Tzoulaki I (2015) Environmental risk factors and multiple sclerosis: an umbrella review of systematic reviews and meta-analyses. Lancet Neurol 14:263–273CrossRefPubMed
11.
go back to reference Brettschneider J, Tumani H, Kiechle U, Muche R, Richards G, Lehmensiek V, Ludolph AC, Otto M (2009) IgG antibodies against measles, rubella, and varicella zoster virus predict conversion to multiple sclerosis in clinically isolated syndrome. PLoS One 4:e7638CrossRefPubMedPubMedCentral Brettschneider J, Tumani H, Kiechle U, Muche R, Richards G, Lehmensiek V, Ludolph AC, Otto M (2009) IgG antibodies against measles, rubella, and varicella zoster virus predict conversion to multiple sclerosis in clinically isolated syndrome. PLoS One 4:e7638CrossRefPubMedPubMedCentral
12.
go back to reference Castellazzi M, Contini C, Tamborino C, Fasolo F, Roversi G, Seraceni S, Rizzo R, Baldi E, Tola MR, Bellini T, Granieri E, Fainardi E (2014) Epstein–Barr virus-specific intrathecal oligoclonal IgG production in relapsing-remitting multiple sclerosis is limited to a subset of patients and is composed of low-affinity antibodies. J Neuroinflammation 11:188CrossRefPubMedPubMedCentral Castellazzi M, Contini C, Tamborino C, Fasolo F, Roversi G, Seraceni S, Rizzo R, Baldi E, Tola MR, Bellini T, Granieri E, Fainardi E (2014) Epstein–Barr virus-specific intrathecal oligoclonal IgG production in relapsing-remitting multiple sclerosis is limited to a subset of patients and is composed of low-affinity antibodies. J Neuroinflammation 11:188CrossRefPubMedPubMedCentral
13.
go back to reference Castellazzi M, Tamborino C, Cani A, Negri E, Baldi E, Seraceni S, Tola MR, Granieri E, Contini C, Fainardi E (2010) Epstein–Barr virus-specific antibody response in cerebrospinal fluid and serum of patients with multiple sclerosis. Mult Scler 16:883–887CrossRefPubMed Castellazzi M, Tamborino C, Cani A, Negri E, Baldi E, Seraceni S, Tola MR, Granieri E, Contini C, Fainardi E (2010) Epstein–Barr virus-specific antibody response in cerebrospinal fluid and serum of patients with multiple sclerosis. Mult Scler 16:883–887CrossRefPubMed
15.
go back to reference Delorenze GN, Munger KL, Lennette ET, Orentreich N, Vogelman JH, Ascherio A (2006) Epstein–Barr virus and multiple sclerosis: evidence of association from a prospective study with long-term follow-up. Arch Neurol 63:839–844CrossRefPubMed Delorenze GN, Munger KL, Lennette ET, Orentreich N, Vogelman JH, Ascherio A (2006) Epstein–Barr virus and multiple sclerosis: evidence of association from a prospective study with long-term follow-up. Arch Neurol 63:839–844CrossRefPubMed
16.
go back to reference Denne C, Kleines M, Dieckhofer A, Ritter K, Scheithauer S, Merz U, Hausler M (2007) Intrathecal synthesis of anti-viral antibodies in pediatric patients. Eur J Paediatr Neurol 11:29–34CrossRefPubMed Denne C, Kleines M, Dieckhofer A, Ritter K, Scheithauer S, Merz U, Hausler M (2007) Intrathecal synthesis of anti-viral antibodies in pediatric patients. Eur J Paediatr Neurol 11:29–34CrossRefPubMed
17.
go back to reference Felgenhauer K, Reiber H (1992) The diagnostic significance of antibody specificity indices in multiple sclerosis and herpes virus induced diseases of the nervous system. Clin Investig 70:28–37CrossRefPubMed Felgenhauer K, Reiber H (1992) The diagnostic significance of antibody specificity indices in multiple sclerosis and herpes virus induced diseases of the nervous system. Clin Investig 70:28–37CrossRefPubMed
19.
go back to reference Graef IT, Henze T, Reiber H (1994) Polyspecific immune reaction in the central nervous system in autoimmune diseases with CNS involvement. Z Arztl Fortbild Jena 88:587–591PubMed Graef IT, Henze T, Reiber H (1994) Polyspecific immune reaction in the central nervous system in autoimmune diseases with CNS involvement. Z Arztl Fortbild Jena 88:587–591PubMed
20.
go back to reference Handel AE, Williamson AJ, Disanto G, Handunnetthi L, Giovannoni G, Ramagopalan SV (2010) An updated meta-analysis of risk of multiple sclerosis following infectious mononucleosis. PLoS One 5:e12496CrossRefPubMedPubMedCentral Handel AE, Williamson AJ, Disanto G, Handunnetthi L, Giovannoni G, Ramagopalan SV (2010) An updated meta-analysis of risk of multiple sclerosis following infectious mononucleosis. PLoS One 5:e12496CrossRefPubMedPubMedCentral
21.
go back to reference Hottenrott T, Dersch R, Berger B, Rauer S, Huzly D, Stich O (2017) The MRZ reaction in primary progressive multiple sclerosis. Fluids Barriers CNS 14:2CrossRefPubMedPubMedCentral Hottenrott T, Dersch R, Berger B, Rauer S, Huzly D, Stich O (2017) The MRZ reaction in primary progressive multiple sclerosis. Fluids Barriers CNS 14:2CrossRefPubMedPubMedCentral
22.
go back to reference Jacobi C, Lange P, Reiber H (2007) Quantitation of intrathecal antibodies in cerebrospinal fluid of subacute sclerosing panencephalitis, herpes simplex encephalitis and multiple sclerosis: discrimination between microorganism-driven and polyspecific immune response. J Neuroimmunol 187:139–146CrossRefPubMed Jacobi C, Lange P, Reiber H (2007) Quantitation of intrathecal antibodies in cerebrospinal fluid of subacute sclerosing panencephalitis, herpes simplex encephalitis and multiple sclerosis: discrimination between microorganism-driven and polyspecific immune response. J Neuroimmunol 187:139–146CrossRefPubMed
23.
go back to reference Jarius S, Eichhorn P, Franciotta D, Petereit HF, Akman-Demir G, Wick M, Wildemann B (2017) The MRZ reaction as a highly specific marker of multiple sclerosis: re-evaluation and structured review of the literature. J Neurol 264:453–466CrossRefPubMed Jarius S, Eichhorn P, Franciotta D, Petereit HF, Akman-Demir G, Wick M, Wildemann B (2017) The MRZ reaction as a highly specific marker of multiple sclerosis: re-evaluation and structured review of the literature. J Neurol 264:453–466CrossRefPubMed
24.
go back to reference Jarius S, Franciotta D, Bergamaschi R, Rauer S, Wandinger KP, Petereit HF, Maurer M, Tumani H, Vincent A, Eichhorn P, Wildemann B, Wick M, Voltz R (2008) Polyspecific, antiviral immune response distinguishes multiple sclerosis and neuromyelitis optica. J Neurol Neurosurg Psychiatry 79:1134–1136CrossRefPubMed Jarius S, Franciotta D, Bergamaschi R, Rauer S, Wandinger KP, Petereit HF, Maurer M, Tumani H, Vincent A, Eichhorn P, Wildemann B, Wick M, Voltz R (2008) Polyspecific, antiviral immune response distinguishes multiple sclerosis and neuromyelitis optica. J Neurol Neurosurg Psychiatry 79:1134–1136CrossRefPubMed
25.
go back to reference Krone B, Pohl D, Rostasy K, Kahler E, Brunner E, Oeffner F, Grange JM, Gartner J, Hanefeld F (2008) Common infectious agents in multiple sclerosis: a case–control study in children. Mult Scler 14:136–139CrossRefPubMed Krone B, Pohl D, Rostasy K, Kahler E, Brunner E, Oeffner F, Grange JM, Gartner J, Hanefeld F (2008) Common infectious agents in multiple sclerosis: a case–control study in children. Mult Scler 14:136–139CrossRefPubMed
26.
go back to reference Levin LI, Munger KL, O’Reilly EJ, Falk KI, Ascherio A (2010) Primary infection with the Epstein–Barr virus and risk of multiple sclerosis. Ann Neurol 67:824–830PubMedPubMedCentral Levin LI, Munger KL, O’Reilly EJ, Falk KI, Ascherio A (2010) Primary infection with the Epstein–Barr virus and risk of multiple sclerosis. Ann Neurol 67:824–830PubMedPubMedCentral
27.
go back to reference Levin LI, Munger KL, Rubertone MV, Peck CA, Lennette ET, Spiegelman D, Ascherio A (2005) Temporal relationship between elevation of Epstein–Barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis. JAMA 293:2496–2500CrossRefPubMed Levin LI, Munger KL, Rubertone MV, Peck CA, Lennette ET, Spiegelman D, Ascherio A (2005) Temporal relationship between elevation of Epstein–Barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis. JAMA 293:2496–2500CrossRefPubMed
28.
go back to reference Makhani N, Banwell B, Tellier R, Yea C, McGovern S, O’Mahony J, Ahorro JM, Arnold D, Sadovnick AD, Marrie RA, Bar-Or A (2016) Viral exposures and MS outcome in a prospective cohort of children with acquired demyelination. Mult Scler 22:385–388CrossRefPubMed Makhani N, Banwell B, Tellier R, Yea C, McGovern S, O’Mahony J, Ahorro JM, Arnold D, Sadovnick AD, Marrie RA, Bar-Or A (2016) Viral exposures and MS outcome in a prospective cohort of children with acquired demyelination. Mult Scler 22:385–388CrossRefPubMed
29.
go back to reference Munger KL, Levin LI, O’Reilly EJ, Falk KI, Ascherio A (2011) Anti-Epstein–Barr virus antibodies as serological markers of multiple sclerosis: a prospective study among United States military personnel. Mult Scler 17:1185–1193CrossRefPubMedPubMedCentral Munger KL, Levin LI, O’Reilly EJ, Falk KI, Ascherio A (2011) Anti-Epstein–Barr virus antibodies as serological markers of multiple sclerosis: a prospective study among United States military personnel. Mult Scler 17:1185–1193CrossRefPubMedPubMedCentral
30.
go back to reference Otto C, Hofmann J, Ruprecht K (2016) Antibody producing B lineage cells invade the central nervous system predominantly at the time of and triggered by acute Epstein–Barr virus infection: a hypothesis on the origin of intrathecal immunoglobulin synthesis in multiple sclerosis. Med Hypotheses 91:109–113CrossRefPubMed Otto C, Hofmann J, Ruprecht K (2016) Antibody producing B lineage cells invade the central nervous system predominantly at the time of and triggered by acute Epstein–Barr virus infection: a hypothesis on the origin of intrathecal immunoglobulin synthesis in multiple sclerosis. Med Hypotheses 91:109–113CrossRefPubMed
31.
go back to reference Otto C, Oltmann A, Stein A, Frenzel K, Schroeter J, Habbel P, Gartner B, Hofmann J, Ruprecht K (2011) Intrathecal EBV antibodies are part of the polyspecific immune response in multiple sclerosis. Neurology 76:1316–1321CrossRefPubMed Otto C, Oltmann A, Stein A, Frenzel K, Schroeter J, Habbel P, Gartner B, Hofmann J, Ruprecht K (2011) Intrathecal EBV antibodies are part of the polyspecific immune response in multiple sclerosis. Neurology 76:1316–1321CrossRefPubMed
32.
go back to reference Pakpoor J, Disanto G, Gerber JE, Dobson R, Meier UC, Giovannoni G, Ramagopalan SV (2012) The risk of developing multiple sclerosis in individuals seronegative for Epstein–Barr virus: a meta-analysis. Mult Scler 19:162–166CrossRefPubMed Pakpoor J, Disanto G, Gerber JE, Dobson R, Meier UC, Giovannoni G, Ramagopalan SV (2012) The risk of developing multiple sclerosis in individuals seronegative for Epstein–Barr virus: a meta-analysis. Mult Scler 19:162–166CrossRefPubMed
33.
go back to reference Pebody RG, Andrews N, Brown D, Gopal R, De Melker H, Francois G, Gatcheva N, Hellenbrand W, Jokinen S, Klavs I, Kojouharova M, Kortbeek T, Kriz B, Prosenc K, Roubalova K, Teocharov P, Thierfelder W, Valle M, Van Damme P, Vranckx R (2004) The seroepidemiology of herpes simplex virus type 1 and 2 in Europe. Sex Transm Infect 80:185–191CrossRefPubMedPubMedCentral Pebody RG, Andrews N, Brown D, Gopal R, De Melker H, Francois G, Gatcheva N, Hellenbrand W, Jokinen S, Klavs I, Kojouharova M, Kortbeek T, Kriz B, Prosenc K, Roubalova K, Teocharov P, Thierfelder W, Valle M, Van Damme P, Vranckx R (2004) The seroepidemiology of herpes simplex virus type 1 and 2 in Europe. Sex Transm Infect 80:185–191CrossRefPubMedPubMedCentral
34.
go back to reference Petereit HF, Reske D (2005) Expansion of antibody reactivity in the cerebrospinal fluid of multiple sclerosis patients—follow-up and clinical implications. Cerebrospinal Fluid Res 2:3CrossRefPubMedPubMedCentral Petereit HF, Reske D (2005) Expansion of antibody reactivity in the cerebrospinal fluid of multiple sclerosis patients—follow-up and clinical implications. Cerebrospinal Fluid Res 2:3CrossRefPubMedPubMedCentral
35.
go back to reference Pfuhl C, Oechtering J, Rasche L, Giess RM, Behrens JR, Wakonig K, Freitag E, Pache FC, Otto C, Hofmann J, Eberspacher B, Bellmann-Strobl J, Paul F, Ruprecht K (2015) Association of serum Epstein–Barr nuclear antigen-1 antibodies and intrathecal immunoglobulin synthesis in early multiple sclerosis. J Neuroimmunol 285:156–160CrossRefPubMed Pfuhl C, Oechtering J, Rasche L, Giess RM, Behrens JR, Wakonig K, Freitag E, Pache FC, Otto C, Hofmann J, Eberspacher B, Bellmann-Strobl J, Paul F, Ruprecht K (2015) Association of serum Epstein–Barr nuclear antigen-1 antibodies and intrathecal immunoglobulin synthesis in early multiple sclerosis. J Neuroimmunol 285:156–160CrossRefPubMed
36.
go back to reference Poethko-Muller C, Mankertz A (2012) Seroprevalence of measles-, mumps- and rubella-specific IgG antibodies in German children and adolescents and predictors for seronegativity. PLoS One 7:e42867CrossRefPubMedPubMedCentral Poethko-Muller C, Mankertz A (2012) Seroprevalence of measles-, mumps- and rubella-specific IgG antibodies in German children and adolescents and predictors for seronegativity. PLoS One 7:e42867CrossRefPubMedPubMedCentral
37.
go back to reference Pohl D, Krone B, Rostasy K, Kahler E, Brunner E, Lehnert M, Wagner H-J, Gärtner J, Hanefeld F (2006) High seroprevalence of Epstein–Barr virus in children with multiple sclerosis. Neurology 67:2063–2065CrossRefPubMed Pohl D, Krone B, Rostasy K, Kahler E, Brunner E, Lehnert M, Wagner H-J, Gärtner J, Hanefeld F (2006) High seroprevalence of Epstein–Barr virus in children with multiple sclerosis. Neurology 67:2063–2065CrossRefPubMed
38.
go back to reference Pohl D, Rostasy K, Jacobi C, Lange P, Nau R, Krone B, Hanefeld F (2009) Intrathecal antibody production against Epstein–Barr and other neurotropic viruses in pediatric and adult onset multiple sclerosis. J Neurol 257:212–216CrossRefPubMedPubMedCentral Pohl D, Rostasy K, Jacobi C, Lange P, Nau R, Krone B, Hanefeld F (2009) Intrathecal antibody production against Epstein–Barr and other neurotropic viruses in pediatric and adult onset multiple sclerosis. J Neurol 257:212–216CrossRefPubMedPubMedCentral
39.
go back to reference Puccioni-Sohler M, Kitze B, Felgenhauer K, Graef IT, Lange P, Novis S, Reiber H, Vaz B (1995) The value of CSF analysis for the differential diagnosis of HTLV-I associated myelopathy and multiple sclerosis. Arq Neuropsiquiatr 53:760–765CrossRefPubMed Puccioni-Sohler M, Kitze B, Felgenhauer K, Graef IT, Lange P, Novis S, Reiber H, Vaz B (1995) The value of CSF analysis for the differential diagnosis of HTLV-I associated myelopathy and multiple sclerosis. Arq Neuropsiquiatr 53:760–765CrossRefPubMed
40.
go back to reference Rand KH, Houck H, Denslow ND, Heilman KM (2000) Epstein–Barr virus nuclear antigen-1 (EBNA-1) associated oligoclonal bands in patients with multiple sclerosis. J Neurol Sci 173:32–39CrossRefPubMed Rand KH, Houck H, Denslow ND, Heilman KM (2000) Epstein–Barr virus nuclear antigen-1 (EBNA-1) associated oligoclonal bands in patients with multiple sclerosis. J Neurol Sci 173:32–39CrossRefPubMed
41.
go back to reference Reiber H (2017) Polyspecific antibodies without persisting antigen in multiple sclerosis, neurolupus and Guillain–Barre syndrome: immune network connectivity in chronic diseases. Arq Neuropsiquiatr 75:580–588CrossRefPubMed Reiber H (2017) Polyspecific antibodies without persisting antigen in multiple sclerosis, neurolupus and Guillain–Barre syndrome: immune network connectivity in chronic diseases. Arq Neuropsiquiatr 75:580–588CrossRefPubMed
42.
go back to reference Reiber H, Kruse-Sauter H, Quentin CD (2015) Antibody patterns vary arbitrarily between cerebrospinal fluid and aqueous humor of the individual multiple sclerosis patient: specificity-independent pathological B cell function. J Neuroimmunol 278:247–254CrossRefPubMed Reiber H, Kruse-Sauter H, Quentin CD (2015) Antibody patterns vary arbitrarily between cerebrospinal fluid and aqueous humor of the individual multiple sclerosis patient: specificity-independent pathological B cell function. J Neuroimmunol 278:247–254CrossRefPubMed
43.
go back to reference Reiber H, Lange P (1991) Quantification of virus-specific antibodies in cerebrospinal fluid and serum: sensitive and specific detection of antibody synthesis in brain. Clin Chem 37:1153–1160PubMed Reiber H, Lange P (1991) Quantification of virus-specific antibodies in cerebrospinal fluid and serum: sensitive and specific detection of antibody synthesis in brain. Clin Chem 37:1153–1160PubMed
44.
go back to reference Reiber H, Peter JB (2001) Cerebrospinal fluid analysis: disease-related data patterns and evaluation programs. J Neurol Sci 184:101–122CrossRefPubMed Reiber H, Peter JB (2001) Cerebrospinal fluid analysis: disease-related data patterns and evaluation programs. J Neurol Sci 184:101–122CrossRefPubMed
45.
go back to reference Reiber H, Teut M, Pohl D, Rostasy KM, Hanefeld F (2009) Paediatric and adult multiple sclerosis: age-related differences and time course of the neuroimmunological response in cerebrospinal fluid. Mult Scler 15:1466–1480CrossRefPubMed Reiber H, Teut M, Pohl D, Rostasy KM, Hanefeld F (2009) Paediatric and adult multiple sclerosis: age-related differences and time course of the neuroimmunological response in cerebrospinal fluid. Mult Scler 15:1466–1480CrossRefPubMed
46.
go back to reference Reiber H, Ungefehr S, Jacobi C (1998) The intrathecal, polyspecific and oligoclonal immune response in multiple sclerosis. Mult Scler 4:111–117CrossRefPubMed Reiber H, Ungefehr S, Jacobi C (1998) The intrathecal, polyspecific and oligoclonal immune response in multiple sclerosis. Mult Scler 4:111–117CrossRefPubMed
47.
go back to reference Rickinson AB, Kieff E (2001) Epstein–Barr virus. In: Knipe DM, Howley PM (eds) Virology. Lippincott Williams and Wilkins, New York, pp 2575–2627 Rickinson AB, Kieff E (2001) Epstein–Barr virus. In: Knipe DM, Howley PM (eds) Virology. Lippincott Williams and Wilkins, New York, pp 2575–2627
48.
go back to reference Robinson-Agramonte M, Reiber H, Cabrera-Gomez JA, Galvizu R (2007) Intrathecal polyspecific immune response to neurotropic viruses in multiple sclerosis: a comparative report from Cuban patients. Acta Neurol Scand 115:312–318CrossRefPubMed Robinson-Agramonte M, Reiber H, Cabrera-Gomez JA, Galvizu R (2007) Intrathecal polyspecific immune response to neurotropic viruses in multiple sclerosis: a comparative report from Cuban patients. Acta Neurol Scand 115:312–318CrossRefPubMed
49.
go back to reference Rosche B, Laurent S, Conradi S, Hofmann J, Ruprecht K, Harms L (2012) Measles IgG antibody index correlates with T2 lesion load on MRI in patients with early multiple sclerosis. PLoS One 7:e28094CrossRefPubMedPubMedCentral Rosche B, Laurent S, Conradi S, Hofmann J, Ruprecht K, Harms L (2012) Measles IgG antibody index correlates with T2 lesion load on MRI in patients with early multiple sclerosis. PLoS One 7:e28094CrossRefPubMedPubMedCentral
50.
go back to reference Rostasy K, Reiber H, Pohl D, Lange P, Ohlenbusch A, Eiffert H, Maass M, Hanefeld F (2003) Chlamydia pneumoniae in children with MS: frequency and quantity of intrathecal antibodies. Neurology 61:125–128CrossRefPubMed Rostasy K, Reiber H, Pohl D, Lange P, Ohlenbusch A, Eiffert H, Maass M, Hanefeld F (2003) Chlamydia pneumoniae in children with MS: frequency and quantity of intrathecal antibodies. Neurology 61:125–128CrossRefPubMed
51.
go back to reference Sargsyan SA, Shearer AJ, Ritchie AM, Burgoon MP, Anderson S, Hemmer B, Stadelmann C, Gattenlohner S, Owens GP, Gilden D, Bennett JL (2010) Absence of Epstein–Barr virus in the brain and CSF of patients with multiple sclerosis. Neurology 74:1127–1135CrossRefPubMedPubMedCentral Sargsyan SA, Shearer AJ, Ritchie AM, Burgoon MP, Anderson S, Hemmer B, Stadelmann C, Gattenlohner S, Owens GP, Gilden D, Bennett JL (2010) Absence of Epstein–Barr virus in the brain and CSF of patients with multiple sclerosis. Neurology 74:1127–1135CrossRefPubMedPubMedCentral
52.
go back to reference Schubert J, Weissbrich B (2007) Detection of virus-specific intrathecally synthesised immunoglobulin G with a fully automated enzyme immunoassay system. BMC Neurol 7:12CrossRefPubMedPubMedCentral Schubert J, Weissbrich B (2007) Detection of virus-specific intrathecally synthesised immunoglobulin G with a fully automated enzyme immunoassay system. BMC Neurol 7:12CrossRefPubMedPubMedCentral
53.
go back to reference Sindic CJ, Monteyne P, Laterre EC (1994) The intrathecal synthesis of virus-specific oligoclonal IgG in multiple sclerosis. J Neuroimmunol 54:75–80CrossRefPubMed Sindic CJ, Monteyne P, Laterre EC (1994) The intrathecal synthesis of virus-specific oligoclonal IgG in multiple sclerosis. J Neuroimmunol 54:75–80CrossRefPubMed
54.
go back to reference Sisay S, Lopez-Lozano L, Mickunas M, Quiroga-Fernandez A, Palace J, Warnes G, Alvarez-Lafuente R, Dua P, Meier UC (2017) Untreated relapsing remitting multiple sclerosis patients show antibody production against latent Epstein Barr Virus (EBV) antigens mainly in the periphery and innate immune IL-8 responses preferentially in the CNS. J Neuroimmunol 306:40–45CrossRefPubMed Sisay S, Lopez-Lozano L, Mickunas M, Quiroga-Fernandez A, Palace J, Warnes G, Alvarez-Lafuente R, Dua P, Meier UC (2017) Untreated relapsing remitting multiple sclerosis patients show antibody production against latent Epstein Barr Virus (EBV) antigens mainly in the periphery and innate immune IL-8 responses preferentially in the CNS. J Neuroimmunol 306:40–45CrossRefPubMed
55.
go back to reference Sundstrom P, Juto P, Wadell G, Hallmans G, Svenningsson A, Nystrom L, Dillner J, Forsgren L (2004) An altered immune response to Epstein–Barr virus in multiple sclerosis: a prospective study. Neurology 62:2277–2282CrossRefPubMed Sundstrom P, Juto P, Wadell G, Hallmans G, Svenningsson A, Nystrom L, Dillner J, Forsgren L (2004) An altered immune response to Epstein–Barr virus in multiple sclerosis: a prospective study. Neurology 62:2277–2282CrossRefPubMed
56.
go back to reference Thorley-Lawson DA (2005) EBV persistence and latent infection in vivo. In: Robertson ES (ed) Epstein–Barr virus. Caister Academic Press, Wymondham, pp 309–358 Thorley-Lawson DA (2005) EBV persistence and latent infection in vivo. In: Robertson ES (ed) Epstein–Barr virus. Caister Academic Press, Wymondham, pp 309–358
57.
go back to reference Villegas E, Santiago O, Carrillo JA, Sorlozano A, Guerrero M, Fernandez O, Gutierrez J (2011) Low intrathecal immune response of anti-EBNA-1 antibodies and EBV DNA from multiple sclerosis patients. Diagn Microbiol Infect Dis 70:85–90CrossRefPubMed Villegas E, Santiago O, Carrillo JA, Sorlozano A, Guerrero M, Fernandez O, Gutierrez J (2011) Low intrathecal immune response of anti-EBNA-1 antibodies and EBV DNA from multiple sclerosis patients. Diagn Microbiol Infect Dis 70:85–90CrossRefPubMed
58.
go back to reference Waubant E, Mowry EM, Krupp L, Chitnis T, Yeh EA, Kuntz N, Ness J, Chabas D, Strober J, McDonald J, Belman A, Milazzo M, Gorman M, Weinstock-Guttman B, Rodriguez M, Oksenberg JR, James JA (2011) Common viruses associated with lower pediatric multiple sclerosis risk. Neurology 76:1989–1995CrossRefPubMedPubMedCentral Waubant E, Mowry EM, Krupp L, Chitnis T, Yeh EA, Kuntz N, Ness J, Chabas D, Strober J, McDonald J, Belman A, Milazzo M, Gorman M, Weinstock-Guttman B, Rodriguez M, Oksenberg JR, James JA (2011) Common viruses associated with lower pediatric multiple sclerosis risk. Neurology 76:1989–1995CrossRefPubMedPubMedCentral
Metadata
Title
Low intrathecal antibody production despite high seroprevalence of Epstein–Barr virus in multiple sclerosis: a review of the literature
Authors
Klemens Ruprecht
Brigitte Wildemann
Sven Jarius
Publication date
01-02-2018
Publisher
Springer Berlin Heidelberg
Published in
Journal of Neurology / Issue 2/2018
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI
https://doi.org/10.1007/s00415-017-8656-z

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