scholarly journals Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis

Science ◽  
2022 ◽  
Kjetil Bjornevik ◽  
Marianna Cortese ◽  
Brian C. Healy ◽  
Jens Kuhle ◽  
Michael J. Mina ◽  

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system of unknown etiology. We tested the hypothesis that MS is caused by Epstein-Barr virus (EBV) in a cohort comprising more than 10 million young adults on active duty in the US military, 955 of whom were diagnosed with MS during their period of service. Risk of MS increased 32-fold after infection with EBV but was not increased after infection with other viruses, including the similarly transmitted cytomegalovirus. Serum levels of neurofilament light chain, a biomarker of neuroaxonal degeneration, increased only after EBV seroconversion. These findings cannot be explained by any known risk factor for MS and suggest EBV as the leading cause of MS.

2010 ◽  
Vol 16 (7) ◽  
pp. 883-887 ◽  
Massimiliano Castellazzi ◽  
Carmine Tamborino ◽  
Alice Cani ◽  
Elena Negri ◽  
Eleonora Baldi ◽  

Cerebrospinal fluid and serum levels and intrathecal synthesis of anti-Epstein—Barr virus (EBV) IgG were measured by enzyme-linked immunosorbent assay in 80 relapsing—remitting multiple sclerosis patients grouped according to clinical and magnetic resonance imaging (MRI) evidence of disease activity. Eighty patients with other inflammatory neurological disorders (OIND) and 80 patients with non-inflammatory neurological disorders (NIND) served as neurological controls. Cerebrospinal fluid concentrations were higher in OIND than in multiple sclerosis ( p < 0.0001) and NIND ( p < 0.01) for anti-viral-capsid-antigen (anti-VCA) IgG, in multiple sclerosis than in NIND ( p < 0.01) and in OIND than in NIND ( p < 0.05) for anti-EBV nuclear antigen-1 (EBNA-1) IgG. Serum levels were more elevated in OIND than in multiple sclerosis ( p < 0.05) and in MRI inactive than in MRI active multiple sclerosis ( p < 0.0001) for anti-VCA IgG, and in multiple sclerosis than in OIND and NIND ( p < 0.01) for anti-EBNA-1 IgG. Serum titres of anti-VCA and anti-EBNA-1 IgG were also positively ( p < 0.05) and inversely ( p < 0.001) correlated, respectively, with the Expanded Disability Status Scale. An intrathecal IgG production of anti-VCA and anti-EBNA-1 IgG, as indicated by Antibody Index, was present only in a limited number of multiple sclerosis patients and controls (range from 1.3 to 6.3%). These findings do not support a direct pathogenetic role of EBV-targeted humoral immune response in multiple sclerosis.

2013 ◽  
Vol 19 (9) ◽  
pp. 1222-1225 ◽  
N Caucheteux ◽  
A Maarouf ◽  
L Daelman ◽  
O Toupance ◽  
S Lavaud ◽  

Acute disseminated encephalomyelitis (ADEM) is a rare inflammatory demyelinating disease of the central nervous system, usually occurring after a vaccination or infectious disease. It has been exceptionally described in transplanted patients. The pathophysiology remains incompletely understood. We report the clinical, biological and magnetic resonance imaging (MRI) presentation and evolution of two kidney-transplanted patients with ADEM associated with local Epstein-Barr virus (EBV) reactivation. ADEM may occur in transplanted patients with favorable evolution. Its pathophysiology is uncertain, and the implication of EBV is discussed.

2014 ◽  
Vol 20 (14) ◽  
pp. 1825-1832 ◽  
Michael P Pender ◽  
Peter A Csurhes ◽  
Casey MM Pfluger ◽  
Scott R Burrows

Background: Patients with multiple sclerosis (MS) have a deficiency of circulating CD8+ T cells, which might impair control of Epstein–Barr virus (EBV) and predispose to MS by allowing EBV-infected autoreactive B cells to accumulate in the central nervous system. Based on the expression of CD45RA and CD62L, CD4+ T cells and CD8+ T cells can be subdivided into four subsets with distinct homing and functional properties, namely: naïve, central memory, effector memory (EM) and effector memory re-expressing CD45RA (EMRA) cells. Objective: Our aim was to determine which memory subsets are involved in the CD8+ T cell deficiency and how these relate to clinical course. Methods: We used flow cytometry to analyze the memory phenotypes of T cells in the blood of 118 MS patients and 112 healthy subjects. Results: MS patients had a decreased frequency of EM (CD45RA–CD62L–) and EMRA (CD45RA+CD62L–) CD8+ T cells, which was present at the onset of disease and persisted throughout the clinical course. The frequencies of CD4+ EM and EMRA T cells were normal. Conclusion: Deficiency of effector memory CD8+ T cells is an early and persistent feature of MS and might underlie the impaired CD8+ T cell control of EBV.

Brain ◽  
2009 ◽  
Vol 133 (5) ◽  
pp. e137-e137 ◽  
Laura A. N. Peferoen ◽  
Floris Lamers ◽  
Lenthe N. R. Lodder ◽  
Wouter H. Gerritsen ◽  
Inge Huitinga ◽  

2014 ◽  
Vol 20 (11) ◽  
pp. 1541-1544 ◽  
Michael P Pender ◽  
Peter A Csurhes ◽  
Corey Smith ◽  
Leone Beagley ◽  
Kaye D Hooper ◽  

Defective control of Epstein–Barr virus (EBV) infection by cytotoxic CD8+ T cells might predispose to multiple sclerosis (MS) by allowing EBV-infected autoreactive B cells to accumulate in the central nervous system. We have treated a patient with secondary progressive MS with in vitro-expanded autologous EBV-specific CD8+ T cells directed against viral latent proteins. This adoptive immunotherapy had no adverse effects and the patient showed clinical improvement with reduced disease activity on magnetic resonance imaging and decreased intrathecal immunoglobulin production. This is the first report of the use of EBV-specific adoptive immunotherapy to treat MS or any other autoimmune disease.

2015 ◽  
Vol 2015 ◽  
pp. 1-5 ◽  
Massimiliano Castellazzi ◽  
Serena Delbue ◽  
Francesca Elia ◽  
Matteo Gastaldi ◽  
Diego Franciotta ◽  

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system. Natalizumab, a humanized anti-α4 integrin monoclonal antibody, is a highly effective treatment approved for MS. An association between MS and an exposure to Epstein-Barr Virus (EBV) sustained by the levels of antiviral capsid antigen (VCA) and anti-Epstein-Barr nuclear antigen-1 (EBNA-1) IgG has been described. Our goal was to verify the utility of EBV-specific IgG as a marker in Natalizumab treated MS. Twenty patients (17 female and 3 male) in treatment with Natalizumab were enrolled. Serum levels of anti-VCA and anti-EBNA-1 IgG were determined and expressed as arbitrary units (AU) before treatment and every three months for 21 months of therapy. Anti-VCA IgG levels were increased at the 15th month (235410 ± 196712 AU) comparing with the 3rd (98146 ± 47145 AU) and the 6th (109866 ± 52270 AU) months of therapyp<0.05. No significant differences were found for serum anti-EBNA-1 IgG levels. Our data indicate that a transient, self-limited, EBV reactivation can occur in MS during Natalizumab therapy but our results do not support the use of serum EBV-specific antibody levels as biomarkers for monitoring therapeutic response to Natalizumab in the course of MS.

2021 ◽  
Vol 9 (11) ◽  
pp. 2191
Fabienne Läderach ◽  
Christian Münz

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) for which both genetic and environmental risk factors have been identified. The strongest synergy among them exists between the MHC class II haplotype and infection with the Epstein Barr virus (EBV), especially symptomatic primary EBV infection (infectious mononucleosis) and elevated EBV-specific antibodies. In this review, we will summarize the epidemiological evidence that EBV infection is a prerequisite for MS development, describe altered EBV specific immune responses in MS patients, and speculate about possible pathogenic mechanisms for the synergy between EBV infection and the MS-associated MHC class II haplotype. We will also discuss how at least one of these mechanisms might explain the recent success of B cell-depleting therapies for MS. While a better mechanistic understanding of the role of EBV infection and its immune control during MS pathogenesis is required and calls for the development of innovative experimental systems to test the proposed mechanisms, therapies targeting EBV-infected B cells are already starting to be explored in MS patients.

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