Absence of Epstein-Barr virus in the brain and CSF of patients with multiple sclerosis

Abstract

Objective: Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that becomes latent in B-lymphocytes and has been implicated in the pathogenesis of multiple sclerosis (MS). We searched for latent and active EBV infection in MS brain and CSF.Methods: Nested and non-nested real-time PCR were used to detect cell-specific and EBVspecific transcripts in 15 fresh-frozen and 5 formalin-fixed paraffin-embedded MS plaques and in single MS CSF B-lymphocytes and plasma cells. Intrathecal anti-EBV antibody synthesis was measured by ELISA. Immunocytochemistry was used to detect binding of MS CSF and recombinant antibodies (rAbs) generated from clonally expanded plasma cells in MS CSF to EBV-infected cells. Results:No EBV RNA was found in MS CSF B-lymphocytes or plasma cells. In active MS plaques, EBV-encoded RNA (EBER)-1 was the only and rarely detected transcript. The frequency of detected intrathecal anti-EBV antibody synthesis in patients with MS did not differ from that in non-MS inflammatory CNS disease control patients. Anti-EBV antibodies were detected in the CSF of patients with MS, but MS rAbs did not react with EBV. Epstein-Barr virus (EBV) is a common herpesvirus that is widespread in all human populations. EBV is spread orally and is the etiologic agent of infectious mononucleosis. Conclusions:1 Most primary infections are asymptomatic. More than 90% of adults are positive for serum immunoglobulin G (IgG) antibodies to the EBV capsid antigen.2 EBV becomes latent in peripheral blood B cells. EBV infection has been associated with multiple sclerosis (MS). 3In a large meta-analysis, EBV-seropositive individuals were found to have an increased risk for MS (odds ratio [OR] ϭ 13.5). 4 In a subsequent prospective study, a fourfold elevation in serum anti-EBV nuclear antigen (EBNA)-2 antibody titer was associated with a fourfold increased risk of developing MS.5 Further evidence of a link between EBV and MS came from reported enhanced immunoreactivity to EBV-specific proteins BRRF2 and EBNA-1 in serum and CSF of patients with MS, and the demonstration that a small fraction of CSF oligoclonal IgG of 13% of patients with MS was removed by incubation with purified BRRF2 and EBNA-1 proteins.6 Recently, about 90% of B-lymphocytes in active and chronic-active MS perivascular white matter lesions and about 80% of brain-infiltrating plasma cells were reported to be infected with EBV. 7 Immunohistologic detection of latent e-Pub ahead of print on March 10, 2010, at www.neurology.org.

Late B Cell Depletion with a Human Anti-Human CD20 IgG1κ Monoclonal Antibody Halts the Development of Experimental Autoimmune Encephalomyelitis in Marmosets

“…In view of recent data on the pathogenic function of intra-CNSlocalized EBV-infected B cells in MS (42), although not confirmed by others (43,44), it is tempting to speculate whether the clinical effect of the anti-CD20 Ab can be explained by the depletion of B cells from the CNS. Several lines of evidence indicate that MOG 34-56 -specific T cells, which have a key role in the clinical expression of EAE in marmosets, can be activated ex vivo by EBVtransformed B cells (21,22) (K.G.…”

Exploring the origins of grey matter damage in multiple sclerosis

“…It has been proposed that failure to control latent EBV infection in an immune privileged site, such as the subarachnoid space, could lead to recurrent intrathecal reactivation of EBV and tissue damage in the nearby grey matter 62,63 . However, a number of other studies have been unable to detect EBV in the brain or lesions of MS patients 64,65 and this remains a highly debated controversy 66 . The different results found in these studies are likely to be due to the different types of tissues and MS cases used, the variable preservation of meningeal tissues in the samples, and differences in the sensitivity of the techniques used to detect EBV infection 67 .…”

Contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis

“…EBV was found in 90% of meningeal B-cell follicles and in perivascular cuffs of patients with MS in one study [Serafini et al 2007] but was either not found or not frequently observed in a number of subsequent studies [Willis et al 2009;Aloisi et al 2010;Lassmann et al 2010;Peferoen et al 2010;Sargsyan et al 2010;Torskilden et al 2010;Owens and Bennett, 2012;Tracy et al 2012]. Nevertheless, latent EBV infection, with residual viral particles possibly remaining chronically in B lymphocytes, may contribute to the inflammatory milieu in active MS lesions by activating an innate and adaptive immune response, including B-cell activation and proinflammatory IFNα production [Serafini et al 2010;Tzartos et al 2012;Ascherio et al 2012a].…”