Increased CD8+ T Cell Response to Epstein-Barr Virus Lytic Antigens in the Active Phase of Multiple Sclerosis

Abstract

It has long been known that multiple sclerosis (MS) is associated with an increased Epstein-Barr virus (EBV) seroprevalence and high immune reactivity to EBV and that infectious mononucleosis increases MS risk. This evidence led to postulate that EBV infection plays a role in MS etiopathogenesis, although the mechanisms are debated. This study was designed to assess the prevalence and magnitude of CD8+ T-cell responses to EBV latent (EBNA-3A, LMP-2A) and lytic (BZLF-1, BMLF-1) antigens in relapsing-remitting MS patients (n = 113) and healthy donors (HD) (n = 43) and to investigate whether the EBV-specific CD8+ T cell response correlates with disease activity, as defined by clinical evaluation and gadolinium-enhanced magnetic resonance imaging. Using HLA class I pentamers, lytic antigen-specific CD8+ T cell responses were detected in fewer untreated inactive MS patients than in active MS patients and HD while the frequency of CD8+ T cells specific for EBV lytic and latent antigens was higher in active and inactive MS patients, respectively. In contrast, the CD8+ T cell response to cytomegalovirus did not differ between HD and MS patients, irrespective of the disease phase. Marked differences in the prevalence of EBV-specific CD8+ T cell responses were observed in patients treated with interferon-β and natalizumab, two licensed drugs for relapsing-remitting MS. Longitudinal studies revealed expansion of CD8+ T cells specific for EBV lytic antigens during active disease in untreated MS patients but not in relapse-free, natalizumab-treated patients. Analysis of post-mortem MS brain samples showed expression of the EBV lytic protein BZLF-1 and interactions between cytotoxic CD8+ T cells and EBV lytically infected plasma cells in inflammatory white matter lesions and meninges. We therefore propose that inability to control EBV infection during inactive MS could set the stage for intracerebral viral reactivation and disease relapse.

Epstein-Barr virus reactivation in critically ill immunocompetent patients

“…[ [21][22][23] The pathophysiology of EBV reactivation remains uncertain. Recent data suggest that EBV could trigger inflammatory process through interleukin-6 modulation.…”

Epstein-Barr virus genetic variants are associated with multiple sclerosis

“…The extent of genotype intraindividual variability proved to be high in both patients and controls with a greater occurrence of coexisting alleles in patients, possibly accounted for by the known higher rate of EBV reactivation in MS. 26,27 Our study demonstrates the appropriateness of deep-sequencing platforms to investigate patterns of genetic variation of a virus that latently infects peripheral blood cells at a very low frequency. Next-generation sequencing proved to be sensitive to such an extent that when used to study the EBV genotype in immune infiltrates microdissected from postmortem brain samples of a patient with secondary progressive MS (see appendix e-1), it allowed identification of a sequence of the EBNA2 allele 1.1 and related variants (table e-3) that was not detected using a conventional sequencing method.…”

Exploring the origins of grey matter damage in multiple sclerosis

“…Several epidemiological studies have suggested that Epstein-Barr virus (EBV) is one of the strongest candidates for this infectious agent [56][57][58] and EBV proteins and RNA have been detected in B-cells in the meninges and perivascular spaces of MS cases with extensive meningeal infiltrates and cortical demyelination [59][60][61] . 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 .…”