The big hole in the EBV hypothesis of MS is how does the virus cause the disease at a molecular and immunological level. There are as many theories as thinkers.
One theory is that EBV infects the CNS and MS is caused by an immune response to the virus in the brain of MSers. MS is then due to bystander damage of the immune cells finding and attacking the EBV infected cells. The evidence that EBV infects the brain is strengthening but is not an accepted fact. In fact, it remains very controversial.
In the paper below from Francesca Aloisi’s laboratory, it shows that a large number of CD8 T-cells in the brains of MSers are EBV-specific targeting EBV proteins from both the latent and lytic phase of the EBV life-cycle. This is potentially a very important paper but needs to be reproduced.
The big hole in the EBV-infected brain and CD8+ T-cell hypothesis is why do patients do so well on natalizumab and why does anti-CD20 therapy prevent rebound post-natalizumab?
If the brain was infected with EBV and you blocked immune surveillance using natalizumab surely you could expect some ill-effects? We don’t see this happening clinically. In fact, we see the opposite; MSers on natalizumab have NEDA, a lot of them see an improvement in disability, they ‘normalise’ brain volume loss, they see a reversal of fatigue and/or sickness behaviour, etc. Surely natalizumab is the one experiment that argues against a direct CNS infection as being the cause of MS? Maybe not. Natalizumab may not stop smouldering MS which is the true disease and this may take many decades to manifest itself.
If MS is due to EBV-specific CD8+ cytotoxic T-lymphocytes attacking the brain of MSers, why does rituximab a drug that takes out predominantly B-cells and not CD8+ cells prevent rebound post-natalizumab? Some have argued that the B-cells are needed to travel to the brain to present antigen to the CD8+ T-cells. I don’t by this there are other professional antigen-presenting cells in the brains of MSers that can do this job. Others quote the new evidence that T-cells need help from B-cells to cross the blood-brain barrier. This does not explain why some of the carry-over PML cases from natalizumab to rituximab (or ocrelizumab) have developed IRIS (immune reconstitution inflammatory syndrome). In the latter cases IRIS causing T-cells are trafficking to the brain in the absence of circulating B-cells.
So this paper generates more questions than it answers. It does demonstrate that we need to really find-out if EBV is driving MS from within the CNS or from its effects on the immune system in the periphery. These two scenarios require different treatment approaches. However, this should not stop us from exploring both approaches, often it is the experiment that disproves the hypothesis.
It looks as if October 2019 is going to be the month of EBV and MS.
Serafini et al. Epstein-Barr virus-specific CD8 T cells selectively infiltrate the multiple sclerosis brain and interact locally with virus-infected cells: a clue for a virus-driven immunopathological mechanism. J Virol 2019 (accepted manuscript) DOI: 10.1128/JVI.00980-19
ABSTRACT: Epstein-Barr virus (EBV) is a ubiquitous herpesvirus strongly associated with multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS). Yet, the mechanisms linking EBV infection to MS pathology are uncertain. Neuropathological and immunological studies suggest that a persistent EBV infection in the CNS could stimulate a CD8 T-cell response aimed at clearing the virus but inadvertently causing CNS injury. Inasmuch as in situ demonstration of EBV-specific CD8 T cells and their effector function is missing, we searched for EBV-specific CD8 T cells in MS brain tissue using the pentamer technique.
Postmortem brain samples from 12 donors with progressive MS and known HLA class I genotype were analyzed. Brain sections were stained with HLA-matched pentamers coupled with immunogenic peptides from EBV-encoded proteins, control virus (cytomegalovirus, influenza A virus) proteins and myelin basic protein. CD8 T cells recognizing proteins expressed in the latent and lytic phases of the EBV life cycle were visualized in white matter lesions and/or meninges of 11/12 MS donors. The fraction (median value) of CD8 T cells recognizing individual EBV epitopes ranged from 0.5 to 2.5% of CNS-infiltrating CD8 T cells. Cytomegalovirus-specific CD8 T cells were detected at a lower frequency (≤0.3%) in brain sections from 4/12 MS donors. CNS-infiltrating EBV-specific CD8 T cells were CD107a-positive, suggesting a cytotoxic phenotype, and stuck to EBV infected cells.
Together with local EBV dysregulation, selective enrichment of EBV-specific CD8 T cells in the MS brain supports the notion that skewed immune responses toward EBV may contribute to inflammation causing CNS injury.
IMPORTANCE: EBV establishes a lifelong and asymptomatic infection in most individuals and more rarely causes infectious mononucleosis and malignancies, like lymphomas. The virus is also strongly associated with MS, a chronic neuroinflammatory disease with unknown etiology. Infectious mononucleosis increases the risk of developing MS and immune reactivity toward EBV is higher in persons with MS indicating inadequate control of the virus. Previous studies have suggested that persistent EBV infection in the CNS might stimulate an immunopathological response causing bystander neural cell damage. To verify this, we need to identify the immune “culprits” responsible for the detrimental antiviral response in the CNS. In this study, we analyzed postmortem brains donated by persons with MS and show that CD8 cytotoxic T cells recognizing EBV enter the brain and interact locally with the virus infected cells. This antiviral CD8 T cell-mediated immune response likely contributes to MS pathology.