Clin Transl Immunology. 2017;6(1):e126.
Mounting evidence indicates that infection with Epstein-Barr virus (EBV) has a major role in the pathogenesis of multiple sclerosis (MS). Defective elimination of EBV-infected B cells by CD8+ T cells might cause MS by allowing EBV-infected autoreactive B cells to accumulate in the brain. Here we undertake a comprehensive analysis of the T-cell response to EBV in MS, using flow cytometry and intracellular IFN-γ staining to measure T-cell responses to EBV-infected autologous lymphoblastoid cell lines and pools of human leukocyte antigen (HLA)-class-I-restricted peptides from EBV lytic or latent proteins and cytomegalovirus (CMV), in 95 patients and 56 EBV-seropositive healthy subjects. In 20 HLA-A2+ healthy subjects and 20 HLA-A2+ patients we also analysed CD8+ T cells specific for individual peptides, measured by binding to HLA-peptide complexes and production of IFN-γ, TNF-α and IL-2. We found a decreased CD8+ T-cell response to EBV lytic, but not CMV lytic, antigens at the onset of MS and at all subsequent disease stages. CD8+ T cells directed against EBV latent antigens were increased but had reduced cytokine polyfunctionality indicating T-cell exhaustion. During attacks the EBV-specific CD4+ and CD8+ T-cell populations expanded, with increased functionality of latent-specific CD8+ T cells. With increasing disease duration, EBV-specific CD4+ and CD8+ T cells progressively declined, consistent with T-cell exhaustion. The anti-EBNA1 IgG titre correlated inversely with the EBV-specific CD8+ T-cell frequency. We postulate that defective CD8+ T-cell control of EBV reactivation leads to an expanded population of latently infected cells, including autoreactive B cells.
- The T-cell response to EBV-infected B cells is reduced at all stages of MS except during clinical attacks
- The T-cell response to EBV-infected B cells progressively decreases with increasing duration of MS.
These results are consistent with progressive T-cell exhaustion of EBV-specific CD4+ T cells and CD8+ T cells during the course of MS although they could also be due to other factors, for example an age-related decline in the tendency of EBV to reactivate.
The CD8+ T-cell response to EBV lytic phase antigens is reduced at the onset of MS and throughout its course
CD8+ T cells recognizing EBV latent phase antigens in MS show T-cell exhaustion##
Proposed model of defective CD8+ T-cell control of EBV infection in MS. In healthy EBV carriers, (a) there is a dynamic equilibrium between the EBV-infected cell populations and the T-cell response. EBV-specific CD8+ T cells (T cell) exert a key role in controlling EBV infection by killing infected cells in the B blast, germinal centre (GC) B cell, plasma cell and tonsil epithelial cell, but not memory B cell, populations. The large arrows indicate the cycle of EBV infection: virion→B blast→GC B cell→memory B cell→plasma cell→virion→epithelial cell→virion→B blast. Smaller arrows indicate stimulation of T cells by EBV antigens from the infected populations. The relative sizes of the different EBV-infected cell populations are indicated by the circle sizes, based on the study by Hawkins et al.6 The relative sizes of the EBV-specific CD8+ T-cell populations are also indicated by the circle sizes; however, it is important to note that the EBV-specific CD8+ T-cell population is several orders of magnitude larger than the EBV-infected cell population, a distinction not depicted here. For simplicity, the EBV-specific CD4+ T-cell population and anti-EBV antibody response are not shown. At all stages of MS (b–d) the EBV-lytic-specific CD8+ T-cell population is decreased, allowing increased production of virions which infect naive B cells driving them into the blast phase. The resultant expansion of the infected blast population stimulates EBV-latent-specific CD8+ T cells which proliferate and restrict this expansion, but not without increased flow out of infected blast cells into a consequently enlarged EBV-infected GC cell population, which in turn is partially controlled by the augmented EBV-latent-specific CD8+ T-cell population. In the same way the EBV-infected memory B cell pool also grows, as does the population of plasma cells reactivating EBV infection. During clinical attacks of MS (c) there is increased differentiation of EBV-infected memory B cells into lytically infected plasma cells as a result of the various microbial infections that trigger attacks of MS. This EBV reactivation is inadequately regulated by the already deficient EBV-lytic-specific CD8+ T-cell response, resulting in increased virion production and increased infection of the blast pool, this in turn stimulating proliferation of the EBV-latent-specific CD8+ T-cell population which restricts further growth of the infected blast population. In progressive MS (d) the EBV-latent-specific CD8+ T-cell response becomes exhausted (indicated by fading), resulting in unchecked expansion of the infected GC population and the development of EBV-infected lymphoid tissue in the CNS.
we have shown that patients with MS have defective T-cell control of EBV infection which might underlie the accumulation of EBV-infected B cells in the CNS and subsequent development of the disease. We have proposed a model where decreased CD8+ T-cell control of EBV reactivation permits increased production of virus and consequent expansion of the latently infected B-cell population.
To test this model they suggest that further studies are necessary to determine:
(i) the cause of CD8+ EM/EMRA T-cell deficiency in MS, whether it genetically determined, and related to decreased type I IFN production;
(ii) whether CD8+ T-cell deficiency precedes the onset of MS and is present in healthy first-degree relatives of people with MS,
(iii) whether sunlight deprivation and vitamin D deficiency aggravate the CD8+ T-cell deficiency
(iv) how and why the EBV-specific CD4+ T-cell response declines during the course of MS;
(v) whether oral shedding of EBV is increased during clinical attacks;
(vi) whether the frequency of EBV-infected memory B cells in the blood is increased in MS, as in rheumatoid arthritis and systemic lupus erythematosus;
(vii) whether EBV-infected B cells and plasma cells in the CNS in MS are autoreactive, and (viii) finally and most importantly, whether therapies aimed at controlling EBV infection, such as EBV-specific T-cell therapy,prevent and cure MS.
Just a questions I had that I forgot to ask sometime ago.
Has there been any indication of EBV+ in pediatric MS?
Yes many paedeactric are positive intact most there real question are the environment negative.
If negative are they misdiagnosed or off negative is this the ugly fact that torpedo's ProfG viral hypothetis
The Cat People went to war over what colour hats would be worn in Fuchal. Some believed them to be red and others blue. Most of the Cat People were killed during the civil war, which astounded Lister, since he had intended the hats to be green.
I like the very last test. Am I right to say that, given this study Tecfidera might not be the best option as I can depletes lymphocytes (both B and T?) ? This would mean that this medecine might accelerate progression.
MD, slightly off topic… if the viral hypothesis of MS is true, is the effect of alemtuzumab partly due to aciclovir being given for at least a month after each alemtuzumab treatment ( in the US at least 2 months)? The reason behind it was preventing herpes reactivation, but EBV is also a herpes virus.
viruses hijeck cells to hicack them selves, there was a higher number of herpes infections after alemtuzumab than interferons but will few CD8, is this surprising.
However i agree a bit of anti viral may help.
I hope you are quietly doing an anti CD20 + antiviral trial then 🙂
What does Prof G think about this research? Does it fit with his EBV theory? Does it fit with the Charcot project?
Epstein–Barr virus and multiple sclerosis: potential opportunities for immunotherapy
"Following the treatment, the patient experienced a reduction in fatigue and painful lower limb spasms, an improvement in cognition and hand function, and increased productivity at work. These improvements were sustained up to the time of the latest review, 21 weeks after the final T-cell infusion, when neurological examination demonstrated increased voluntary movement of the lower limbs. Following treatment, the frequency of circulating EBV-specific CD8+ T cells increased and there were decreases in intrathecal IgG production and disease activity on brain MRI.142 The beneficial effects of the therapy were attributed to the killing of EBV-infected B cells in the CNS by the adoptively transferred CD8+ T cells."
http://www.nature.com/cti/journal/v3/n10/full/cti201425a.html
I am very confused. I have to learn this further 🙁
http://www.obatperedaasamlambungtinggi.suppliergreenworld.com/
So by the hypothesis who is EBV negative or had a false negative result or doesn't actually have MS but another disease?
If I understand well from this study the action of DMTs on T cells would not make MS worse then?