Multiple Sclerosis etc. strongly associated with Epstein-Barr virus (and vitamin D)

Vitamin D, Epstein-Barr virus, and endogenous retroviruses in multiple sclerosis - facts and hypotheses - March 2021

J Integr Neurosci. 2021 Mar 30;20(1):233-238. doi: 10.31083/j.jin.2021.01.392.
Christine Brütting 1, Gabriele I Stangl 1, Martin S Staege 2

The pathogenesis of multiple sclerosis (MS) remains poorly understood. Presumably, MS is caused by multiple environmental, epigenetic, and genetic factors. Among them, human endogenous retroviruses (HERVs), Epstein-Barr virus (EBV) and vitamin D have been suggested to play a role in the pathogenesis and course of MS. Because vitamin D can affect the immune system and infections, it can be hypothesized that there is a close interplay between vitamins, EBV and ERV in the pathogenesis of MS. Here, we summarize the important data on vitamin D, including polymorphisms in genes related to vitamin D metabolism, EBV and ERV, in the pathogenesis of MS and create hypotheses regarding their interactions. Data indicate that vitamin D has a strong impact on viral infections and interferes with EBV infection, while EBV is capable of activating silent ERVs. We believe that EBV could be the missing link between vitamin D and ERV in MS pathogenesis.
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Evidence for the role of a virus in MS National MS Org 2021

  • "Ninety to ninety-five percent of people with MS have proteins in their spinal fluid that are typically found in the spinal fluid of people with nervous system diseases that are known to be reactions to viruses."
  • "HHV-6 may also be involved in MS — specifically related to triggering relapses. A team in Spain found that HHV-6 antibodies reached their highest levels in people with MS two weeks before a relapse occurred. "

Epstein–Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies - March 2020

Trends in Molecular Medicine Vol 26, ISSUE 3, P296-310 DOI:
Amit Bar-Or. Michael P. Pender. Rajiv Khanna. Blake T. Aftab. Gavin Giovannoni. Manher A. Joshi
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  • Clinical studies show that depletion of B cells reduces disease burden in both relapsing-remitting and progressive multiple sclerosis (MS) patients.
  • B cell-tropic viruses may trigger aberrant immune responses in MS in genetically susceptible individuals owing, in part, to a failure in viral surveillance and clearance.
  • The most compelling data supporting an etiologic role for viral involvement in MS have emerged for Epstein–Barr virus (EBV).

Targeting mechanisms by which EBV is thought to participate in MS pathogenesis provides an opportunity for new drug development in MS.
New treatments for multiple sclerosis (MS) focused on B cells have created an atmosphere of excitement in the MS community. B cells are now known to play a major role in disease, demonstrated by the highly impactful effect of a B cell-depleting antibody on controlling MS. The idea that a virus may play a role in the development of MS has a long history and is supported mostly by studies demonstrating a link between B cell-tropic Epstein–Barr virus (EBV) and disease onset. Efforts to develop antiviral strategies for treating MS are underway. Although gaps remain in our understanding of the etiology of MS, the role, if any, of viruses in propagating pathogenic immune responses deserves attention.

The role of Epstein-Barr virus in multiple sclerosis:
from molecular pathophysiology to in vivo imaging - March 2019

Neural Regen Res. 2019 Mar; 14(3): 373–386. doi: 10.4103/1673-5374.245462
Yi Guan,1 Dejan Jakimovski,1 Murali Ramanathan,2,3 Bianca Weinstock-Guttman,2 and Robert Zivadinov, MD, PhD, FAAN, FEAN, FANA1,4,*
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Multiple sclerosis (MS) is a disease of the central nervous system characterized by inflammation, demyelination, and neuronal damage. Environmental and genetic factors are associated with the risk of developing MS, but the exact cause still remains unidentified.

Epstein-Barr virus (EBV), vitamin D, and smoking are among the most well-established environmental risk factors in MS.
Infectious mononucleosis, which is caused by delayed primary EBV infection, increases the risk of developing MS.

EBV may also contribute to MS pathogenesis indirectly by activating silent human endogenous retrovirus-W. The emerging B-cell depleting therapies, particularly anti-CD20 agents such as rituximab, ocrelizumab, as well as the fully human ofatumumab, have shown promising clinical and magnetic resonance imaging benefit. One potential effect of these therapies is the depletion of memory B-cells, the primary reservoir site where EBV latency occurs. In addition, EBV potentially interacts with both genetic and other environmental factors to increase susceptibility and disease severity of MS. This review examines the role of EBV in MS pathophysiology and summarizes the recent clinical and radiological findings, with a focus on B-cells and in vivo imaging. Addressing the potential link between EBV and MS allows the better understanding of MS pathogenesis and helps to identify additional disease biomarkers that may be responsive to B-cell depleting intervention.

Exploring the effect of vitamin D3 supplementation on the anti-EBV antibody response in relapsing-remitting multiple sclerosis - 2018

Linda Rolf, Anne-Hilde Muris, Amandine Mathias, Renaud Du Pasquier, Inga Koneczny, Giulio Disanto, Jens Kuhle, Sreeram Ramagopalan, Jan Damoiseaux, Joost Smolders, and Raymond Hupperts

Epstein–Barr virus (EBV) infection and vitamin D insufficiency are potentially interacting risk factors for multiple sclerosis (MS).

To investigate the effect of high-dose vitamin D3 supplements on antibody levels against the EBV nuclear antigen-1 (EBNA-1) in patients with relapsing-remitting multiple sclerosis (RRMS) and to explore any underlying mechanism affecting anti-EBNA-1 antibody levels.

This study utilized blood samples from a randomized controlled trial in RRMS patients receiving either vitamin D3 (14,000 IU/day; n = 30) or placebo (n = 23) over 48 weeks. Circulating levels of 25-hydroxyvitamin-D, and anti-EBNA-1, anti-EBV viral capsid antigen (VCA), and anti-cytomegalovirus (CMV) antibodies were measured. EBV load in leukocytes, EBV-specific cytotoxic T-cell responses, and anti-EBNA-1 antibody production in vitro were also explored.

The median antibody levels against EBNA-1, but not VCA and CMV, significantly reduced in the vitamin D3 group (526 (368–1683) to 455 (380–1148) U/mL) compared to the placebo group (432 (351–1280) to 429 (297–1290) U/mL; p = 0.023). EBV load and cytotoxic T-cell responses were unaffected. Anti-EBNA-1 antibody levels remained below detection limits in B-cell cultures.

High-dose vitamin D3 supplementation selectively reduces anti-EBNA-1 antibody levels in RRMS patients. Our exploratory studies do not implicate a promoted immune response against EBV as the underlying mechanism.
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VitaminDWiki pages containing EPSTEIN in title

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Epstein-Barr Virus and Mononucleosis

Other diseases associated with Epstein-Barr Virus

July 2019
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EPSTEIN-BARR VIRUS – Symptoms, Causes,
10 Ways To Fight Epstein-Barr Virus Naturally and Epstein-Barr Diet – 24 Healing Foods

Symptoms of Epstein-Barr virus fourth stage – a viral inflammation may include:
Muscle and joint pain
Painful and tender points
Back pain
Stinging and/or numbness of the hands and feet
Constant fatigue
Blurred vision
Restless sleep
Night sweats
Tinnitus – Or ringing in the ear, is usually caused by EBV getting into the inner ear’s nerve channel, called the labyrinth. The ringing is the result of the virus inflaming and vibrating the labyrinth and the vestibulocochlear nerve.
Vertigo and Meniere’s Disease – Vertigo and Meniere’s disease are often attributed by doctors to calcium crystals, or stones, becoming disrupted in the inner ear. However, most chronic cases are actually caused by EBV’s neurotoxin inflaming the vagus nerve.
Chest tightness
Chest pain
Esophageal spasms, and asthma can also be caused by EBV inflaming the vagus nerve.
Tingling and numbness in hands and feet, can be caused by phrenic nerves becoming perpetually inflamed by EBV.
And heart palpitations can result from buildup of EBV’s poisonous virus corpses and byproduct in the heart’s mitral valve.

Hypothesis:Vitamin D Epstein-Barr interaction increases MS risk – Sept 2011

Vitamin D: a link between Epstein–Barr virus and multiple sclerosis development?
Expert Review of Neurotherapeutics - - - - - (PDF is attached at bottom of this page)
September 2011, Vol. 11, No. 9, Pages 1221-1224 , DOI 10.1586/ern.11.97
Giulio Disanto; University of Oxford, Oxford, UK
Ute Meier; Blizard Institute, Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London, UK
Gavin Giovannoni; Blizard Institute, Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London, UK
Sreeram V Ramagopalan; University of Oxford, Oxford, UK and Queen Mary University of London, Blizard Institute, Barts and The London School of Medicine and Dentistry, 4 Newark Street, London, E1 2AT, UK.

Multiple sclerosis (MS) is a complex immune-mediated disorder of the CNS, which results from a combination of genetic and environmental factors and their interactions (1). Although genome-wide association studies have discovered numerous genetic variants predisposing to MS, the environment exerts a greater influence on susceptibility (2). That nurture is fundamental in MS has been known for decades. Monozygotic twins are, at most, 30% concordant, and familial MS risk is significantly influenced by location and season of birth and the childhood environment (1,2). Growing evidence lends strong support to vitamin D deficiency and Epstein–Barr virus (EBV) infection as being key environmental risk factors.

The data supporting a role for vitamin D in the development of MS are overwhelming. The worldwide prevalence of MS positively correlates with latitude (3). Essential for the production of vitamin D, ultraviolet B (UVB) light radiation is the factor that most likely mediates such a correlation, and this is especially clear in national studies from France and England (2,4). Vitamin D intake significantly decreases the risk of MS, and vitamin D levels inversely correlate with risk of MS later in life (5,6). Furthermore, CYP27B1, the gene encoding 1?-hydroxylase (the enzyme that activates vitamin D) is associated with MS susceptibility (7). In addition, vitamin D can also influence MS course. A recent prospective investigation of a large cohort of MS patients has demonstrated that vitamin D status is inversely associated with disease activity over the subsequent 6 months (8).

Functional evidence comes from studies showing that both the vitamin D receptor (VDR) and CYP27B1 genes are expressed in an exceptionally broad range of immune cells, including those that are known to play a central role in MS, such as Th1 and Th17 subsets, FOXP3+ regulatory T cells and B cells (9,10). This extremely pleiotropic hormone is able to influence cellular function and proliferation through a fine regulation of gene expression. Using chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-seq), our group has demonstrated the presence of 2776 different vitamin D responsive elements (VDREs) through the entire genome bound by the VDR in B cells. Notably, genetic loci associated with MS are strikingly enriched for VDR binding sites (11).

However, vitamin D is not the only environmental factor implicated in MS. EBV is a B-lymphotropic human DNA herpes virus associated with lymphoproliferative and immune disorders (12). Although more than 90% of the general population appears to encounter EBV at some point during their life, several lines of evidence highlight its role in the pathogenesis of MS. Large independent studies have shown that nearly all MS patients have been infected with EBV. Furthermore, both high anti-EBV antibody titers and a history of infectious mononucleosis (IM) increase the risk of developing MS (1,13).

Whether such a strong association between MS and EBV is actually causal has been, and still is, debated. For example, the elevated risk of MS after IM could arise from a common genetic susceptibility to MS and IM. However, this suggestion can be refuted since the HLA-DRB1*1501 class II allele, the main genetic risk factor for MS, is not associated with the development of IM (14). Similarly, the hypothesis that good hygiene during childhood may predispose both to MS and to a later contact with EBV, and therefore IM, should be equally rejected given the observation that EBV-negative individuals (likely to be exposed to the highest levels of hygiene) have the lowest risk of MS (13). Pediatric MS represents a valuable tool for the identification of environmental risk factors. As a consequence of early disease onset, less time is available for potential confounders, and thus any associated factor is more likely to be truly causative. In a recent investigation of a large cohort of pediatric MS patients, both EBV positivity and high EBV antibody titers predicted conversion to MS independently of HLA and vitamin D status, although not all pediatric patients were infected with EBV (15).

While it is possible that vitamin D and EBV may be influencing MS risk through independent mechanisms, another hypothesis is also plausible, which is that these two factors may be biologically interacting to increase the risk of MS. This idea is supported by our recent observation that a statistical interaction between IM prevalence and UVB light radiation could explain 72% of the variance in MS prevalence across England (4). How this interaction may take place at the molecular level remains largely unknown, but there are a number of potential explanations.

First, it is plausible that vitamin D deficiency influences the immune response to EBV. Vitamin D increases the production of the anti-microbial peptide cathelicidin, which may protect against EBV (10,16). Furthermore, serum levels of 25-hydroxyvitamin D correlate positively with the ability of Tregs to suppress T-cell proliferation (17), and it has been suggested that Tregs are important in controlling primary EBV infection to a subclinical level in most cases and that IM represents a failure of this protective mechanism (18). This idea is somewhat supported by the epidemiological evidence indicating that early vitamin D deficiency influences MS risk prior to EBV infection (i.e., place and month of birth precedes IM) (19) and the finding that individuals with a high serum 25-hydroxyvitamin D were less likely to have viral (EBV) shedding in saliva (20). However, as vitamin D deficiency affects all ages there needs to be an explanation as to why the peak age of IM is in the early teens/late 20s. Furthermore, given the variable nature of vitamin D status, it is not clear how this interaction could predispose to MS over the long term if EBV is suppressed when vitamin D levels are high. It is possible that this could be related to an ‘immunological imprint’ that is left as a result of vitamin D deficiency during a critical time period of development or after infection with EBV.

Another theory comes from the demonstration that the EBV protein EBNA-3 is able to stop the expression of the vitamin D-regulated genes C-FOS, CYCLIN C, CYP24A1, GADD45A and P21 by blocking VDR activity (21). A recent study identified the expression profiles of lymphoblastoid cell lines obtained by infecting primary B cells with either wild-type EBV or an EBV mutant strain lacking the EBNA-3 gene (22). To explore to what extent EBNA-3 may influence the expression of vitamin D responsive genes we calculated how many of the putative EBNA-3 regulated genes are characterized by the presence of a VDRE using data from our VDR ChIP-seq map. Interestingly, of the 296 genes that were differentially expressed between EBNA-3 positive and EBNA-3 negative lymphoblastoid cell lines, 82 (27.7%) were characterized by the presence of a VDRE, which was much greater than expected by chance (p = 0.003). A gene ontology analysis demonstrated that the genes with both an EBNA-3 and VDR influence were involved in cell proliferation, apoptosis and immune response processes. This analysis suggests that a substantial proportion of the genes regulated by the viral protein EBNA-3 are likely to be regulated by vitamin D, so it may be that EBV potentiates vitamin D deficiency by blocking the effect of vitamin D. The extent to which EBNA-3 is expressed may be dependent on the host immune response, which may include MS susceptibility genes. From an evolutionary perspective, EBV has evolved several mechanisms to evade immunological attack (23) and one of these mechanisms may be EBNA-3’s interaction with vitamin D, which has well-described antiviral effects (24).

Understanding how risk factors for MS integrate to lead to MS development is critical for disease prevention. The proposition that low vitamin D levels may be influencing the immune response against EBV is not surprising since vitamin D is a potent modulator of the adaptive immune system and low levels are known to increase the risk of other viral infections, such as influenza (25,26). However, further work is needed to address this question. In particular, future prospective studies should investigate whether the risk of IM and EBV antibody titers are influenced by vitamin D status at the time of infection.

If confirmed, this notion would open up the question as to whether the association between EBV and MS is merely a consequence of vitamin D deficiency predisposing to both MS and EBV infection. Although this possibility cannot currently be ruled out, it appears highly unlikely given the amount of evidence (mentioned above) supporting EBV as being specifically involved in MS causation. It is particularly intriguing to suppose that vitamin D-deficient individuals may be more likely to develop IM after EBV infection, and MS risk is increased in some of these individuals who have higher expression of EBNA-3, which blocks vitamin D action in B cells, which are gaining increasing recognition as being key players in the pathogenesis of MS (27,28). As EBV has coevolved with us over millions of years it may be of interest to study EBV–vitamin D interactions and responses between ancestral populations from Africa and Caucasians.

Great strides are being made in cataloguing the pleiotropic effects of vitamin D in the immune and nervous systems (16). A major facet to understanding better the interaction between vitamin D and EBV in MS is to better understand how EBV predisposes to MS – that is, is it through molecular mimicry, bystander activation or another mechanism (29)? More basic research is needed to fully understand the environmental risk factors in MS, as this will provide new strategies for both disease prevention and treatment. Longitudinal studies of at-risk populations will be extremely useful.

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