This is not about coronavirus.
Epstein-Barr Virus is an(other) extremely common virus which has infected the vast majority of people (~95%) by their late 20s. Unlike coronavirus, EBV has co-evolved with humans and the observation that it is so ubiquitous suggests that it actually may confer some kind of evolutionary benefit, e.g. by enhancing the host’s ability to respond to novel infections.
There are lots of highly suggestive lines of evidence pointing to a possible role for EBV in causing MS:
- Evidence of prior EBV infection is more common among pwMS
- It is exceptionally rare to have MS and not have evidence of prior EBV infection
- Symptomatic (severe) EBV infection (Infectious Mononucleosis – IM) is associated with increased MS risk
- Higher levels of anti-EBV antibodies correlate with higher MS risk
- Higher levels of anti-EBV antibodies correlate with more severe disease if you have MS
- EBV is present in active MS lesions
- There is some overlap between genetic risk factors for MS and genetic risk factors for more severe EBV infection
Sceptics will (rightly) point out that this is all circumstantial evidence, and that the only definitive proof would be if you could either cause MS by injecting an individual with EBV, or prevent/treat MS by preventing/treating infection with EBV. Regular readers of the blog will be aware of some exciting but very preliminary evidence suggesting that controlling EBV infection using engineered T cells can control progressive disease.
We are of the view that vaccinating against EBV may be an effective strategy for preventing MS in carefully selected individuals. Lots of the work that I, my supervisor Ruth and ProfG are doing aims to define MS risk so that we can identify which people are more likely to benefit from this approach.
To support any kind of prevention trial, it is important to clarify exactly what evidence there is to support an association between EBV and MS. That’s what we did here. We did a meta-analysis – essentially a formal summary – of all the relevant published studies looking at the link between EBV and MS.
You can read the paper if you want but I’ll summarise the key findings here:
- EBV is more common among people with MS: 93% of adults with MS had evidence of prior EBV infection vs 86% of controls. This difference is even more striking for children (85% vs 51%).
- IM (=glandular fever) is more common among people with MS: pwMS were about 2x as likely to have have glandular fever, which represents severe, symptomatic EBV infection.
- HLA DRB1*15, the strongest genetic risk factor for MS, potentiates the effect of EBV infection: having HLA DRB1*15 appears to amplify the effect of EBV on MS risk. People who have this risk gene and get IM seem to have a far greater risk of MS than those who do not have the risk gene. The same applies for people who have high anti-EBV antibody titres. The graph below illustrates the risk of MS on the y axis (expressed as an ‘Odds Ratio’) for people with low and high anti-EBV antibody titres, and for people with and without the HLA DRB1*15 risk allele. Hopefully the legend is intuitive – EBVhiHLA+ means high EBV antibody titre and HLA DRB1*15 positive.
The take home is that the effect of EBV infection on MS risk seems to depend on an individual’s prior genetic risk of MS. This is helpful for any future prevention trial design using an EBV vaccine, because it means that we should focus on people with the high risk HLA gene to maximise the chance they will benefit (and so justify the risks that come with any treatment or vaccine).
Importantly, this stuff is all based on observational data, and requires a bit more mechanistic evidence to prove that this interaction between HLA genes and EBV is really important in driving the MS disease process.
If you’d like to read the paper it’s available here: https://bit.ly/3bbMRx8
Abstract:
Background:
Epstein–Barr virus (EBV) infection is thought to play a central role in the development of multiple sclerosis (MS). If causal, it represents a target for interventions to reduce MS risk.
Objective:
To examine the evidence for interaction between EBV and other risk factors, and explore mechanisms via which EBV infection may influence MS risk.
Methods:
Pubmed was searched using the terms ‘multiple sclerosis’ AND ‘Epstein Barr virus’, ‘multiple sclerosis’ AND EBV, ‘clinically isolated syndrome’ AND ‘Epstein Barr virus’ and ‘clinically isolated syndrome’ AND EBV. All abstracts were reviewed for possible inclusion.
Results:
A total of 262 full-text papers were reviewed. There was evidence of interaction on the additive scale between anti-EBV antibody titre and HLA genotype (attributable proportion due to interaction (AP) = 0.48, p < 1 × 10−4). Previous infectious mononucleosis (IM) was associated with increased odds ratio (OR) of MS in HLA-DRB1*1501 positive but not HLA-DRB1*1501 negative persons. Smoking was associated with a greater risk of MS in those with high anti-EBV antibodies (OR = 2.76) but not low anti-EBV antibodies (OR = 1.16). No interaction between EBV and risk factors was found on a multiplicative scale.
Conclusion:
EBV appears to interact with at least some established MS risk factors. The mechanism via which EBV influences MS risk remains unknown.
There is lots more ‘circumstantial’ evidence than presented here. The argument about 95% percent of the population carrying EBV, but not all of these developing MS holds no weight given that Burkitt’s Lymphoma is an accepted consequence of EBV infection yet this is much rarer than MS. There is some evidence that EBV might be causal in a great many conditions like Rheumatoid disease, SLE, ME and some other cancers. When an effective vaccine is developed is developed, I’d like to see it introduced like the current whooping cough vaccination to try to eradicate EBV.
Nice work!
Dr Ben: What are your thoughts on the effects on our (collective) immune system if we eliminate this virus from circulation? If the hypothesis stands the test, and really does enhance immune responses to antigens, and in susceptiple patients auto-antigens, it likely also helps us with certain foreign antigens? Would be we be better of with or without it, collectively?
Interestingly, another virus does the “opposite”: Measles induce long term immunesuppression of memory repertoires in individuals that were infected. https://immunology.sciencemag.org/content/4/41/eaay6125?fbclid=IwAR2IlZ2P76B6gm3wdwykfGlMkL-FBYWedX1fYNme_Ux97rO0w7kLpEEFA_U
Can a virus (EBV but what about HERV) target oligodendrocytes and direct the healthy immune system against these cells to go out of them – causing MS?
I know about the viral hypothesis concerning Multiple Sclerosis (MS), the case of Feroe Island and the latest research on Temelimab. The COVID-19 pandemic, however, brought for me this question forward. The cytokine storm induced by the virus causes most of the damages and I am wondering if a similar phenomenon happens in MS. (see also my multiple previous comments on the subject to which I had at best one or two sentences answer, if not just question marks)
Do the so-called autoimmune diseases cluster in families?
It seems that way to me, because of my own family history, but is that really the case?
If so, different autoimmune diseases may have similar root causes. And the fact that different diseases come under different medical disciplines (neurology, endocrinology, rheumatology, …) may be an obstacle to uncovering the cause and working towards disease prevention. Ea
There is evidence from genetics
Do the so-called autoimmune diseases cluster in families?
It seems that way to me, because of my own family history, but is that really the case?
If so, different autoimmune diseases may have similar root causes. And the fact that different diseases come under different medical disciplines (neurology, endocrinology, rheumatology, dermatology, …) may be an obstacle to uncovering the cause and working towards disease prevention. Each discipline focuses on treatment of its own problems
“EBV has co-evolved with humans and the observation that it is so ubiquitous suggests that it actually may confer some kind of evolutionary benefit, e.g. by enhancing the host’s ability to respond to novel infections.” So chickenpox, before vaccines, infected almost everybody and remained in their bodies until they died. It offers no enhanced ability to the immune system. This tends to indicate that it does not need to provide a benefit. All it has to do is not kill or injure enough to cause significant evolutionary pressure.
Epstein-Barr virus nuclear antigen 2 (EBNA2) extensively rewires the human chromatin landscape at autoimmune risk loci.
https://www.biorxiv.org/content/10.1101/2020.04.15.043612v1.abstract