EBV appears to central to MS and other conditions. The big question is how?
This is important because it depends on the the effect that you may get if you try and inhibit it. Some people think it is a target and so if you get rid of it, you get rid of MS. Most of the MS science world is not convinced and this is why it is difficult to get support to do trials.
As it is sunday and if you are interested here are two recent reviews that are open access and see if you buy the ideas or not.
Läderach F, Münz C. Epstein Barr Virus Exploits Genetic Susceptibility to Increase Multiple Sclerosis Risk. Microorganisms. 2021 Oct 21;9(11):2191. doi: 10.3390/microorganisms9112191.
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) for which both genetic and environmental risk factors have been identified. The strongest synergy among them exists between the MHC class II haplotype and infection with the Epstein Barr virus (EBV), especially symptomatic primary EBV infection (infectious mononucleosis) and elevated EBV-specific antibodies. In this review, we will summarize the epidemiological evidence that EBV infection is a prerequisite for MS development, describe altered EBV specific immune responses in MS patients, and speculate about possible pathogenic mechanisms for the synergy between EBV infection and the MS-associated MHC class II haplotype. We will also discuss how at least one of these mechanisms might explain the recent success of B cell-depleting therapies for MS. While a better mechanistic understanding of the role of EBV infection and its immune control during MS pathogenesis is required and calls for the development of innovative experimental systems to test the proposed mechanisms, therapies targeting EBV-infected B cells are already starting to be explored in MS patients.
Meier UC, Cipian RC, Karimi A, Ramasamy R, Middeldorp JM. Cumulative Roles for Epstein-Barr Virus, Human Endogenous Retroviruses, and Human Herpes Virus-6 in Driving an Inflammatory Cascade Underlying MS Pathogenesis. Front Immunol. 2021 Nov 1;12:757302. doi: 10.3389/fimmu.2021.757302.
Roles for viral infections and aberrant immune responses in driving localized neuroinflammation and neurodegeneration in multiple sclerosis (MS) are the focus of intense research. Epstein-Barr virus (EBV), as a persistent and frequently reactivating virus with major immunogenic influences and a near 100% epidemiological association with MS, is considered to play a leading role in MS pathogenesis, triggering localized inflammation near or within the central nervous system (CNS). This triggering may occur directly via viral products (RNA and protein) and/or indirectly via antigenic mimicry involving B-cells, T-cells and cytokine-activated astrocytes and microglia cells damaging the myelin sheath of neurons. The genetic MS-risk factor HLA-DR2b (DRB1*1501β, DRA1*0101α) may contribute to aberrant EBV antigen-presentation and anti-EBV reactivity but also to mimicry-induced autoimmune responses characteristic of MS. A central role is proposed for inflammatory EBER1, EBV-miRNA and LMP1 containing exosomes secreted by viable reactivating EBV+ B-cells and repetitive release of EBNA1-DNA complexes from apoptotic EBV+ B-cells, forming reactive immune complexes with EBNA1-IgG and complement. This may be accompanied by cytokine- or EBV-induced expression of human endogenous retrovirus-W/-K (HERV-W/-K) elements and possibly by activation of human herpesvirus-6A (HHV-6A) in early-stage CNS lesions, each contributing to an inflammatory cascade causing the relapsing-remitting neuro-inflammatory and/or progressive features characteristic of MS. Elimination of EBV-carrying B-cells by antibody- and EBV-specific T-cell therapy may hold the promise of reducing EBV activity in the CNS, thereby limiting CNS inflammation, MS symptoms and possibly reversing disease. Other approaches targeting HHV-6 and HERV-W and limiting inflammatory kinase-signaling to treat MS are also being tested with promising results. This article presents an overview of the evidence that EBV, HHV-6, and HERV-W may have a pathogenic role in initiating and promoting MS and possible approaches to mitigate development of the disease.
I have given you an alternative idea and if correct then the influence is before you get MS and so treating it wouldnt make any differece
My vote is for theory #1 (Munz)……I have always believed I was genetically predisposed to MS and certain environmental factors/exposures tipped the scales to actually developing MS. Could have been an infection, cancer, military, etc.
Probably explains why all pwms are EBV+, but not all individuals with +EBV levels have MS.
Nice to see a post about the role of genetics in MS. Maybe all the research into the COVID vaccine will yield more efforts into genetic hacking. Thanks for sharing an unbiased option MD1.
Not sure I’m unbiased by I like to be constructive.
So far we have identified 200 genes and suspect about 200 more. I started to do mice genetics in the 1980s and stopped shortly afterwards. It was too early as the technology was not sufficiently developed. However I wonder that if I knew the cause of EAE in number of mice (not the same path to same problem) and I threw them into a grain silo to have a bonk and I cam back a year later…could I find the genetic cause?. We have known about HLA-DR for fifty years has it given a solution, we have known about sickle cell anaemia/haemophilia for a lot longer and where are we treatment wise. However, I like the suggestion that the HLA-DR influences viral load, it saves hunting for antigen molecule mimics
SARS-COV-2 will be the worlds most studied set of antigens
What is there to lose if treating it a tenofovir-oike agent?
Most importantly, what better theories are there that can be immediately tested to stop disease progression?
“Most of the MS science world is not convinced and this is why it is difficult to get support to do trials.”
Has the MS science world fixed MS with the billions in funding received to date? How about we cut that significantly since most of this bunch are useless and simply draining resources? Or set very immediate targets to be met?
“How about we cut that significantly since most of this bunch are useless and simply draining resources?”…..Turkeys don’t vote for Christma. If you are an advisor on grant panels you may support studies on sexy science…how many studies were done on vitamin D? How many worked?
Set immediate targets to be met…but what would it be and would those demands be reasonable
What’s the alternative idea? I seem not to grasp it from this post alone…
It generates memory B cells
What’s your thoughts MD?
The first article is available here:
https://www.mdpi.com/2076-2607/9/11/2191/htm
The second is here:
https://www.frontiersin.org/articles/10.3389/fimmu.2021.757302/full
Both seem to be Open Access. The full text is a available.
Hey MD, any thoughts on ATA 188, the experimental treatment being worked on by Atara Therapeutics? They are taking T cells engineered to target EBV, and using them as an MS treatment. Phase 1 study (very small, about 25 patients) seemed to provide some promising results, with eight or nine patients actually exhibiting disability improvement. And this was on progressive patients, notoriously hard to treat. The company is currently recruiting for a larger phase 2 study.
These results have created a bit of a buzz in the MS patient community, but oddly the company’s stock price tanked when they were released. So who has it right, MSers or investors? Or neither…
I have a load of thoughts about it…the idea was generated by Prof Pender in Australia using people own cells to target EBV….when Atara developed it as a therapeutic there use other peoples cells (this throws immunology 101 out of the window), but if this is the answer are the results…sufficiently staggering
“(this throws immunology 101 out of the window)”
What’s the problem? Potential of developing ADAs? Or will these cells cause issues in the body?
Even though the T cells are directed to EBV Self MHC has the capcity to see non-self MHC this is called alloreactivity and is the basis of graft verses host disease when you use allografts (non-self) in transplantation. They are giving cells with a different MHC (not a perfect match) what stops mismatch MHC recognition, I guess if graft verses disease happens it is the end of the line for the approach and host verses graft to get rid of the cells is more likely
There is still ATA189 which I think is autologous. If they can get allogenic to work, big advantages for them (much easier to produce) and possibly for patients, too (might put it in the accessible realm, other personalized T cell treatments are way in the 6 figures).
One off the issues i have with Ebv theory off ms
Is pediatric ms
If the diagnosed age of ms peak about 30 ,40 years off age it sugests that those biologic processes
Take some time
So how do you explain a kid with 6 years develop ms ?
Does his/her immune system as had contact with the virus allready?
I dont seen to fing any paper regarding the role off ebv in pediatric ms
Maybe got something from the mother plus years of development.
Is EBV viral load a predicting factor for disease reactivation after IRT? Alemtuzumab/Cladribine. I was reading Alemtuzumab could potentially cause EBV reactivation (not on MS), how would it apply to MS?
Ebv viral load after Irt
Is a predictor of ptld (pre cancer risk)
https://ashpublications.org/blood/article/130/Supplement%201/4535/72203/EBV-Reactivation-Incidence-and-Severity-in
MS patients were more likely to develop high EBV (>500k) levels (p-0.03) and receiver operating characteristics (ROC) curve analysis (Fig 1) confirmed high EBV levels>500,000 correlate with high sensitivity 85.5%, specificity 82.5% (p-0.004) for clinical events requiring treatment. No significant rituximab related adverse events noted in treated group. As expected, no significant symptomatic EBV and no PTLD events were noted in AA cohort and none required any rituximab therapy for the EBV
Ebv must be doing something diferent to the ms cohort than AA ohort
If EBV induces the production of memory B cells, killing the virus would not be enough, would it have to stop these autoreactive B cells? Sars-Cov-2 could induce this same mechanism? (I read somewhere that the virus generates an exacerbated immune response similar to that of Lupus)
I doubt it works the same way as EBV produces mimics of B cell activation.
Dear MD & TB
I comment as someone who has spent a sizeable proportion of their life in research biochem. I am further qualified to speak as the mother of 2 daughters with MS, and the 3rd generation of a family affected with an autosomal dominant form of Ehlers-Danlos for 5 generations. I would therefore like to make the following comments:
1) I blame epigenetics.
2) the epigenetics of both Ehlers-Danlos and MS are latitude dependant.
3) the MS population has x13 probability of being co-diagnosed with EDS as the general population.
4) there is a current case to answer in re MS as a spectrum disorder.
5) bleeding edge research says occipito-cervical instability from birth permits CSF leaks.
6) my genetic predecessors and I grew up in the southern part of the US, and there has never been any sign of MS. I had severe Epstein-Barr, as did my children.
7) my children grew up in the UK following then current government health advice.
8) my grandchildren, both born of my elder daughter, daughter then son, did my best guess from researchers I knew online at he time, which was Vit D at a dosage then regarded as toxic by NHS medical professionals. They both have EDS, but neither have MS.
9) I was advised 5 years ago by the Prof/Rheum/immunology bloke at Oxford that I should double my own dosage of vit D- think original research is very old French colonial in Africa about dark skin, sun, and vit D absorption by MSF, but really couldn’t swear to it anymore.
Hope this lends some sort of perspective anyway.
Best, Paula
PS: I am also currently managing a significantly older husband on a palliative care pathway for AML. Heigh-ho, how sad, never mind… P
Having considered the comments I would appear to have generated, I would like to ask if you guys are all a bit on team USA side.
I have followed this blog for many years, despite never having posted previously. By my lights, the best research into MS comes from Canada, Scandinavia, and Scotland. I am willing to countenance Australian universities in Melbourne, but not Sydney. SA has not yet arrived. Team USA may or may not care to consider latitude dependency and other factors involved in general epigenetics, in re MS, EDS, or quite a number of other immune disorders,, dunno. In my experience, any lab rat in the universe knows how evidence happens.
I should declare an interest, in that:
1) I am a dual citizen, as are both my daughters. They are in different positions in re this citizenship, as the elder daughter was born in NYC in 1973, and the younger at my UK place of residence in 1982.
2) I’m reasonably competent at stats on the back of an envelope.
3) In the words of the old Woody Guthrie song, “I ain’t got no home in this world anymore”.
Best to all,
Paula
epigenetics whats the evidence…?Team USA…..”By my lights, the best research into MS comes from Canada, Scandinavia, and Scotland”…..Charming….on what basis
Oh dear- apologies for any offence caused, MD. You have also inadvertently insulted me twice now, and made wholly unwarranted assumptions about my history, age, experience, extensive highly relevant qualifications, and personal familiarity with how education, funding, and politics work in a number of other national cultures. You demonstrate my central point, which you have patently failed to take, so very well indeed.
I am 69, and did not begin to read Biochem at Warwick U until after you appear to have qualified yourself, having left NYC for England with my husband in 1977. I self-identify as a lab-rat merely in that I am academic and not clinical, and find a lab a comforting environment. I also take comfort in playing the violin, but have never done so professionally.
In this country at the time, it was merely the easiest route to learning stuff I needed to know for personal reasons about connective tissues. Obviously I am no longer in paid employment, but my (transferable) research skills have not deserted me overnight. My immunology is well past 101, thank you, as is my virology, and my maths is really rather extensive- my father once addressed the NAS during the enquiry into the first space shuttle disaster.
– Canada, the Scandinavian nations, and Scotland have high percentages of their entire populations affected with MS, so there is political incentive to invest. MS doesn’t happen much at the latitude of Sydney, but does at that of Melbourne- kind of like the difference between, say, Chicago and New Orleans. This gives me pause in re national stats in both countries. South Africa understandably has far more pressing research priorities.
– old French colonial refers to former French colonies in Africa, rather like the US being a former British colony. The MSF research was somewhere in the late 1990s.
– I am thrilled to bits about mRNA tech, and have huge respect for Dr Ozlem Tureci, who stuck to her guns through academic demotion when others had moved on to follow the investment money as it all started to look too difficult and long term.
– I found a 2015 presentation by the impassioned American physician Dr Heidi Collins on connective tissue disease inspirational. Given the 2017 international reclassification of EDS, it was also prescient.
– I have no idea as to your own current practice, but if you are clinical with that attitude, I’d jump out of windows to avoid being your patient.
– I totally agree with you re good luck and good hunting, but have never seen any evidence that any virus that has co-evolved with humans can ever be eradicated permanently. Vaccination is, in my opinion, essentially a highly valuable harm reduction strategy.
– I would respectfully remind you that the WHO has been warning about the lack of global pandemic readiness for a good 10 years now.
Regards, Paula
PS: Almost 6 years ago, I was fortunate in being a patient of Professor **** *****, Consultant Rheumatologist with special interest in Immunology, ******. His verbal advice to me was to increase my 4,000iu dose of vit D to 8,000-12,000iu. I was surprised, but continue to regard him as better qualified to comment than I am. Haven’t slightest clue about you, of course. I am able to argue the case for both evidence and educated instinct; I believe you have recently admitted to not being entirely unbiased in this respect.
Sorry for offence caused
If you think I made unwarranted assumptions about you, sorry to say I made no assumptions about you, but one needs to be evidence based and ask on what evidence you base you opinions. I see it is based on prevalence and location, so I am not sure I agree but dont want you to jump out of too many windows:-).
P.S. I didnt know what Gl and Gh meant,when I searched we got Good Hunting etc