I think most people now acccept that EBV has some activity in the development of MS, but there is debate on what it does and how and when it does it. If it is involved as a trigger then but the time you get diagnosed with MS, the influence has happened and therefore it may be a little late to anything about it. Is is the trigger of disease activity, some people think it is the target for attack, but many others do not find supportive data. But what does it do after HSCT when the immune system is replaced…It is well known to me that following HSCT there is often explansion of memory B cells and so if this creates an EBV dilema. If there is EBV activity why is HSCT so good at stopping MS relapse, when surely it should be triggering disease activity…..Is the idea not quite right.
Both genetic susceptibility and environmental exposures are thought to be involved in multiple sclerosis (MS) pathogenesis. Of all viruses potentially relevant to MS aetiology, Epstein-Barr virus (EBV) is the best-studied. EBV is a B cell lymphotropic virus which is able to evade the immune system by establishing latent infection in memory B cells, and EBV reactivation is restricted by CD8 cytotoxic T cell (CTL) responses in immune competent individuals. Autologous haematopoietic stem cell transplantation (AHSCT) is considered to be the most effective therapy in the treatment of relapsing MS even though chemotherapy-induced lymphopenia can associate with the re-emergence of latent viruses. Despite the increasing interest in EBV and MS pathogenesis the relationship between AHSCT, EBV and viral immunity in people with MS has not been investigated to date. This study analysed immune responses to EBV in a well characterised cohort of 13 individuals with MS by utilising pre-AHSCT, and 6-, 12- and 24-month post AHSCT bio-banked peripheral blood mononuclear cells and plasma samples. It is demonstrated that the infused stem cell product contains latently EBV-infected memory B cells, and that EBV viremia (expansion of virus) occurs in the immune-compromised recipient post-transplant. High throughput TCR analysis detected expansion and diversification of the CD8 CTL responses reactive with EBV lytic and latent antigens from 6 to 24 months following AHSCT. (So AHSCT expands EBV infected B cells and T cells are expanded to kill them and kills lytic and latent virus…..so it could get into brain to remove EBV…but we know this is not associated with relapse). Increased levels of latent EBV infection found within the B cell pool following treatment, as measured by EBV genomic detection, did not associate with disease relapse. (Shouldn’t we have relapse, if EBV and memory B cells are important?) This not only raises important questions about the role of EBV infection in MS pathogenesis, but is of clinical importance given the expanding clinical trials of adoptive EBV-specific CTLs in MS. (So are they going to be a failure..is the writing on the wall?). (The disease was not associated with EBNA1 antibodies, which have been implicated by some as being important in MS.
I have not jumped on the EBV bandwagon and so do not spend my day contenplating everything about EBV, but the answers to such questions need to be brought into World view of MS….If it is a trigger it has already triggered.
So how can we detrigger?
if its a trigger you have disease so dont need to measure it,,,its happened.
There needs to be a study measuring neurofilament light levels comparing it with EBV activity on a weekly basis over time amongst people with relapsing MS, progressive MS and a healthy control. That way you can see if disease activity and EBV activity are in any way linked.
Not so easy and clear cut as you think. First I was going to say Neurofilament levels vary depending on the time of day but apparently not the case in some peoples hands
Hviid et al. Clin Chem Lab Med. 2021 PMID: 33759425; PMID: 33244083 but I see a problem and that is half-life How quickly does it appear and dcaay, In mic we did a study with NDG it did not pick up NFL when the inflammatory response was being generated it developed days later and then remained high for weeks despite resolution of the lesion. In humans apparently the NfLincreases with a maximum sometimes between 7 and 10 days, perhaps even longer after an injury and has a half-life of several weeks to a month or two. This may be kept in compllexes with anti-NFL antibody as this is eliminated. Next up is measuring EBV where do you measure it in blood in saliva in brain are you looking for lytic or latent infection.
HSCT often does not clear the brain of cells. EBV reactivation and lymphoproliferation is apparently a common occurrence. Relapse after HSCT does occur. if autoimmunity develops is it same as before…need to do soe tinking but good you have started that process
How can we detrigger…immune tolerance?
“If it is a trigger it has already triggered.” – how do you know if you’re not measuring it?
There needs to be a study measuring neurofilament light levels comparing it with EBV activity on a weekly basis over time amongst people with relapsing MS, progressive MS and a healthy control. That way you can see if disease activity and EBV activity are in any way linked.
Secondly HSCT resets the immune system. Bear in mind that 95% of people are infected with EBV but only a tiny percentage develop MS. If HSCT resets the immune system properly, why would it exhibit the aberrant behaviour a second time round? If it has not fully reset things then one would expect MS relapses to occur again. But if the immune system has been properly reset it should have no memory of MS and therefore should be successful.
if its a trigger you have disease so dont need to measure it,,,its happened.
There needs to be a study measuring neurofilament light levels comparing it with EBV activity on a weekly basis over time amongst people with relapsing MS, progressive MS and a healthy control. That way you can see if disease activity and EBV activity are in any way linked.
Not so easy and clear cut as you think. First I was going to say Neurofilament levels vary depending on the time of day but apparently not the case in some peoples hands
Hviid et al. Clin Chem Lab Med. 2021 PMID: 33759425; PMID: 33244083 but I see a problem and that is half-life How quickly does it appear and dcaay, In mic we did a study with NDG it did not pick up NFL when the inflammatory response was being generated it developed days later and then remained high for weeks despite resolution of the lesion. In humans apparently the NfLincreases with a maximum sometimes between 7 and 10 days, perhaps even longer after an injury and has a half-life of several weeks to a month or two. This may be kept in compllexes with anti-NFL antibody as this is eliminated. Next up is measuring EBV where do you measure it in blood in saliva in brain are you looking for lytic or latent infection.
HSCT often does not clear the brain of cells. EBV reactivation and lymphoproliferation is apparently a common occurrence. Relapse after HSCT does occur. if autoimmunity develops is it same as before…need to do soe tinking but good you have started that process
Why is serum NFL been discussed over and over if it is so bad? Some MS center offer sNFL test which cost a lot and not useful at all. I know patients persuaded to do monthly sNFL tests which cost them ~$300 a month.
They you go Ker Ching….do they act on the result?
I’m not sure if they act on the results – told patients this help predicting relapses which doesnt work for the ones I talk to.
Nice find
Thanks
Thank you for asking these questions!
Ever since I had a vicious EBV-reactivation in 2019 (post MS, diagnosed in 2013), I have been wondering about the relation EBV-MS-DMT/HSCT…:
– in my view, DMT-induced long-term lymphopenia was the likely cause of my EBV-reactivation
– because of the severe consequences of my EBV-reactivation (i.a. unable to walk 100m for 2 years, let alone work), and the risk of reactivation following HSCT, I decided HSCT was out for me
– given the relationship infection/MS-relapse or EBV/MS, I was more or less expecting a severe relapse following my EBV-reactivation, but that didn’t occur…
The whole episode left me with a lot of questions.
Is EBV-activity related to MS-activity?
Does EBV-reactivation imply that the DMT used is probably not working properly against MS either?
Are DMTs doing anything against EBV-reactivation? (other than guesses like that depletion B cells means getting rid of an important EBV-reservoir)
And indeed, how can HSCT be a succesfull MS-therapy?
I really look forward to see these type of questions debated. And to read your thoughts on them.
this study raises some interesting observations in relation to defining the role of EBV infection in MS pathogenesis.
Notably, AHSCT correlates with a therapeutic response that extends for
years after the period of immune reconstitution and this occurs despite
an increase in EBV viral load in the two years following AHSCT in most
of the treated patients. In the two-year follow-up period two individuals
experienced clinical relapses. While previous studies have indicated that
higher EBNA1 IgG levels are predictive of inflammatory activity [7],
EBNA1 IgG levels did not rise in these two participants
Hit and run?
Hypothesis?
It is well known to me that following HSCT there is often explansion of memory B cells
Well i dont understand
You been saying for years that most highly efficacious dmts work because they clear memory b cells number for years
Anti cd 20 ,hsct
Massive overshoot of B cells, due to mature B cell over population, that masks a major deletion of memory B cells. CD4 T cells disappear for over 2 years , CD8 are down for 8 months. Black bars 5th and 95th percentile of health and dotted line is the medium of health. No reports of autoimmunity in the report. Does this say anything, but the memory B cells were down
https://multiple-sclerosis-research.org/2017/05/blast-from-the-past-memory-b-cells-depleted-by-hsct/
Have you changed your mind?
No…this is why efficacy is associated with the capacity to get rid of them, but their retunr does not associate with disease.
I see
Their memory are against patogens and not self antigens
EBV is known to cause Hodkin’s lymphoma by modifying and immortalising B cells. When these people are treated for lymphoma with chemotherapy the cancer cells are destroyed but the virus remains. In many people the lymphoma does not come back even though they carry the virus. This points to the cause being a very rare mutation in the B cells rather than a direct effect of the virus. Could not something similar be happening in MS? It is not the virus itself but an outcome of a rare event that is infrequently caused by the virus.
HLA-DR15?
https://en.wikipedia.org/wiki/HLA-DR15
🙂