This is the edge of knowledge we neurologists most inhabit and become familiar with if we treat a disease like Ms. We have these highly effective treatments now but we don’t really know what risks we’re running long term, or whether our patients’ current good progress will be sustained. MS-Selfie is almost essential to any general neurologist treating MS, which really includes the so-called neuro-immunologists, whose title in some ways reflects their very limited knowledge of immunology. Thank you Prof Giovannoni for this immersion. We need this in other sub-specialties but what you’ve done for patients with MS and neurologists who treat it is remarkable.
The human organism is complicated. There's impressive focus on how to stop the disease progression, to which I'm grateful but there is far less focus into optimizing or helping the body's own potential to repair or replenish. The body when everything is in order 'wants' to heal itself. Why so little effort there as well. Am I wrong for asking?!
Thanks for the post. If you were a teacher and MS research was your student, what grade would you give your student? Why after 50+ years of well funded research (and 40 years of ECTRIMS annual meeting) can’t a question like “is MS an autoimmune disease” be answered? The blinkered obsession with tackling relapses showed us that, even if you turn relapses / focal inflammation off, the disease (neurodegeneration) continues. So the cause/s of the neurodegeneration need to be identified and tackled (hopefully the BTK inhibitor trials and Sizomus trials will provide some valuable insights). Surely the learning for MS should not come from autoimmune diseases, but neurodegenerative diseases (MND, Parkinson’s, dementias). Also, if EBV is required but not sufficient to cause MS, a well thought through anti-viral trial should generate data / insights to explain how MS is triggered and what drives it.
Very interesting information, though far over my head. Targeted therapy makes so much sense. I agree that we’re using a sledgehammer approach. And it’s not working so well as we get to neida. Thanks for this, Prof G.
So, if you believe that EBV is the primary culprit behind MS, then aren't you also supporting an 'outside in' model of MS? If EBV is changing something to trigger an immune response, then there won't be an autoantigen. There will just be immune cells responding to something not currently being measured.
For example, the EBV noncoding small RNA, EBER2, competes with adenosine deanimase resulting in a rise in adenosine. That will open calcium channels, causing cell death and consequent elevation of DAMP related activity. It will also downregulate CD8+ T cell activity which Pender noted was happening over 10 years ago. No one seems to measure adenosine but it's long been established that the breakdown product, uric acid, is low in MS patients. Low uric acid will give peroxynitrite a free kick, adding to inflammatory settings. None of that needs an autoantigen.
Intense science! But also a useful explainer for me of how immunology works as that's handy to know for my work but I haven't ever quite wrapped my head around it. Very grateful for your work here
Many thanks, it's really interesting to read and learn more about the research, I did resort to ChatGPT now and again! Just wondering you get any clues from looking at T-cell clones in AHSCT patients if they start to relapse again?
Thank-you for such a clear and informative explanation of the current state of my innate promiscuity and the mirror scoundrels (who turn out to be me too). Yes, I (my brain/body) needs a primer on how to either calm down my roaming interest or learn how to identify the imposter scoundrel that has shown up. The discovery of the identity of the offending imposters will go a long way to finding ways to block or deprive them of replication. Then, if the threat is blocked or damped completely down I can, maybe, with help or alone, repair my myelin. (I am taking a chance here to display my complete misunderstanding, but heck a girl gotta try). In any case, I deeply appreciate that you share your research and knowledge with the people who most want to understand.
It seems the debate between possibly B-cell mediated or T-cell mediated will stand for many years to come. For now the evidence for the B-cell mechanisms seems more meaningful to me, perhaps autoreactive T-cells play less of a role than research funding gives them and there should be more focus on the intricate B cell control mechanisms?
What makes you more hopeful: T-cell targeting or B-cell targeting?
This post and thread is really important to understand how much work still needs to be done, and how much space we we all need to get into for full expression of understanding this wickedly pernicious affliction. Thank you, Prof G.
oh wow....this one stretched my brain! well written and informative. i got stuck on "huh?", the T - i thought it was all about the B cells - i'm so confused. did a re-read to shelve that persisting "huh" & the read made more sense. i do like the closing metaphor referring to a "sledgehammer".
This is the edge of knowledge we neurologists most inhabit and become familiar with if we treat a disease like Ms. We have these highly effective treatments now but we don’t really know what risks we’re running long term, or whether our patients’ current good progress will be sustained. MS-Selfie is almost essential to any general neurologist treating MS, which really includes the so-called neuro-immunologists, whose title in some ways reflects their very limited knowledge of immunology. Thank you Prof Giovannoni for this immersion. We need this in other sub-specialties but what you’ve done for patients with MS and neurologists who treat it is remarkable.
The human organism is complicated. There's impressive focus on how to stop the disease progression, to which I'm grateful but there is far less focus into optimizing or helping the body's own potential to repair or replenish. The body when everything is in order 'wants' to heal itself. Why so little effort there as well. Am I wrong for asking?!
Thanks for the post. If you were a teacher and MS research was your student, what grade would you give your student? Why after 50+ years of well funded research (and 40 years of ECTRIMS annual meeting) can’t a question like “is MS an autoimmune disease” be answered? The blinkered obsession with tackling relapses showed us that, even if you turn relapses / focal inflammation off, the disease (neurodegeneration) continues. So the cause/s of the neurodegeneration need to be identified and tackled (hopefully the BTK inhibitor trials and Sizomus trials will provide some valuable insights). Surely the learning for MS should not come from autoimmune diseases, but neurodegenerative diseases (MND, Parkinson’s, dementias). Also, if EBV is required but not sufficient to cause MS, a well thought through anti-viral trial should generate data / insights to explain how MS is triggered and what drives it.
Very interesting information, though far over my head. Targeted therapy makes so much sense. I agree that we’re using a sledgehammer approach. And it’s not working so well as we get to neida. Thanks for this, Prof G.
So, if you believe that EBV is the primary culprit behind MS, then aren't you also supporting an 'outside in' model of MS? If EBV is changing something to trigger an immune response, then there won't be an autoantigen. There will just be immune cells responding to something not currently being measured.
For example, the EBV noncoding small RNA, EBER2, competes with adenosine deanimase resulting in a rise in adenosine. That will open calcium channels, causing cell death and consequent elevation of DAMP related activity. It will also downregulate CD8+ T cell activity which Pender noted was happening over 10 years ago. No one seems to measure adenosine but it's long been established that the breakdown product, uric acid, is low in MS patients. Low uric acid will give peroxynitrite a free kick, adding to inflammatory settings. None of that needs an autoantigen.
Intense science! But also a useful explainer for me of how immunology works as that's handy to know for my work but I haven't ever quite wrapped my head around it. Very grateful for your work here
Ok, I am dropping this graph here. Look at the research timeline. So much research taking off 2020, 2021. https://gregory-ms.com/observatory/
Many thanks, it's really interesting to read and learn more about the research, I did resort to ChatGPT now and again! Just wondering you get any clues from looking at T-cell clones in AHSCT patients if they start to relapse again?
Thank-you for such a clear and informative explanation of the current state of my innate promiscuity and the mirror scoundrels (who turn out to be me too). Yes, I (my brain/body) needs a primer on how to either calm down my roaming interest or learn how to identify the imposter scoundrel that has shown up. The discovery of the identity of the offending imposters will go a long way to finding ways to block or deprive them of replication. Then, if the threat is blocked or damped completely down I can, maybe, with help or alone, repair my myelin. (I am taking a chance here to display my complete misunderstanding, but heck a girl gotta try). In any case, I deeply appreciate that you share your research and knowledge with the people who most want to understand.
thank you for an interesting read
Thanks for the write up.
It seems the debate between possibly B-cell mediated or T-cell mediated will stand for many years to come. For now the evidence for the B-cell mechanisms seems more meaningful to me, perhaps autoreactive T-cells play less of a role than research funding gives them and there should be more focus on the intricate B cell control mechanisms?
What makes you more hopeful: T-cell targeting or B-cell targeting?
Very well written, thanks for the explanation.
This post and thread is really important to understand how much work still needs to be done, and how much space we we all need to get into for full expression of understanding this wickedly pernicious affliction. Thank you, Prof G.
oh wow....this one stretched my brain! well written and informative. i got stuck on "huh?", the T - i thought it was all about the B cells - i'm so confused. did a re-read to shelve that persisting "huh" & the read made more sense. i do like the closing metaphor referring to a "sledgehammer".
Thank you for taking the time to share....