Hi Scott,
here is the paper: http://www.nature.com/nsmb/journal/v19/ ... b.2367.pdf
it explains how EBV inactivates the immune system so the virus can stay 'under the radar' and continue to do its devastating work.
Regards, Leo
Theoretical Immunology
Re: A new concept and treatment options for MS
Last edited by Leonard on Mon Feb 23, 2015 2:24 am, edited 2 times in total.
A new vision on Multiple Sclerosis (MS)
Post script: see the more updated thesis of 26 March further down.
The thesis has been amended to take account of our latest learnings, and the material was condensed a bit further.
I do believe this is pretty much it, this is what is MS.
The view is supported by literally hundreds of links to relevant articles in the medical literature.
They can be found on this thread above.
The challenge will now be to effectively treat the disease.
A number of possible avenues seem to open up for that including chemo, anti-herpetics, boosting immunity and a variety of monoclonal antibodies.
A new vision on Multiple Sclerosis (MS)
The viral connection
The primate’s immune system and the herpes virus have coevolved alongside, for millions of years. However, over the last 50 years our living conditions have changed so profoundly that the immune system does not keep the virus in check anymore. There is accumulating evidence of the role of the herpes virus and in particular the Epstein-Barr virus (EBV) in the pathogenesis of MS. The association of MS with EBV is strongly supported in an epidemiological sense with the virtual non-existence of MS in EBV seronegative people (5 - 10 % of population).
Disruption of the highly evolved balance between the EBV lytic and latent life cycles and host immune control results in a range of EBV-associated diseases involving B-cells, epithelial cells, T-cells, natural killer (NK) cells and muscle cells. Here we may differentiate between two processes: an EBV protein inactivates monocyte signaling resulting in a subverted and ineffective immune response with EBV residing in the B cell and immortalizing it and T-lymphocyte imbalances; and cell disorders where pre-incubation of cells with EBV results in pro-inflammatory expression of the tissue.
High EBV antibody levels and alterations in EBV-specific CD8+ T-cell immunity are commonly observed and likely to be a causal factor in MS rather than the result of MS.
The viral tolerance theory – the EBV infected autoreactive B cells
During periods that people are immune compromised (can be the fetal period, the period of the newborn and immune deficient periods), the virus can incorporate some of its genes in the DNA of permissible cells. Chronic Cerebro Spinal Venous Insufficiency (CCSVI) is a factor here too causing hypoperfusion, lower AMP and adonesine, and with that a reduced control of the EBV infection. The incorporated viral genes (transgenes) are tolerant to the body or no immune memory against these transgenes has established. In MS, in particular the oligodendrocyte precursor cells (OPCs) in locally affected tissue will be infected but also the bone marrow.
People with transgenes in their body are healthy but predisposed to develop a disease. Predisposed people become diseased when they are infected with a microbe that shares epitodes with the transgenes present in the transgenic cells and will cause an immunological reaction.
In MS, EBV infected autoreactive T- and B-cells will pass the Central Nervous System (CNS) and cross-react with the transgenes in the OPCs. Due to this cross-reaction, many OPCs will die which leads to a diminishing number of OPCs, of dendrocytes and a reduced myelination of neurons. During this cross-reaction, many mediators will be released by the infiltrating T-cells. This will increase angiogenesis and cause hyperproliferation of surrounding tissue cells in the CNS which in turn causes the pathological lesions (sclerotic plaques) typical for MS.
The biochemical reaction hypothesis
The autoreactive B-cells have substantial super-oxygen generating capability. The superoxide reacts with the nitric oxide (NO) in the finest capillaries and forms peroxynitrite which is by far the worst free radical. Over time we produce excess peroxynitrite. Although the peroxynitrite may inhibit viral replication, it disables glyceraldehyde 3 phosphate which impacts the sodium/potassium pump and cell viability. Women have higher NO than men which explains the gender bias.
Over time the vitality of the cell declines as ATP levels decline and the loss of some AMP leads to a fall in Adenosine (endogenous inhibitor of arachidonic acid) and, in time, a loss of purine from Adenosine loss. Ultimately energy levels decline and uric acid levels fall. The loss of Adenosine will lower the ability to control inflammation and indeed the suppression of the transfer of EBV from latently infected cells to other cells. And the endothelium inflammates leading to an endothelial dysfunction.
The huge oxidative stress jams the gates/mitochondria of the cells, causes effects on the mitochondrial electron transport chain, electron pump inactivation, inhibits ADP to ATP conversion and depletes energy in the form of ATP. And it poisons fat tissue and causes lesions where the brains, biologically seen, are just a lump of fat.
As the number of active gates goes down, we see an increasingly big temperature effect in patients with MS and a loss of muscle strength and sensitivity in the periphery. As cells shrink in size because gates/mitochondria successively fail, it causes whole brain atrophy.
Hence, the typical fatigue, weakening of muscles and whole-brain atrophy observed in MS patients is partly caused by the CAEBV infection but with a completely different underlying mechanism than the demyelinating plaques in the brains. And the typical MS motor dysfynction will be caused by combination of factors.
A general dysregulation of the metabolism – interlocking vicious cycles
The virus is causal and leads to a general dysregulation of the metabolism involving metabolic factors (HPA axis affecting cortisol and gut function) and infection by bacteria and fungi including Borrelia, Cpn and toxoplasmose.
(Short term) stressors initiate cases of multisystem illnesses by stimulating nitric oxide synthase (NOS) activity and consequently produce increased levels of nitric oxide and its oxidant product peroxynitrite. The immune system will be triggered by the biochemical cycle mechanism with NF-кB a first responder to the harmful cellular stimuli. The increased NF-кB activity will lead to increased iNOS activity by stimulating through the inflammatory cytokines the activity of the iNOS gene itself.
There is a combination of stability and instability, positive and negative feed back loops, leading to what is essentially inflammatory biochemistry.
MS is therefore a subtle multi factorial disease where a number mechanisms and vicious loops are convolved. This explains the erratic course of the disease, and the large variety of symptoms and disease progression seen in MS patients.
Specific features of the MS timeline confirm the line of thinking
The MS timeline has a number of very specific features that can be fully explained by the foregoing analysis. If identical twins get separated at young age but before adolescence, the person that moves further South has less risk to develop MS at a later date. That person will have more sun exposure and therefore a higher vitamin D level in the circulation during adolescence when the body goes through a main phase of cellular growth. When the cells are formed, they take vitamin D directly from the circulation where the vitamin D level determines the number of mitochondria per cell (1500-3000). And when the cells have more mitochondria, they will be more resilient. Extending that line of thinking, all players of the Canadian ice hockey team – a physically very demanding sports - were born in February. The foetus went through the main phase of cellular growth during the end of Summer early Autumn when the vitamin D level in the circulation of their mother must have peaked.
Another feature of the MS timeline is the double peak in the graph of age of onset where a first peak appears around 27 years of age and a second peak around 43. This provides an indication for a two stage process with different underlying mechanisms. In the first phase, the virus spreads in meningeal follicles, the lymphatic system and stem cells including OPCs and bone marrow. Every now and then when receptors get blocked, you get an acute relapse, the immune system removes the infectious agent, and you see remission (RR). But as the virus spreads, more and more cells in particular stem cells get infected and become transgenic. People with transgenic cells are healthy but predisposed. As of mid age, another phenomenon kicks in. The virus has spread so far that increasingly B-cells get infected with a lack of sufficient T-cell function to contain an unbridled B-cell replication. As B-cells cross-react with transgenic cells (common epitodes), a lot of damage is done and the typical MS plaques show up. The neurological path is weakened and because of that any new problems with receptor blocking which were not sufficiently severe before to get diagnosed will now result in more severe symptoms and one gets diagnosed. At this point the progressive mechanism is already underway and one will be generally worse off.
A third feature of the MS timeline is the extinction of the disease above 60 years of age, with no new cases reported after 60. Immunosenescence results in a natural decline in humoral immunity above 60 caused by a reduction in the population of antibody producing B-cells. Where apparently the immune system - after millions of years of coevolution with the virus - says: if I can't get you (EBV) under control, I have to switch back one gear to avoid further damage is done.
Beyond MS - towards to a new paradigm for autoimmune diseases in general
In our current system for medicare, we see a very large number of overlapping autoimmune diseases with different names. Every expression of a neurological set of symptoms got its own name, based on several types of observations. And we see various signs and symptoms that are overlapping.
But in fact, a bigger common scheme is underlying. A scheme that encompasses the wide variety of observations, their patterns of case initiation, their chronic nature and many of their shared and unique symptoms and signs of the chronic phase of the disease. A scheme that explains many unexplained observations and the multiple similarities of these illnesses by a simple conceptual framework.
We need to develop and accept a new paradigm based on the understanding of a viral cause of autoimmunity and indeed MS. Traditional major disease paradigms should be complemented by a new model based on virology and biochemistry.
The thesis has been amended to take account of our latest learnings, and the material was condensed a bit further.
I do believe this is pretty much it, this is what is MS.
The view is supported by literally hundreds of links to relevant articles in the medical literature.
They can be found on this thread above.
The challenge will now be to effectively treat the disease.
A number of possible avenues seem to open up for that including chemo, anti-herpetics, boosting immunity and a variety of monoclonal antibodies.
A new vision on Multiple Sclerosis (MS)
The viral connection
The primate’s immune system and the herpes virus have coevolved alongside, for millions of years. However, over the last 50 years our living conditions have changed so profoundly that the immune system does not keep the virus in check anymore. There is accumulating evidence of the role of the herpes virus and in particular the Epstein-Barr virus (EBV) in the pathogenesis of MS. The association of MS with EBV is strongly supported in an epidemiological sense with the virtual non-existence of MS in EBV seronegative people (5 - 10 % of population).
Disruption of the highly evolved balance between the EBV lytic and latent life cycles and host immune control results in a range of EBV-associated diseases involving B-cells, epithelial cells, T-cells, natural killer (NK) cells and muscle cells. Here we may differentiate between two processes: an EBV protein inactivates monocyte signaling resulting in a subverted and ineffective immune response with EBV residing in the B cell and immortalizing it and T-lymphocyte imbalances; and cell disorders where pre-incubation of cells with EBV results in pro-inflammatory expression of the tissue.
High EBV antibody levels and alterations in EBV-specific CD8+ T-cell immunity are commonly observed and likely to be a causal factor in MS rather than the result of MS.
The viral tolerance theory – the EBV infected autoreactive B cells
During periods that people are immune compromised (can be the fetal period, the period of the newborn and immune deficient periods), the virus can incorporate some of its genes in the DNA of permissible cells. Chronic Cerebro Spinal Venous Insufficiency (CCSVI) is a factor here too causing hypoperfusion, lower AMP and adonesine, and with that a reduced control of the EBV infection. The incorporated viral genes (transgenes) are tolerant to the body or no immune memory against these transgenes has established. In MS, in particular the oligodendrocyte precursor cells (OPCs) in locally affected tissue will be infected but also the bone marrow.
People with transgenes in their body are healthy but predisposed to develop a disease. Predisposed people become diseased when they are infected with a microbe that shares epitodes with the transgenes present in the transgenic cells and will cause an immunological reaction.
In MS, EBV infected autoreactive T- and B-cells will pass the Central Nervous System (CNS) and cross-react with the transgenes in the OPCs. Due to this cross-reaction, many OPCs will die which leads to a diminishing number of OPCs, of dendrocytes and a reduced myelination of neurons. During this cross-reaction, many mediators will be released by the infiltrating T-cells. This will increase angiogenesis and cause hyperproliferation of surrounding tissue cells in the CNS which in turn causes the pathological lesions (sclerotic plaques) typical for MS.
The biochemical reaction hypothesis
The autoreactive B-cells have substantial super-oxygen generating capability. The superoxide reacts with the nitric oxide (NO) in the finest capillaries and forms peroxynitrite which is by far the worst free radical. Over time we produce excess peroxynitrite. Although the peroxynitrite may inhibit viral replication, it disables glyceraldehyde 3 phosphate which impacts the sodium/potassium pump and cell viability. Women have higher NO than men which explains the gender bias.
Over time the vitality of the cell declines as ATP levels decline and the loss of some AMP leads to a fall in Adenosine (endogenous inhibitor of arachidonic acid) and, in time, a loss of purine from Adenosine loss. Ultimately energy levels decline and uric acid levels fall. The loss of Adenosine will lower the ability to control inflammation and indeed the suppression of the transfer of EBV from latently infected cells to other cells. And the endothelium inflammates leading to an endothelial dysfunction.
The huge oxidative stress jams the gates/mitochondria of the cells, causes effects on the mitochondrial electron transport chain, electron pump inactivation, inhibits ADP to ATP conversion and depletes energy in the form of ATP. And it poisons fat tissue and causes lesions where the brains, biologically seen, are just a lump of fat.
As the number of active gates goes down, we see an increasingly big temperature effect in patients with MS and a loss of muscle strength and sensitivity in the periphery. As cells shrink in size because gates/mitochondria successively fail, it causes whole brain atrophy.
Hence, the typical fatigue, weakening of muscles and whole-brain atrophy observed in MS patients is partly caused by the CAEBV infection but with a completely different underlying mechanism than the demyelinating plaques in the brains. And the typical MS motor dysfynction will be caused by combination of factors.
A general dysregulation of the metabolism – interlocking vicious cycles
The virus is causal and leads to a general dysregulation of the metabolism involving metabolic factors (HPA axis affecting cortisol and gut function) and infection by bacteria and fungi including Borrelia, Cpn and toxoplasmose.
(Short term) stressors initiate cases of multisystem illnesses by stimulating nitric oxide synthase (NOS) activity and consequently produce increased levels of nitric oxide and its oxidant product peroxynitrite. The immune system will be triggered by the biochemical cycle mechanism with NF-кB a first responder to the harmful cellular stimuli. The increased NF-кB activity will lead to increased iNOS activity by stimulating through the inflammatory cytokines the activity of the iNOS gene itself.
There is a combination of stability and instability, positive and negative feed back loops, leading to what is essentially inflammatory biochemistry.
MS is therefore a subtle multi factorial disease where a number mechanisms and vicious loops are convolved. This explains the erratic course of the disease, and the large variety of symptoms and disease progression seen in MS patients.
Specific features of the MS timeline confirm the line of thinking
The MS timeline has a number of very specific features that can be fully explained by the foregoing analysis. If identical twins get separated at young age but before adolescence, the person that moves further South has less risk to develop MS at a later date. That person will have more sun exposure and therefore a higher vitamin D level in the circulation during adolescence when the body goes through a main phase of cellular growth. When the cells are formed, they take vitamin D directly from the circulation where the vitamin D level determines the number of mitochondria per cell (1500-3000). And when the cells have more mitochondria, they will be more resilient. Extending that line of thinking, all players of the Canadian ice hockey team – a physically very demanding sports - were born in February. The foetus went through the main phase of cellular growth during the end of Summer early Autumn when the vitamin D level in the circulation of their mother must have peaked.
Another feature of the MS timeline is the double peak in the graph of age of onset where a first peak appears around 27 years of age and a second peak around 43. This provides an indication for a two stage process with different underlying mechanisms. In the first phase, the virus spreads in meningeal follicles, the lymphatic system and stem cells including OPCs and bone marrow. Every now and then when receptors get blocked, you get an acute relapse, the immune system removes the infectious agent, and you see remission (RR). But as the virus spreads, more and more cells in particular stem cells get infected and become transgenic. People with transgenic cells are healthy but predisposed. As of mid age, another phenomenon kicks in. The virus has spread so far that increasingly B-cells get infected with a lack of sufficient T-cell function to contain an unbridled B-cell replication. As B-cells cross-react with transgenic cells (common epitodes), a lot of damage is done and the typical MS plaques show up. The neurological path is weakened and because of that any new problems with receptor blocking which were not sufficiently severe before to get diagnosed will now result in more severe symptoms and one gets diagnosed. At this point the progressive mechanism is already underway and one will be generally worse off.
A third feature of the MS timeline is the extinction of the disease above 60 years of age, with no new cases reported after 60. Immunosenescence results in a natural decline in humoral immunity above 60 caused by a reduction in the population of antibody producing B-cells. Where apparently the immune system - after millions of years of coevolution with the virus - says: if I can't get you (EBV) under control, I have to switch back one gear to avoid further damage is done.
Beyond MS - towards to a new paradigm for autoimmune diseases in general
In our current system for medicare, we see a very large number of overlapping autoimmune diseases with different names. Every expression of a neurological set of symptoms got its own name, based on several types of observations. And we see various signs and symptoms that are overlapping.
But in fact, a bigger common scheme is underlying. A scheme that encompasses the wide variety of observations, their patterns of case initiation, their chronic nature and many of their shared and unique symptoms and signs of the chronic phase of the disease. A scheme that explains many unexplained observations and the multiple similarities of these illnesses by a simple conceptual framework.
We need to develop and accept a new paradigm based on the understanding of a viral cause of autoimmunity and indeed MS. Traditional major disease paradigms should be complemented by a new model based on virology and biochemistry.
Last edited by Leonard on Mon May 04, 2015 4:01 am, edited 5 times in total.
chemo for MS
There is overwhelming evidence of EBV causing Hodgkin lymphoma. http://www.ncbi.nlm.nih.gov/pubmed/19339934
The evidence is accumulating for a role of EBV in the aetiology of MS.
There is strong evidence for the EBV trail in my family (nasopharyngeal carcinoma, coronary artery aneurysm in two branches of the family from the 1st generation down, rheuma arthritis, mitochondrial energy failure (CFS?), MS, Hodgkin).
This is spread over 5 generations in a family of hundreds.
My cousin who had Hodgkin was treated with chemo therapy: adriamycin vinblastine bleomycin dacarbazine.
From a search on the Internet, this is apparently the standard regimen for Hodgkin.
Sometimes it is combined with Rituximab (I guess to get EBV B-complexes down? http://en.wikipedia.org/wiki/Chemotherapy_regimen ).
We'r a few years later now. He has completely recovered.
What happened really in his microcosm during the chemo?
What happened with the Chronically Active EBV?
Why not measure in new Hodgkin patients the EBV viral load prior to and 1 week after each session of the treatment?
The EBV viral load can be measured accurately with DNA techniques.
This would give a first indication as to what happens with the EBV infection without imposing any extra risk on the patient.
Prior to his treatment, my cousin - he is young, was 18 when he was diagnosed with Hodgkin - had episodes of high temperature with flares up to 41.5 degree C (106.7 F).
Perhaps the virus induced the fever.
He had a series of 8 chemo sessions but after his first session the fever never came back.
If the virus induced it, perhaps it was knocked down already after the first chemo session.
Apparently some patients go back every year for a new chemo session.
I know this is all speculation but if there would be a glimpse of hope for patients with progressive MS, I think it would be worth to give it a try.
If I would have a 33% chance that my MS progression would stop and I would get back on a recovery path, I would be prepared to take the chemo.
The evidence is accumulating for a role of EBV in the aetiology of MS.
There is strong evidence for the EBV trail in my family (nasopharyngeal carcinoma, coronary artery aneurysm in two branches of the family from the 1st generation down, rheuma arthritis, mitochondrial energy failure (CFS?), MS, Hodgkin).
This is spread over 5 generations in a family of hundreds.
My cousin who had Hodgkin was treated with chemo therapy: adriamycin vinblastine bleomycin dacarbazine.
From a search on the Internet, this is apparently the standard regimen for Hodgkin.
Sometimes it is combined with Rituximab (I guess to get EBV B-complexes down? http://en.wikipedia.org/wiki/Chemotherapy_regimen ).
We'r a few years later now. He has completely recovered.
What happened really in his microcosm during the chemo?
What happened with the Chronically Active EBV?
Why not measure in new Hodgkin patients the EBV viral load prior to and 1 week after each session of the treatment?
The EBV viral load can be measured accurately with DNA techniques.
This would give a first indication as to what happens with the EBV infection without imposing any extra risk on the patient.
Prior to his treatment, my cousin - he is young, was 18 when he was diagnosed with Hodgkin - had episodes of high temperature with flares up to 41.5 degree C (106.7 F).
Perhaps the virus induced the fever.
He had a series of 8 chemo sessions but after his first session the fever never came back.
If the virus induced it, perhaps it was knocked down already after the first chemo session.
Apparently some patients go back every year for a new chemo session.
I know this is all speculation but if there would be a glimpse of hope for patients with progressive MS, I think it would be worth to give it a try.
If I would have a 33% chance that my MS progression would stop and I would get back on a recovery path, I would be prepared to take the chemo.
Re: A new concept and treatment options for MS
Terry Wahls used chemo. the chemo is mentioned here: http://thesmarterscienceofslim.com/terry-wahls/ arguably - I quote from the script under the link - to suppress my immune cells so they could not attack my brain as vigorously unquote.
but I have learned in the meanwhile that this is all guess work. even the reports of our medicine agencies about the working mechanisms of many medicine are no more than an educated best guess. nobody can look into our microcosm and understand the complexity of the full biological picture.
MS is clearly associated with EBV. whether EBV is causal is not clear, but EBV most certainly seems to be a necessary prerequisite. epidemiological analysis, in particular the fact that MS is virtually non-existant in EBV seronegative people (=5-10% of global population), reduces the chances of being wrong here to almost zero.
not all people react the same to a chronic EBV infection, with the virus submerged deep in our endothelium. I think it has to do something with the 'plasticity' of our immune system in response to EBV. this article is groundbreaking in describing the interaction between EBV and the immune system http://www.nature.com/nsmb/journal/v19/ ... b.2367.pdf for sure, the reaction of the primate's immune system is different than that of any other living species, which, among others, renders mouse models useless.
my attention was just now drawn to this study which seems to aim to enhance the understanding of the interaction of the immune system and the EBV http://www.msra.org.au/studying-interac ... barr-virus
whether chemo for MS will ever happen is not sure. there are many forms of chemo, lighter and heavier. EBV is also causal for many forms of cancer including Hodgkin. what precisely happens when cancer patients get chemo is not clear, but it can not be excluded that the virus is effectively knocked down. as such in the medical literature I see an overlap between the regimens in use for Hodgkin and what Terry Wahls used for MS (mitozantrone or novantrone).
where I do not exclude that if the trigger (EBV) is removed, over time the immune system resurrects or can resurrect itself. this may be a year or years. of course helped by anti-oxidants to clean the body as Terry Wahls did (diet). and one may enter a recovery path some good time after chemo.
but I have learned in the meanwhile that this is all guess work. even the reports of our medicine agencies about the working mechanisms of many medicine are no more than an educated best guess. nobody can look into our microcosm and understand the complexity of the full biological picture.
MS is clearly associated with EBV. whether EBV is causal is not clear, but EBV most certainly seems to be a necessary prerequisite. epidemiological analysis, in particular the fact that MS is virtually non-existant in EBV seronegative people (=5-10% of global population), reduces the chances of being wrong here to almost zero.
not all people react the same to a chronic EBV infection, with the virus submerged deep in our endothelium. I think it has to do something with the 'plasticity' of our immune system in response to EBV. this article is groundbreaking in describing the interaction between EBV and the immune system http://www.nature.com/nsmb/journal/v19/ ... b.2367.pdf for sure, the reaction of the primate's immune system is different than that of any other living species, which, among others, renders mouse models useless.
my attention was just now drawn to this study which seems to aim to enhance the understanding of the interaction of the immune system and the EBV http://www.msra.org.au/studying-interac ... barr-virus
whether chemo for MS will ever happen is not sure. there are many forms of chemo, lighter and heavier. EBV is also causal for many forms of cancer including Hodgkin. what precisely happens when cancer patients get chemo is not clear, but it can not be excluded that the virus is effectively knocked down. as such in the medical literature I see an overlap between the regimens in use for Hodgkin and what Terry Wahls used for MS (mitozantrone or novantrone).
where I do not exclude that if the trigger (EBV) is removed, over time the immune system resurrects or can resurrect itself. this may be a year or years. of course helped by anti-oxidants to clean the body as Terry Wahls did (diet). and one may enter a recovery path some good time after chemo.
A nose-brain connection
My blood was tested for a Chronically Active Epstein Barr virus infection. The result was negative, I do not have a Chronically Active Epstein Barr virus infection.
The test method used was a quantitative Epstein-Barr PCR. It is a molecular diagnostic test on viral DNA basis which should presumably be accurate.
Although I may have hoped differently, the negative outcome does not come as a real surprise. An eminent immunologist once told me that the virus is normally removed from the circulation within hours.
The outcome made me reflect again on the situation.
I believe that at the time of the diagnosis now 10 years ago, there was an active phase (spots in the groin, red spots in the neck after shaving which made a doctor once say: you should use an after-shave, the latter 'shaving spots' occurred for a longer period of time). Whether this implies that at that time the virus would have been found in the blood remains unclear.
At that time, in the year preceding diagnosis, I also severely suffered from a stiff neck. I even had physiotherapy treatment, for the first time in my life. It must have had something to do with `things` spreading through the neck.
Besides that, I suffered from severe pains in the ´sinus´, during several years preceding diagnosis, always in the Spring when the immune system is low. I reported this here before.
The common theme here is the pharynx and perhaps the tonsil. At that time, the ´things´ must have spread not only in the neck but also in the brain compartment and its cartilages. The lymphatic drainage of the (naso)pharynx into the extracellular fluid circulation of the CNS is probably an issue here. Gay (see first link below) refers to it as the nose-to-brain transport.
Primary lytic replication of EBV in oropharyngeal mocusal epithelium precedes long-lived latent infection of resting memory B-cells. The striking aspect here concerns the lytic-cycle early secretion of BARF1, a binding protein for hCSF-1, which establishes an immunomodulatory role of BARF1. And, interestingly, BARF1 inhibits the secretion of antiviral interferon (IFN-alfa). (See second and third link below)
The whole picture that emerges then fits nicely together. During my life, I had several periods of immune deficiency (at 14 loss of control of left hand; at 21/22 dry eyes; at 29 limping right leg; at 37 blurred vision caused by eye nerve). At 45, a new numbness on the left hand and a bit on the right. These periods of immune deficiency must have allowed the herpes virus to anchor itself in particular in stem cells such as OPCs making them transgenic [CCSVI may have been a factor here too, weakening the cell machinery].
With hindsight, the periods of severe pain in the ‘sinus’ started here, at 45, always during Spring early Summer. At 47 then, three Spring seasons later, I was diagnosed with MS. The extended period of immune deficiency must have led to a change – perhaps a boost - in the progression of the disease. I think the progressive track was already underway at that time, with several short incidences of weakness in the legs noted before, between the age of 40 and 45.
The pharynx is drained into the pterygoid plexus of veins and the directly into the Internal Jugular Veins. Possibly, here lies the explanation for the correlation of MS with CCSVI where poor drainage results in weakening pharynx/tonsil tissue and the growth and eventually spreading of virus and other infectious agents. (See first and fourth link below)
The pharynx is innervated by numerous branches including branches of the vagus nerve. In nasopharengual carcinoma, the involvement of the nerves may enable the tumor to spread more easily through the jugular foramen. I think it can not be excluded that this nerve stimuli or the lack thereof is a factor too in the ‘spreading’ of MS.
Another interesting feature is that in childhood, the paryngeal tonsil is relatively large compared to the nasopharinx. Possibly, here we may find an explanation why EBV infection at young age gives a different much stronger and protective immune response.
The following articles provide more information and seem central to this thesis.
http://www.sciencedirect.com/science/ar ... 4813000059
http://www.nature.com/nsmb/journal/v19/ ... b.2367.pdf
http://journals.plos.org/plospathogens/ ... at.1003095
http://ozradonc.wikidot.com/anatomy:nasopharynx
The test method used was a quantitative Epstein-Barr PCR. It is a molecular diagnostic test on viral DNA basis which should presumably be accurate.
Although I may have hoped differently, the negative outcome does not come as a real surprise. An eminent immunologist once told me that the virus is normally removed from the circulation within hours.
The outcome made me reflect again on the situation.
I believe that at the time of the diagnosis now 10 years ago, there was an active phase (spots in the groin, red spots in the neck after shaving which made a doctor once say: you should use an after-shave, the latter 'shaving spots' occurred for a longer period of time). Whether this implies that at that time the virus would have been found in the blood remains unclear.
At that time, in the year preceding diagnosis, I also severely suffered from a stiff neck. I even had physiotherapy treatment, for the first time in my life. It must have had something to do with `things` spreading through the neck.
Besides that, I suffered from severe pains in the ´sinus´, during several years preceding diagnosis, always in the Spring when the immune system is low. I reported this here before.
The common theme here is the pharynx and perhaps the tonsil. At that time, the ´things´ must have spread not only in the neck but also in the brain compartment and its cartilages. The lymphatic drainage of the (naso)pharynx into the extracellular fluid circulation of the CNS is probably an issue here. Gay (see first link below) refers to it as the nose-to-brain transport.
Primary lytic replication of EBV in oropharyngeal mocusal epithelium precedes long-lived latent infection of resting memory B-cells. The striking aspect here concerns the lytic-cycle early secretion of BARF1, a binding protein for hCSF-1, which establishes an immunomodulatory role of BARF1. And, interestingly, BARF1 inhibits the secretion of antiviral interferon (IFN-alfa). (See second and third link below)
The whole picture that emerges then fits nicely together. During my life, I had several periods of immune deficiency (at 14 loss of control of left hand; at 21/22 dry eyes; at 29 limping right leg; at 37 blurred vision caused by eye nerve). At 45, a new numbness on the left hand and a bit on the right. These periods of immune deficiency must have allowed the herpes virus to anchor itself in particular in stem cells such as OPCs making them transgenic [CCSVI may have been a factor here too, weakening the cell machinery].
With hindsight, the periods of severe pain in the ‘sinus’ started here, at 45, always during Spring early Summer. At 47 then, three Spring seasons later, I was diagnosed with MS. The extended period of immune deficiency must have led to a change – perhaps a boost - in the progression of the disease. I think the progressive track was already underway at that time, with several short incidences of weakness in the legs noted before, between the age of 40 and 45.
The pharynx is drained into the pterygoid plexus of veins and the directly into the Internal Jugular Veins. Possibly, here lies the explanation for the correlation of MS with CCSVI where poor drainage results in weakening pharynx/tonsil tissue and the growth and eventually spreading of virus and other infectious agents. (See first and fourth link below)
The pharynx is innervated by numerous branches including branches of the vagus nerve. In nasopharengual carcinoma, the involvement of the nerves may enable the tumor to spread more easily through the jugular foramen. I think it can not be excluded that this nerve stimuli or the lack thereof is a factor too in the ‘spreading’ of MS.
Another interesting feature is that in childhood, the paryngeal tonsil is relatively large compared to the nasopharinx. Possibly, here we may find an explanation why EBV infection at young age gives a different much stronger and protective immune response.
The following articles provide more information and seem central to this thesis.
http://www.sciencedirect.com/science/ar ... 4813000059
http://www.nature.com/nsmb/journal/v19/ ... b.2367.pdf
http://journals.plos.org/plospathogens/ ... at.1003095
http://ozradonc.wikidot.com/anatomy:nasopharynx
Re: A new concept and treatment options for MS
When considering the situation in my own family, I see my brother with a mitochondrial energy failure and his son who had Hodgkin. I see my farther who had symptoms of MS in his late 50's which later on when his humoral immune system switched back the B-cells completely recovered, his brother - my uncle - who had symptoms too and sold his farm in his mid 50's and later on recovered completely. Both are in the late 80's and in good health. And I see my grandfarther who died from an NPC, a naso pharyngeal cancer (note the connection with the pharynx). And another uncle who died from a coronary artery aneurism. The common theme is: we all suffer an EBV infection, there is an EBV trail in the family.
What is the difference between my brother and me? Not a whole lot, our energy is waning. He has less energy than me when cycling but his gait is better. Both our muscles shrink and are seriously weakened. His EBV immune complexes (B cells) are probably even higher than mine with more oxidative stress. I think the real difference is the pharynx (note the connection to grand dad who had a problem there too). CCSVI caused the OPCs in my brain to become transgenic and the pharynx/tonsil to get infected. The latter then caused the infectious 'mess' to get from the pharynx into the CNS compartiment. The B cells then do the rest and cause the typical plaques.
And my other brothers are better protected against the percolating virus into the cells because they were born in the Winter time. They may suffer a bit from degeneration too (not visible to me) but not so severe and they will be above 60 years of age before any symptoms would show up. So they won't show up anymore.
Athough many people seem to have a high load of EBV immune complexes - an eminent virologist recently told me -, I think for me and people with MS it is the pharynx that makes the difference.
For patients with MS in the progressive phase (related to EBV immune complexes ), it will be important to get the count of B-cells down. Chemo may be an option for that (Novantrone is approved by the FDA for MS en Terry Wahls used it; chemo in different forms is used for the treatment of MS). The theory is that the memory cells are eliminated with the first round of chemo.
I also think that all children where there may be an indication should be checked on CCSVI.
What is the difference between my brother and me? Not a whole lot, our energy is waning. He has less energy than me when cycling but his gait is better. Both our muscles shrink and are seriously weakened. His EBV immune complexes (B cells) are probably even higher than mine with more oxidative stress. I think the real difference is the pharynx (note the connection to grand dad who had a problem there too). CCSVI caused the OPCs in my brain to become transgenic and the pharynx/tonsil to get infected. The latter then caused the infectious 'mess' to get from the pharynx into the CNS compartiment. The B cells then do the rest and cause the typical plaques.
And my other brothers are better protected against the percolating virus into the cells because they were born in the Winter time. They may suffer a bit from degeneration too (not visible to me) but not so severe and they will be above 60 years of age before any symptoms would show up. So they won't show up anymore.
Athough many people seem to have a high load of EBV immune complexes - an eminent virologist recently told me -, I think for me and people with MS it is the pharynx that makes the difference.
For patients with MS in the progressive phase (related to EBV immune complexes ), it will be important to get the count of B-cells down. Chemo may be an option for that (Novantrone is approved by the FDA for MS en Terry Wahls used it; chemo in different forms is used for the treatment of MS). The theory is that the memory cells are eliminated with the first round of chemo.
I also think that all children where there may be an indication should be checked on CCSVI.
Last edited by Leonard on Tue Mar 24, 2015 7:44 am, edited 6 times in total.
Re: A new concept and treatment options for MS
Hi Leonard.
I think you are definitely on the right path. It doesn't matter if the infection shows as current or not. EBV is a herpes family virus so it stays resident and we have already seen in many articles that EBV infected B cells are prolific producers of superoxide which is critical to the overproduction of peroxynitrite. I think the trick is in what is critical to the production of superoxide.
p47phox protein is a cytoplasmic component critical to superoxide production. It is important that we prevent recurrent infections by using superoxide and this suggests transformed B cells are not perceived as a serious infection by the immune system. So the test for active or not active EBV is irrelevant. If you have a transformed B cell then it is still pumping superoxide. As p47phox is required to make superoxide the infected B cell is not perceived as foreign as the EBV is masked by p47phox. Eliminating the EBV infected B cell is critical hence long term valacyclovir in my case or Rituxumab in the case of Anonymoose helps.
Regards
I think you are definitely on the right path. It doesn't matter if the infection shows as current or not. EBV is a herpes family virus so it stays resident and we have already seen in many articles that EBV infected B cells are prolific producers of superoxide which is critical to the overproduction of peroxynitrite. I think the trick is in what is critical to the production of superoxide.
p47phox protein is a cytoplasmic component critical to superoxide production. It is important that we prevent recurrent infections by using superoxide and this suggests transformed B cells are not perceived as a serious infection by the immune system. So the test for active or not active EBV is irrelevant. If you have a transformed B cell then it is still pumping superoxide. As p47phox is required to make superoxide the infected B cell is not perceived as foreign as the EBV is masked by p47phox. Eliminating the EBV infected B cell is critical hence long term valacyclovir in my case or Rituxumab in the case of Anonymoose helps.
Regards
Re: A new concept and treatment options for MS
Hi Scott,
Thank you for this last posting which I find conceptually very interesting. The twist that perhaps transformed B cells are not perceived as a serious infection by the immune system but as ‘normal’ presents a new way of thinking, potentially a very important and promising new way of thinking.
The mechanisms for immune system evasion and for B-cell immortalization are fascinating, isn’t it. Let us hope that this Australian study http://www.ms-uk.org/viralcauses and –I am sure- a whole lot of new studies will shine some more light on this in the not-too-distant future.
I have amended the thesis to take account of our most recent learnings (see posting below).
In health care, like most things in live, we are used to simple linear concepts, but in the case of MS and immune evasion, it can not be excluded that a more complex non-linear model underlies, with many inputs, outputs, feed forwards and feedbacks. I see many such links: Vit D inhibiting EBV EBNA, the anti-inflammatory properties of ApoA1 (Omega 3) inhibited by saturated fats, EBV BARF inhibiting the secretion of anti-viral interferon and so on.
The interaction between the immune system and the virus is determined by a highly evolved balance over many millions of years of evolution (EBV is with us as primates for 40 million years; the herpes virus is with us for many hundreds of millions of years, perhaps even a billion years). I am sure a new in-depth understanding of this highly evolved balance will set out the corner stones of a new virological “consciousness” needed for our collective future.
Leo
Thank you for this last posting which I find conceptually very interesting. The twist that perhaps transformed B cells are not perceived as a serious infection by the immune system but as ‘normal’ presents a new way of thinking, potentially a very important and promising new way of thinking.
The mechanisms for immune system evasion and for B-cell immortalization are fascinating, isn’t it. Let us hope that this Australian study http://www.ms-uk.org/viralcauses and –I am sure- a whole lot of new studies will shine some more light on this in the not-too-distant future.
I have amended the thesis to take account of our most recent learnings (see posting below).
In health care, like most things in live, we are used to simple linear concepts, but in the case of MS and immune evasion, it can not be excluded that a more complex non-linear model underlies, with many inputs, outputs, feed forwards and feedbacks. I see many such links: Vit D inhibiting EBV EBNA, the anti-inflammatory properties of ApoA1 (Omega 3) inhibited by saturated fats, EBV BARF inhibiting the secretion of anti-viral interferon and so on.
The interaction between the immune system and the virus is determined by a highly evolved balance over many millions of years of evolution (EBV is with us as primates for 40 million years; the herpes virus is with us for many hundreds of millions of years, perhaps even a billion years). I am sure a new in-depth understanding of this highly evolved balance will set out the corner stones of a new virological “consciousness” needed for our collective future.
Leo
Last edited by Leonard on Thu Mar 26, 2015 11:49 pm, edited 8 times in total.
Re: A new concept and treatment options for MS
A new vision on Multiple Sclerosis (MS)
The viral connection
The primate’s immune system and the herpes virus have coevolved alongside, for millions of years. However, over the last 50 years our living conditions have changed so profoundly that the immune system does not keep the virus in check anymore. There is accumulating evidence of the role of the herpes virus and in particular the Epstein-Barr virus (EBV) in the pathogenesis of MS. With the virtual non-existence of MS in EBV seronegative people (still 5 - 10 % of population), epidemiological analysis would reduce the risk of being wrong on the causal relationship of EBV and MS to an infinitesimal small number.
Universal EBV seropositivity, high EBV antibody levels and alterations in EBV-specific CD8+ T-cell immunity are commonly observed and likely to be a causal factor in MS rather than the result of MS. [post script: it is probably more accurate to suggests that it may be the type of immune response to EBV that predisposes to MS (through EBV primed cells), rather than EBV infection itself. ]
Disruption of the highly evolved balance between the EBV lytic and latent life cycles and host immune control results in a range of EBV-associated diseases involving B-cells, epithelial cells, T-cells, natural killer (NK) cells and muscle cells. Here we may differentiate between two processes: an EBV protein inactivates monocyte signaling resulting in a subverted and ineffective immune response with EBV residing in the B cell and immortalizing it and T-lymphocyte imbalances; and cell disorders where pre-incubation of cells with herpes / EBV results in pro-inflammatory expression of the tissue.
Proposed role of EBV infection in the development of MS
Primary lytic replication of EBV in pharyngeal mocusal epithelium precedes long-lived latent infection of resting memory B-cells [Elegheert/Savvides]. During primary infection, EBV infects autoreactive naïve B-cells in the tonsil, driving them to enter germinal centres where they proliferate intensely and differentiate into latently infected autoreactive memory B cells (Step 1), which then exit from the tonsil and circulate in the blood (Step 2) [Pender].
The number of EBV-infected B cells is normally controlled by EBV-specific cytotoxic CD8+ T cells, which kill proliferating and lytically infected B cells, but not if there is a defect in the defense mechanism.
One concept suggests the EBV secretes lytic-cycle early protein BARF1 which is a binding protein for the hematopoietic cytokine hCSF-1, evading and subverting key host signaling pathways. BARF1 also inhibits the secretion of antiviral interferon (IFN)-α. This impedes the primary response via CD8+ cytotoxic T-cells and natural killer cells to clear EBV-infected cells, in line with T-cell mediated adaptive immunity against EBV.
Another concept suggests EBV is masked by a protein p47phox which is required to make superoxide to prevent recurrent infections. Here, the idea is that these transformed B cells are not perceived as foreign and thus not as a serious infection by the immune system.
Surviving EBV-infected autoreactive memory B cells enter the CNS where they take up residence and produce oligoclonal IgG and pathogenic autoantibodies, which attack myelin and other components of the CNS (Step 3).
Autoreactive T cells that have been activated in peripheral lymphoid organs by common systemic infections circulate in the blood and enter the CNS where they are reactivated by EBV-infected autoreactive B cells presenting CNS peptides (Cp) bound to major histocompatibility complex (MHC) molecules (Step 4). These EBV-infected B cells provide costimulatory survival signals (B7) to the CD28 receptor on the autoreactive T cells and thereby inhibit the activation-induced T-cell apoptosis, which normally occurs when autoreactive T cells enter the CNS and interact with non-professional antigen-presenting cells such as astrocytes and microglia, which do not express B7 costimulatory molecules (Step 5).
After the autoreactive T cells have been reactivated by EBV-infected autoreactive B cells, they produce chemokines and cytokines such as interleukin-2 (IL2), interferon-γ (IFNγ) and tumour necrosis factor (TNFβ) and orchestrate an autoimmune attack on the CNS with resultant oligodendrocyte and myelin destruction (Step 6).
A further concept is described by David Hudnal in his chapter Epstein-Barr Virus: Pathogenesis and Host Immune Response. Following initial exposure to infectious saliva, EBV likely undergoes a brief period of lytic replication in oral and nasal epithelium. Subsequent infection of naïve B cells within subjacent tonsillar lymphoid tissues leads to a brief “pre-latent” period of lytic and latent gene expression prior to epigenetic repression of viral genes. This brief pre-latent period is marked by limited expression of a small set of lytic genes with regulatory function, excluding lytic genes essential for DNA replication and virion assembly. It is likely that by promoting cell growth and inhibiting apoptosis, pre-latent lytic gene products, including BART miRNA, viral BCL-2 homologs, and BZLF1, contribute to the early survival of EBV-infected B cells. Following epigenetic repression of the full complement of lytic genes and a subset of latent gene promoters, rapid growth of latent-infected B cells is induced by expression of the full growth-promoting complement of latency genes, i.e., the latency III program. Expression of the full complement of lytic and latent antigens by infected epithelial cells and B cells triggers a vigorous humoral and cellular immune response that leads to suppression of viral replication. Latent-infected B cells persist by switching from the highly immunogenic latency III program to the less immunogenic latency II program, with virus gene expression restricted to three proteins, EBNA-1, LMP-1, and LMP-2A. EBNA-1 maintains the viral genome, while LMP-1 and LMP-2A maintain cell growth while preventing apoptosis. The absence of EBNA-2-mediated transactivation allows for latency II B cells to adopt a germinal center B-cell phenotype and, in so doing, survive germinal center and/or extrafollicular proliferation and maturation into EBV-infected memory B cells. EBV-infected memory B cells persist by switching from the latency II program to the latency 0 program, with near- complete absence of viral gene expression, with only intermittent LMP-2a expression.
The viral tolerance theory – predisposition by early infection
During periods that people are immune compromised (can be the fetal period, the period of the newborn and immune deficient periods), the virus can incorporate some of its genes in the DNA of permissible cells. In addition, work on human genome sequencing revealed that 8% of our DNA is of viral origin where the (herpes) virus incorporated its DNA in our genes
For the more recent infections, Chronic Cerebro Spinal Venous Insufficiency (CCSVI) may be a factor here too causing hypoperfusion, lower AMP and adonesine, and with that a reduced control of the EBV infection.
The incorporated viral genes (transgenes) are tolerant to the body or no immune memory against these transgenes has established. In MS, in particular the oligodendrocyte precursor cells (OPCs) in locally affected tissue will be infected but also the bone marrow.
People with transgenes in their body are healthy but predisposed to develop a disease. Predisposed people become diseased when they are infected with a microbe that shares epitodes with the transgenes present in the transgenic cells and will cause an immunological reaction.
In MS, EBV infected autoreactive T- and B-cells will later on pass the Central Nervous System (CNS) and cross-react with the transgenes in the OPCs. Due to this cross-reaction, many OPCs will die which leads to a diminishing number of OPCs, of dendrocytes and a reduced myelination of neurons. During this cross-reaction, many mediators will be released by the infiltrating T-cells. This will increase angiogenesis and cause hyperproliferation of surrounding tissue cells in the CNS which in turn causes the pathological lesions (sclerotic plaques) typical for MS.
The biochemical reaction hypothesis – the fatigue explained
The autoreactive B-cells have substantial super-oxygen generating capability. The superoxide reacts with the nitric oxide in the finest capillaries and forms peroxynitrite which is by far the worst free radical. Over time we produce excess peroxynitrite. Although the peroxynitrite may inhibit viral replication, it disables glyceraldehyde 3 phosphate which impacts the sodium/potassium pump and cell viability. Women have higher NO than men which explains the gender bias.
Over time the vitality of the cell declines as ATP levels decline and the loss of some AMP leads to a fall in Adenosine (endogenous inhibitor of arachidonic acid) and, in time, a loss of purine from Adenosine loss. EBV also inhibits the production of intra-cellular interferon gamma and EBV primed cells induce arachidonic acid and inflammation when an agonist is introduced. Ultimately energy levels decline and uric acid levels fall. The loss of Adenosine and cellular interferon will lower the ability to control inflammation and indeed the suppression of the transfer of EBV from latently infected cells to other cells. And the endothelium inflammates leading to an endothelial dysfunction.
The huge oxidative stress jams the gates/mitochondria of the cells, causes effects on the mitochondrial electron transport chain, electron pump inactivation, inhibits ADP to ATP conversion and depletes energy in the form of ATP. And it poisons fat tissue and causes lesions where the brains, biologically seen, are just a lump of fat.
As the pumps already run on their edge and a number have failed and the equilibrium can not be easily maintained and gates close with increasing temperature (either from the outside or fever induced; cooler wheather or high air pressure have the reverse effect), the conduction of the nerve path runs down. Here the ion pumps are the most important energy consumers that require the biggest amount of cellular energy [Sinatra].
As the number of active gates goes down, we see an increasingly big temperature effect in patients with MS and a loss of muscle strength and sensitivity in the periphery. As cells shrink in size because gates/mitochondria successively fail, it causes whole brain atrophy.
Hence, the typical fatigue, weakening of muscles and whole-brain atrophy observed in MS patients is partly caused by the EBV infected B cells but with a completely different underlying mechanism than the demyelinating plaques in the brains. And the typical MS motor dysfunction will be caused by a combination of factors.
A general dysregulation of the metabolism – interlocking vicious cycles
The virus is causal and leads to a general dysregulation of the metabolism involving metabolic factors (HPA axis affecting cortisol and gut function) and infection by bacteria and fungi including Borrelia, Cpn and toxoplasmose.
(Short term) stressors initiate cases of multisystem illnesses by stimulating nitric oxide synthase (NOS) activity and consequently produce increased levels of nitric oxide and its oxidant product peroxynitrite. The immune system will be triggered by the biochemical cycle mechanism with NF-кB a first responder to the harmful cellular stimuli. The increased NF-кB activity will lead to increased iNOS activity by stimulating through the inflammatory cytokines the activity of the iNOS gene itself.
There is a combination of stability and instability, positive and negative feed back loops including brain-bowel-brain and nose-brain connections, leading to what is essentially inflammatory virology and biochemistry.
MS is therefore a subtle multi factorial disease where a number mechanisms and vicious loops are convolved. This explains the erratic course of the disease, and the large variety of symptoms and disease progression seen in MS patients.
Specific features of the MS timeline confirm the line of thinking
The MS timeline has a number of very specific features that can be fully explained by the foregoing analysis.
An interesting feature is that in childhood, the tonsil is relatively large compared to the nasopharinx. Possibly, here we may find an explanation why EBV infection of young children gives a different (less viral load) but stronger (age) protective immune response than in late-infected adolescents or adults. [Hudnall speculates on the link to pharyngual epithelium and the tonsil in his chapter on Epstein-Barr Virus: Pathogenesis and Host Immune Response]
If identical twins get separated at young age but before adolescence, the person that moves further South has less risk to develop MS at a later date. That person will have more sun exposure and therefore a higher vitamin D level in the circulation during adolescence when the body goes through a main phase of cellular growth. When the cells are formed, they take vitamin D directly from the circulation where the vitamin D level determines the number of mitochondria per cell (1500-3000; the heart up to 5000, Sinatra). And when the cells have more mitochondria, they will be more resilient. Extending that line of thinking, all players of the Canadian ice hockey team – a physically very demanding sports - were born in February. The foetus went through the main phase of cellular growth during the end of Summer early Autumn when the vitamin D level in the circulation of their mother must have peaked.
Another feature of the MS timeline is the double peak in the graph of age of onset where a first peak appears around 27 years of age and a second peak around 43. This provides an indication for a two stage process with different underlying mechanisms. In the first phase, the virus spreads in meningeal follicles, the lymphatic system and stem cells including OPCs and bone marrow. Every now and then when receptors get blocked, you get an acute relapse, the immune system removes the infectious agent, and you see remission (RR). In particular the Varicella Zoster virus (VZV) which is an inflammatory virus is suspect here. But as the virus spreads, more and more cells in particular stem cells get infected and become transgenic. People with transgenic cells are healthy but predisposed. As of mid age, another phenomenon kicks in. The EBV virus has spread so far that increasingly B-cells get infected with a lack of sufficient T-cell function to contain an unbridled B-cell replication. CCSVI may be a factor here again because the pharynx/tonsil drain through the Internal Jugular Veins where hypoperfusion may result in pharynx/tonsil infection that may be responsible for the onset of autoimmunity. As B-cells cross-react with transgenic cells (common epitodes), a lot of damage is done and the typical MS plaques show up. The neurological path is weakened and because of that any new problems with receptor blocking which were not sufficiently severe before to get diagnosed will now result in more severe symptoms and one gets diagnosed. At this point the progressive mechanism is already underway and one will be generally worse off.
Another feature of the MS timeline is the extinction of the disease above 60 years of age, with no new cases reported after 60. Immunosenescence results in a natural decline in humoral immunity above 60 caused by a reduction in the population of antibody producing B-cells. Where apparently the immune system - after millions of years of coevolution with the virus - says: if I can't get you (EBV) under control, I have to switch back one gear to avoid further damage is done.
Beyond MS - towards to a new paradigm for autoimmune diseases in general
In our current system for medicare, we see a very large number of overlapping autoimmune diseases with different names. Every expression of a neurological set of symptoms got its own name, based on several types of observations. And we see various signs and symptoms that are overlapping.
But in fact, a bigger common scheme is underlying. A scheme that encompasses the wide variety of observations, their patterns of case initiation, their chronic nature and many of their shared and unique symptoms and signs of the chronic phase of the disease. A scheme that explains many unexplained observations and the multiple similarities of these illnesses by a simple conceptual framework.
We need to accept a new paradigm based on the understanding of a viral cause of autoimmunity and indeed MS, we should develop a new virological consciousness. Traditional major disease paradigms should be complemented by a new model based on virology and biochemistry.
The viral connection
The primate’s immune system and the herpes virus have coevolved alongside, for millions of years. However, over the last 50 years our living conditions have changed so profoundly that the immune system does not keep the virus in check anymore. There is accumulating evidence of the role of the herpes virus and in particular the Epstein-Barr virus (EBV) in the pathogenesis of MS. With the virtual non-existence of MS in EBV seronegative people (still 5 - 10 % of population), epidemiological analysis would reduce the risk of being wrong on the causal relationship of EBV and MS to an infinitesimal small number.
Universal EBV seropositivity, high EBV antibody levels and alterations in EBV-specific CD8+ T-cell immunity are commonly observed and likely to be a causal factor in MS rather than the result of MS. [post script: it is probably more accurate to suggests that it may be the type of immune response to EBV that predisposes to MS (through EBV primed cells), rather than EBV infection itself. ]
Disruption of the highly evolved balance between the EBV lytic and latent life cycles and host immune control results in a range of EBV-associated diseases involving B-cells, epithelial cells, T-cells, natural killer (NK) cells and muscle cells. Here we may differentiate between two processes: an EBV protein inactivates monocyte signaling resulting in a subverted and ineffective immune response with EBV residing in the B cell and immortalizing it and T-lymphocyte imbalances; and cell disorders where pre-incubation of cells with herpes / EBV results in pro-inflammatory expression of the tissue.
Proposed role of EBV infection in the development of MS
Primary lytic replication of EBV in pharyngeal mocusal epithelium precedes long-lived latent infection of resting memory B-cells [Elegheert/Savvides]. During primary infection, EBV infects autoreactive naïve B-cells in the tonsil, driving them to enter germinal centres where they proliferate intensely and differentiate into latently infected autoreactive memory B cells (Step 1), which then exit from the tonsil and circulate in the blood (Step 2) [Pender].
The number of EBV-infected B cells is normally controlled by EBV-specific cytotoxic CD8+ T cells, which kill proliferating and lytically infected B cells, but not if there is a defect in the defense mechanism.
One concept suggests the EBV secretes lytic-cycle early protein BARF1 which is a binding protein for the hematopoietic cytokine hCSF-1, evading and subverting key host signaling pathways. BARF1 also inhibits the secretion of antiviral interferon (IFN)-α. This impedes the primary response via CD8+ cytotoxic T-cells and natural killer cells to clear EBV-infected cells, in line with T-cell mediated adaptive immunity against EBV.
Another concept suggests EBV is masked by a protein p47phox which is required to make superoxide to prevent recurrent infections. Here, the idea is that these transformed B cells are not perceived as foreign and thus not as a serious infection by the immune system.
Surviving EBV-infected autoreactive memory B cells enter the CNS where they take up residence and produce oligoclonal IgG and pathogenic autoantibodies, which attack myelin and other components of the CNS (Step 3).
Autoreactive T cells that have been activated in peripheral lymphoid organs by common systemic infections circulate in the blood and enter the CNS where they are reactivated by EBV-infected autoreactive B cells presenting CNS peptides (Cp) bound to major histocompatibility complex (MHC) molecules (Step 4). These EBV-infected B cells provide costimulatory survival signals (B7) to the CD28 receptor on the autoreactive T cells and thereby inhibit the activation-induced T-cell apoptosis, which normally occurs when autoreactive T cells enter the CNS and interact with non-professional antigen-presenting cells such as astrocytes and microglia, which do not express B7 costimulatory molecules (Step 5).
After the autoreactive T cells have been reactivated by EBV-infected autoreactive B cells, they produce chemokines and cytokines such as interleukin-2 (IL2), interferon-γ (IFNγ) and tumour necrosis factor (TNFβ) and orchestrate an autoimmune attack on the CNS with resultant oligodendrocyte and myelin destruction (Step 6).
A further concept is described by David Hudnal in his chapter Epstein-Barr Virus: Pathogenesis and Host Immune Response. Following initial exposure to infectious saliva, EBV likely undergoes a brief period of lytic replication in oral and nasal epithelium. Subsequent infection of naïve B cells within subjacent tonsillar lymphoid tissues leads to a brief “pre-latent” period of lytic and latent gene expression prior to epigenetic repression of viral genes. This brief pre-latent period is marked by limited expression of a small set of lytic genes with regulatory function, excluding lytic genes essential for DNA replication and virion assembly. It is likely that by promoting cell growth and inhibiting apoptosis, pre-latent lytic gene products, including BART miRNA, viral BCL-2 homologs, and BZLF1, contribute to the early survival of EBV-infected B cells. Following epigenetic repression of the full complement of lytic genes and a subset of latent gene promoters, rapid growth of latent-infected B cells is induced by expression of the full growth-promoting complement of latency genes, i.e., the latency III program. Expression of the full complement of lytic and latent antigens by infected epithelial cells and B cells triggers a vigorous humoral and cellular immune response that leads to suppression of viral replication. Latent-infected B cells persist by switching from the highly immunogenic latency III program to the less immunogenic latency II program, with virus gene expression restricted to three proteins, EBNA-1, LMP-1, and LMP-2A. EBNA-1 maintains the viral genome, while LMP-1 and LMP-2A maintain cell growth while preventing apoptosis. The absence of EBNA-2-mediated transactivation allows for latency II B cells to adopt a germinal center B-cell phenotype and, in so doing, survive germinal center and/or extrafollicular proliferation and maturation into EBV-infected memory B cells. EBV-infected memory B cells persist by switching from the latency II program to the latency 0 program, with near- complete absence of viral gene expression, with only intermittent LMP-2a expression.
The viral tolerance theory – predisposition by early infection
During periods that people are immune compromised (can be the fetal period, the period of the newborn and immune deficient periods), the virus can incorporate some of its genes in the DNA of permissible cells. In addition, work on human genome sequencing revealed that 8% of our DNA is of viral origin where the (herpes) virus incorporated its DNA in our genes
For the more recent infections, Chronic Cerebro Spinal Venous Insufficiency (CCSVI) may be a factor here too causing hypoperfusion, lower AMP and adonesine, and with that a reduced control of the EBV infection.
The incorporated viral genes (transgenes) are tolerant to the body or no immune memory against these transgenes has established. In MS, in particular the oligodendrocyte precursor cells (OPCs) in locally affected tissue will be infected but also the bone marrow.
People with transgenes in their body are healthy but predisposed to develop a disease. Predisposed people become diseased when they are infected with a microbe that shares epitodes with the transgenes present in the transgenic cells and will cause an immunological reaction.
In MS, EBV infected autoreactive T- and B-cells will later on pass the Central Nervous System (CNS) and cross-react with the transgenes in the OPCs. Due to this cross-reaction, many OPCs will die which leads to a diminishing number of OPCs, of dendrocytes and a reduced myelination of neurons. During this cross-reaction, many mediators will be released by the infiltrating T-cells. This will increase angiogenesis and cause hyperproliferation of surrounding tissue cells in the CNS which in turn causes the pathological lesions (sclerotic plaques) typical for MS.
The biochemical reaction hypothesis – the fatigue explained
The autoreactive B-cells have substantial super-oxygen generating capability. The superoxide reacts with the nitric oxide in the finest capillaries and forms peroxynitrite which is by far the worst free radical. Over time we produce excess peroxynitrite. Although the peroxynitrite may inhibit viral replication, it disables glyceraldehyde 3 phosphate which impacts the sodium/potassium pump and cell viability. Women have higher NO than men which explains the gender bias.
Over time the vitality of the cell declines as ATP levels decline and the loss of some AMP leads to a fall in Adenosine (endogenous inhibitor of arachidonic acid) and, in time, a loss of purine from Adenosine loss. EBV also inhibits the production of intra-cellular interferon gamma and EBV primed cells induce arachidonic acid and inflammation when an agonist is introduced. Ultimately energy levels decline and uric acid levels fall. The loss of Adenosine and cellular interferon will lower the ability to control inflammation and indeed the suppression of the transfer of EBV from latently infected cells to other cells. And the endothelium inflammates leading to an endothelial dysfunction.
The huge oxidative stress jams the gates/mitochondria of the cells, causes effects on the mitochondrial electron transport chain, electron pump inactivation, inhibits ADP to ATP conversion and depletes energy in the form of ATP. And it poisons fat tissue and causes lesions where the brains, biologically seen, are just a lump of fat.
As the pumps already run on their edge and a number have failed and the equilibrium can not be easily maintained and gates close with increasing temperature (either from the outside or fever induced; cooler wheather or high air pressure have the reverse effect), the conduction of the nerve path runs down. Here the ion pumps are the most important energy consumers that require the biggest amount of cellular energy [Sinatra].
As the number of active gates goes down, we see an increasingly big temperature effect in patients with MS and a loss of muscle strength and sensitivity in the periphery. As cells shrink in size because gates/mitochondria successively fail, it causes whole brain atrophy.
Hence, the typical fatigue, weakening of muscles and whole-brain atrophy observed in MS patients is partly caused by the EBV infected B cells but with a completely different underlying mechanism than the demyelinating plaques in the brains. And the typical MS motor dysfunction will be caused by a combination of factors.
A general dysregulation of the metabolism – interlocking vicious cycles
The virus is causal and leads to a general dysregulation of the metabolism involving metabolic factors (HPA axis affecting cortisol and gut function) and infection by bacteria and fungi including Borrelia, Cpn and toxoplasmose.
(Short term) stressors initiate cases of multisystem illnesses by stimulating nitric oxide synthase (NOS) activity and consequently produce increased levels of nitric oxide and its oxidant product peroxynitrite. The immune system will be triggered by the biochemical cycle mechanism with NF-кB a first responder to the harmful cellular stimuli. The increased NF-кB activity will lead to increased iNOS activity by stimulating through the inflammatory cytokines the activity of the iNOS gene itself.
There is a combination of stability and instability, positive and negative feed back loops including brain-bowel-brain and nose-brain connections, leading to what is essentially inflammatory virology and biochemistry.
MS is therefore a subtle multi factorial disease where a number mechanisms and vicious loops are convolved. This explains the erratic course of the disease, and the large variety of symptoms and disease progression seen in MS patients.
Specific features of the MS timeline confirm the line of thinking
The MS timeline has a number of very specific features that can be fully explained by the foregoing analysis.
An interesting feature is that in childhood, the tonsil is relatively large compared to the nasopharinx. Possibly, here we may find an explanation why EBV infection of young children gives a different (less viral load) but stronger (age) protective immune response than in late-infected adolescents or adults. [Hudnall speculates on the link to pharyngual epithelium and the tonsil in his chapter on Epstein-Barr Virus: Pathogenesis and Host Immune Response]
If identical twins get separated at young age but before adolescence, the person that moves further South has less risk to develop MS at a later date. That person will have more sun exposure and therefore a higher vitamin D level in the circulation during adolescence when the body goes through a main phase of cellular growth. When the cells are formed, they take vitamin D directly from the circulation where the vitamin D level determines the number of mitochondria per cell (1500-3000; the heart up to 5000, Sinatra). And when the cells have more mitochondria, they will be more resilient. Extending that line of thinking, all players of the Canadian ice hockey team – a physically very demanding sports - were born in February. The foetus went through the main phase of cellular growth during the end of Summer early Autumn when the vitamin D level in the circulation of their mother must have peaked.
Another feature of the MS timeline is the double peak in the graph of age of onset where a first peak appears around 27 years of age and a second peak around 43. This provides an indication for a two stage process with different underlying mechanisms. In the first phase, the virus spreads in meningeal follicles, the lymphatic system and stem cells including OPCs and bone marrow. Every now and then when receptors get blocked, you get an acute relapse, the immune system removes the infectious agent, and you see remission (RR). In particular the Varicella Zoster virus (VZV) which is an inflammatory virus is suspect here. But as the virus spreads, more and more cells in particular stem cells get infected and become transgenic. People with transgenic cells are healthy but predisposed. As of mid age, another phenomenon kicks in. The EBV virus has spread so far that increasingly B-cells get infected with a lack of sufficient T-cell function to contain an unbridled B-cell replication. CCSVI may be a factor here again because the pharynx/tonsil drain through the Internal Jugular Veins where hypoperfusion may result in pharynx/tonsil infection that may be responsible for the onset of autoimmunity. As B-cells cross-react with transgenic cells (common epitodes), a lot of damage is done and the typical MS plaques show up. The neurological path is weakened and because of that any new problems with receptor blocking which were not sufficiently severe before to get diagnosed will now result in more severe symptoms and one gets diagnosed. At this point the progressive mechanism is already underway and one will be generally worse off.
Another feature of the MS timeline is the extinction of the disease above 60 years of age, with no new cases reported after 60. Immunosenescence results in a natural decline in humoral immunity above 60 caused by a reduction in the population of antibody producing B-cells. Where apparently the immune system - after millions of years of coevolution with the virus - says: if I can't get you (EBV) under control, I have to switch back one gear to avoid further damage is done.
Beyond MS - towards to a new paradigm for autoimmune diseases in general
In our current system for medicare, we see a very large number of overlapping autoimmune diseases with different names. Every expression of a neurological set of symptoms got its own name, based on several types of observations. And we see various signs and symptoms that are overlapping.
But in fact, a bigger common scheme is underlying. A scheme that encompasses the wide variety of observations, their patterns of case initiation, their chronic nature and many of their shared and unique symptoms and signs of the chronic phase of the disease. A scheme that explains many unexplained observations and the multiple similarities of these illnesses by a simple conceptual framework.
We need to accept a new paradigm based on the understanding of a viral cause of autoimmunity and indeed MS, we should develop a new virological consciousness. Traditional major disease paradigms should be complemented by a new model based on virology and biochemistry.
Last edited by Leonard on Wed Jun 17, 2015 7:59 am, edited 22 times in total.
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Anonymoose
- Family Elder
- Posts: 1190
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Re: A new concept and treatment options for MS
I think this might fit in somewhere here...
Could it be caused by a combination of infections?
B cells are involved in th17 production and more are likely hanging around with an out of control ebv infection. Rituxan depletes some B cells and reduces th17 response to infection (candida in this study).
http://www.ncbi.nlm.nih.gov/pubmed/21400475
Th17 in autoimmune disease and infection.
http://www.hindawi.com/journals/iji/2014/651503/
Manage the th17 by managing infections that are causing high levels (not by arbitrarily immunosuppressing) and in turn manage the disease?
(Unsubstantiated thought...some infections lower overall immunity. Maybe an underlying unidentified infection is causing lowered cd8+ T cell response to ebv?)
Could it be caused by a combination of infections?
B cells are involved in th17 production and more are likely hanging around with an out of control ebv infection. Rituxan depletes some B cells and reduces th17 response to infection (candida in this study).
http://www.ncbi.nlm.nih.gov/pubmed/21400475
Th17 in autoimmune disease and infection.
http://www.hindawi.com/journals/iji/2014/651503/
Manage the th17 by managing infections that are causing high levels (not by arbitrarily immunosuppressing) and in turn manage the disease?
(Unsubstantiated thought...some infections lower overall immunity. Maybe an underlying unidentified infection is causing lowered cd8+ T cell response to ebv?)
Re: A new concept and treatment options for MS
Thank you Anonymoose.
Because of MS/EBV, many markers will get out of their normal range.
But most of them will be consequential, of an organism that is trying to correct where things go wrong.
I think that the Introduction of this review article simply describes what progressive MS is.
I encourage you all to read it.
http://www.infectagentscancer.com/content/9/1/8
The "virus replication at epithelial surfaces" refers to an inflammation of the nasopharynx.
The "spreading of the virus to new hosts" refers to the lymphatic system and the brain compartment.
The nasopharynx inflammates due to low blood flow which in turn links the matter to CCSVI.
The thesis above explains the rest.
According to the above article, there is a link between EBV carrying B cells, strong telomerase activity and immortalization.
I would not go so far to say that it is a tumor but the underlying mechanisms and variants carry large resemblance.
Therefore, we should be allowed to fight our war against MS with the same weapons as patients with cancers.
As regards options for treatment, I think of the following:
1. Rituximab, chemo, to capture and deplete the infected B cells;
2a. chemotherapy to knock down the virus, you can think of Mitoxantrone but also of lighter chemo as anti-rheumatic Methotrexate, or;
2b. telomerase inhibition followed by anti-viral (are Letermovir / Maribavir related?), or;
2c. intravenous immuno/gamma globulins (IgG3) which apparently has shown efficacy to clean infections and has been seen here before (Jelinek, Coucke; is GeNeuro/IgG4 related?)
I think diet, supplementation etc are all marginal issues which when added together may show their effect after many years of sustained effort. And they may be very useful to help clean the body after the B-cells have been deleted.
Because of MS/EBV, many markers will get out of their normal range.
But most of them will be consequential, of an organism that is trying to correct where things go wrong.
I think that the Introduction of this review article simply describes what progressive MS is.
I encourage you all to read it.
http://www.infectagentscancer.com/content/9/1/8
The "virus replication at epithelial surfaces" refers to an inflammation of the nasopharynx.
The "spreading of the virus to new hosts" refers to the lymphatic system and the brain compartment.
The nasopharynx inflammates due to low blood flow which in turn links the matter to CCSVI.
The thesis above explains the rest.
According to the above article, there is a link between EBV carrying B cells, strong telomerase activity and immortalization.
I would not go so far to say that it is a tumor but the underlying mechanisms and variants carry large resemblance.
Therefore, we should be allowed to fight our war against MS with the same weapons as patients with cancers.
As regards options for treatment, I think of the following:
1. Rituximab, chemo, to capture and deplete the infected B cells;
2a. chemotherapy to knock down the virus, you can think of Mitoxantrone but also of lighter chemo as anti-rheumatic Methotrexate, or;
2b. telomerase inhibition followed by anti-viral (are Letermovir / Maribavir related?), or;
2c. intravenous immuno/gamma globulins (IgG3) which apparently has shown efficacy to clean infections and has been seen here before (Jelinek, Coucke; is GeNeuro/IgG4 related?)
I think diet, supplementation etc are all marginal issues which when added together may show their effect after many years of sustained effort. And they may be very useful to help clean the body after the B-cells have been deleted.
Last edited by Leonard on Wed May 06, 2015 5:40 am, edited 13 times in total.
Re: A new concept and treatment options for MS
Hello Leonard :
You have a potentially valuable therapeutic resource right next to >Brussels (Rixansart?) which might help you (or anyone else interested) Mid 1980’s my San Francisco Kinesiologist Dr Jimmy Scott gave courses for Dr. Dominique Monette and I see she is still associated with Kinesiology at l’IBK at Rixansart. (Info on Internet.) The advantage of muscle testing for diet, food intolerances etc is that theoretically one can have a custom diet/supplement regime worked out specific to your needs. When Dr Scott determined my “allergies” (food intolerances if you like) ideal diet and supplements, I was horrified. “this guy’s a quack” was my first thought. But then what he suggested couldn’t hurt me so I tried it. He said it would take 5 days to detox from food intolerances and the first few days were really like going through drug withdrawal. After 5 days I felt lighter and better and I was VERY lucky because I had been suffering from a right eye vision problem which disappeared after going off glutens etc. Then it returned when I took antibiotics, but since has never returned. So I had an immediate benefit. It took 6 months for my intestines to clear out and a year for the MS damage to heal. (I was young and healing more likely.) I think it is a mistake to ignore nutrition and supplements and launch right into chemotherapy etc. What if EBV/Mononucleosis damages the veins in a growing child, and later it re-activates because of low oxygen due to poor blood circulation?
Anyway, I suggest this resource because it is right next to you. You might find someone who can at least help you think through your personal needs rather than wander blindly through the theoretical.
Regards, Vesta
More on my site www.mscureenigmas.net/
You have a potentially valuable therapeutic resource right next to >Brussels (Rixansart?) which might help you (or anyone else interested) Mid 1980’s my San Francisco Kinesiologist Dr Jimmy Scott gave courses for Dr. Dominique Monette and I see she is still associated with Kinesiology at l’IBK at Rixansart. (Info on Internet.) The advantage of muscle testing for diet, food intolerances etc is that theoretically one can have a custom diet/supplement regime worked out specific to your needs. When Dr Scott determined my “allergies” (food intolerances if you like) ideal diet and supplements, I was horrified. “this guy’s a quack” was my first thought. But then what he suggested couldn’t hurt me so I tried it. He said it would take 5 days to detox from food intolerances and the first few days were really like going through drug withdrawal. After 5 days I felt lighter and better and I was VERY lucky because I had been suffering from a right eye vision problem which disappeared after going off glutens etc. Then it returned when I took antibiotics, but since has never returned. So I had an immediate benefit. It took 6 months for my intestines to clear out and a year for the MS damage to heal. (I was young and healing more likely.) I think it is a mistake to ignore nutrition and supplements and launch right into chemotherapy etc. What if EBV/Mononucleosis damages the veins in a growing child, and later it re-activates because of low oxygen due to poor blood circulation?
Anyway, I suggest this resource because it is right next to you. You might find someone who can at least help you think through your personal needs rather than wander blindly through the theoretical.
Regards, Vesta
More on my site www.mscureenigmas.net/
Re: A new concept and treatment options for MS
Thank you Vesta. I will not ignore nutrition and supplements and should contact Dr. Monette.
But I think that in my case diet, supplements, life style etc. is just not enough.
My B-cells need to get down, they are too destructive.
After that, I am sure diet, anti-oxidants, detoxification etc. will help to speed recovery.
But I think that in my case diet, supplements, life style etc. is just not enough.
My B-cells need to get down, they are too destructive.
After that, I am sure diet, anti-oxidants, detoxification etc. will help to speed recovery.
Last edited by Leonard on Wed Apr 15, 2015 4:37 am, edited 1 time in total.
Re: A new concept and treatment options for MS
On the site of the National MS Society, you find a report of the recent Boston meeting of the Progressive MS Alliance.
http://www.nationalmssociety.org/Nation ... -final.pdf
This means a revolution in MS land!
I recommend you all to read it.
The report mentions the meningeal inflammation, the B-cells, mitochondrial failure, the role of lipids.
All good points.
It asks what comes first.
Good question!
The link with EBV has not yet been made (at least not in the report) but it will come soon, I am sure.
The thesis here above explains the relationship with EBV (see posting 26 March 2015).
On B-cell immortalization, these papers are also interesting:
http://www.infectagentscancer.com/content/9/1/8
and a chapter you can download after googling for: Epstein-Barr Virus: Pathogenesis and Host Immune Response by David Hudnall
http://www.nationalmssociety.org/Nation ... -final.pdf
This means a revolution in MS land!
I recommend you all to read it.
The report mentions the meningeal inflammation, the B-cells, mitochondrial failure, the role of lipids.
All good points.
It asks what comes first.
Good question!
The link with EBV has not yet been made (at least not in the report) but it will come soon, I am sure.
The thesis here above explains the relationship with EBV (see posting 26 March 2015).
On B-cell immortalization, these papers are also interesting:
http://www.infectagentscancer.com/content/9/1/8
and a chapter you can download after googling for: Epstein-Barr Virus: Pathogenesis and Host Immune Response by David Hudnall
Last edited by Leonard on Wed May 06, 2015 12:15 am, edited 1 time in total.
The stages of Project MS
Stage I: Resistance to change
I know that most men, including those at ease with problems of the greatest complexity, can seldom accept even the simplest and most obvious truth if it be such as would oblige them to admit the falsity of conclusions which they have delighted in explaining to colleagues, which they have proudly taught to others, and which they have woven, thread by thread, into the fabric of their lives.
Leo Tolstoy, Translation from: What Is Art and Essays on Art, Oxford University Press, 1930
Stage II: Rethink, to change
What I propose in the following is a reconsideration of the human condition from the vantage point of our newest experiences and most recent fears. This, obviously, is a matter of thought, and thoughtlessness – the heedless recklessness or hopeless confusion or complacent repetition of 'truths' which have become trivial and empty – seems to me among the outstanding characteristics of our time. What I propose, therefore, is very simple: it is nothing more than to think what we are doing.
Hannah Arendt, Prologue of "The Human Condition", 1958
Stage III: Accept change
There is a tide in the affairs of men which, taken at the flood, leads on to fortune; omitted, all the voyage of their life is bound in shallows and in miseries; on such a full sea we are now afloat; and we must take the current when it serves, or lose our ventures.
William Shakespeare, Julius Caesar, IV.iii, 1599
I know that most men, including those at ease with problems of the greatest complexity, can seldom accept even the simplest and most obvious truth if it be such as would oblige them to admit the falsity of conclusions which they have delighted in explaining to colleagues, which they have proudly taught to others, and which they have woven, thread by thread, into the fabric of their lives.
Leo Tolstoy, Translation from: What Is Art and Essays on Art, Oxford University Press, 1930
Stage II: Rethink, to change
What I propose in the following is a reconsideration of the human condition from the vantage point of our newest experiences and most recent fears. This, obviously, is a matter of thought, and thoughtlessness – the heedless recklessness or hopeless confusion or complacent repetition of 'truths' which have become trivial and empty – seems to me among the outstanding characteristics of our time. What I propose, therefore, is very simple: it is nothing more than to think what we are doing.
Hannah Arendt, Prologue of "The Human Condition", 1958
Stage III: Accept change
There is a tide in the affairs of men which, taken at the flood, leads on to fortune; omitted, all the voyage of their life is bound in shallows and in miseries; on such a full sea we are now afloat; and we must take the current when it serves, or lose our ventures.
William Shakespeare, Julius Caesar, IV.iii, 1599
Last edited by Leonard on Mon May 04, 2015 3:01 am, edited 1 time in total.