Sunday, November 12, 2023

Lysine dose may reduce migraine severity in post-COVID 6 day migraine cycle by assisting calcium transport out of the blood and reducing vasoconstriction.

 The reason for posting today is I wanted to share something helpful, which seems significant given the interest in calcium in human physiology in relation to ME shown by Marshall-Gradisnik et al at Griffith in Australia, so I wanted to write it out on the internet to make this observation available.

The story goes, I noticed in one of my migraine cycles I did not get severe headache as usual, just thick head and cognitive decrease.

I keep a food diary so a month later, after a few intervening cycles with normal levels of migraine pain, I attempted to recapitulate the exact same diet over the 6 days cycle, including supplements and found once again I had zero pain.

I then analysed the diet and researched the different elements and to cut a long story short I discovered the relevant factor appears to have been taking a lysine dose just before the inflammatory migraine phase, which reduced pain significantly.

I have since been able to replicate and use this to take lysine as a remedy if I feel a migraine coming on to stop and alleviate it, which is a big relief for me, to have something which helps.

The scientific reasoning behind my conclusion is that Lysine is known to assist calcium transport, among other things.

https://en.wikipedia.org/wiki/Lysine#Biological_roles

Lysine has also been implicated ... in other biological processes including ... calcium homeostasis, and fatty acid metabolism.


Which references a paper "Dietary L-lysine and calcium metabolism in humans" by Civitelli et al.

https://pubmed.ncbi.nlm.nih.gov/1486246/

Studies in animals have shown that dietary supplements with certain amino acids, particularly L-lysine, can increase Ca absorption.


As I discussed in the previous blog, I have already noticed I have a problem with calcium supplements causing headaches and taking its competitor magnesium can help to alleviate some pain during the cycle. Also there is a fluctuation in the 6 day cycle which may indicate changes in calcium levels which meant that I needed to time magnesium supplements to coincide with these. The problem is that high Mg doses can cause diarrhea and also muscle pain if they interfere with Ca absorbtion to muscle cells.

Hypothetically a lysine dose might help manage blood calcium levels by transporting Ca  out of the blood and into cells, where it belongs. So instead of taking large doses of Mg to compete with the Ca flux in the blood I can now just take a dose of lysine to reduce blood Ca content and this in turn might hypothetically be reducing the tendency to vasoconstriction which causes the headaches because Ca in the blood may be promoting vasoconstriction.

All I can say for sure is that it reduces pain if I take lysine before the inflammatory episode which otherwise would result in a migraine.

Hope that makes sense.


Update - Further corroborration comes from a 1989 experiment with human fibroblasts.

Effect of L-lysine on cytosolic calcium homeostasis in cultured human normal fibroblasts. 

Civitelli R, Fedde KN, Harter J, Halstead LR, Gennari C, Avioli LV. Calcif Tissue Int. 1989 Sep;45(3):193-7. doi: 10.1007/BF02556063. PMID:2505911. 

https://pubmed.ncbi.nlm.nih.gov/2505911/

Steady state [Ca2+]i ... in cells cultured ... in a L-lysine-free medium, was significantly higher than in cells grown in the presence of as little as 4 μM L-lysine...

It is concluded that L-lysine is an important modulator of cytosolic calcium homeostasis.


 The implication is that lysine helps calcium cross membranes and get around the body and interestingly that calcium can build up in some compartments, if there is a dearth of lysine. 


P.S. To share my full treatment method, I take NAC (N-Acetyl Cysteine) along with the lysine dose, not regularly, just as a one off of either 600mg or 700mg. I take the larger dose if I have not taken NAC for several days and the smaller dose if I have taken it in the last two days.

I take NAC because that is what I did during the pain free inflammatory cycle, which is the basis of this observation. I have not completed a thorough check yet but would not want to leave this out as it may be relevant. I feel intuitively that NAC assists somehow. All I know about it currently is, it is an acidic mucolytic antioxidant which may thin the blood as it is contraindicated for people with bleeding problems and has reputed antiviral and antibacterial properties. All I know is that if I take them both together (lysine and NAC) it seems to work better.



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Thursday, May 25, 2023

Post COVID Migraine in a Six Day Cycle


After COVID infections and three vaccinations (AZx2 + Modx1), I now have a cycle of inflammation causing migraines which lasts six days. The inflammatory episode lasts three days so that means three days on and three days off. With ME CFIDS related PEM (post exertion malaise) all the time. 

Previously my ME CFIDS involved a recurring virus cycle which started at about 30 days long in 1986 and either caused or was a result of whatever was causing ME CFS. 

Subsequently I caught other viruses and some appeared to become recurrent e.g. recurring swine flu after 2009 whenever my head got cold. In about 2017 I caught something I cant identify but may be an enterovirus like echovirus as it caused rib cramps (Bornholm symptoms) and headaches recurring every two weeks odd. 

Every time I caught a new recurring virus the cycle got shorter. My best guess is its like a ratchet because whichever virus is quickest to recur triggers my immune response first. The others are held at bay by the immune response to the quickest repeater, but some are still there and show themselves from time to time.

The new six day cycle has been accompanied by a new degree of intolerance for some foods, especially maize, in addition to all my other intolerances, which make the headaches much worse. This started to be a problem around the swine flu epidemic in 2009. I found eating tortilla chips, which I used to love, gave me an intolerable headache.

This new phase of 6 day cycle began after a dose of suspected COVID-19 and caught me off guard. At first the migraine was very intense and I honestly feared for my health and wellbeing. 

I noticed it varied in intensity and tried to work out why. After much observing, thinking and experimenting on myself, I have found several factors which all reduce the severity a little. Primarily, during an inflammatory episode my migraine is much worse if I eat any protein, animal or vegetable and also any food high in manganese or vitamin K. 

I can now usually survive the entire cycle with minimum migraine pain as long as I stick to what helps. I score my headaches 1-10 and the worst I got to was 8, which I felt was approaching life threatening due to the sensation of compression inside my head and the fear of aneurism. 10 I think would be very dangerous, probably coma. Right now I can usually manage to keep it below 1, with the worst being 2. This is a big improvement and relief for me so I wanted to share.

Details below, in the hope it might help others in a similar situation and save them some pain.


During the three day migraine phase ...

  • I need a low protein diet excluding both animal and plant protein. i.e. no meat, no eggs, no rice, no lentils or other legumes as these all have more than 5g protein per 100g. I live on assorted vegetables, spices, oils and fats and (not too much) white cassava gari. - I use eatthismuch.com for looking up food data. https://www.eatthismuch.com/food/browse/?q=&type=food
  • I have to avoid foods or supplements rich in vitamin K or manganese (Mn) or the pain increases significantly. (Implicated in blood clotting.)
  • Taking moderate amounts of magnesium (Mg) supplements helps to reduce head pain as well as heart arrhythmia.
  • Head pain is also reduced by taking linseed oil for omega 3 lipids, vitamin D and turmeric extract (Solgar), which are commonly recommended as anti-inflammatory supplements and turmeric is a blood thinner.
  • I have to restrict sugars or the pain can get worse, sugars are considered proinflammatory.
  • I need to relax and avoid using my brain too much or it starts to hurt. I drink hop tea herb tea to help as it is mildly tranquilising. I usually add marigold and bucchu to this, sometimes lavender. (UPDATE I have to be careful with any green plants like hops as they tend to have VitK which can exacerbate migraine, possibly via microclotting.) 
  • I often feel sleepy in the inflammatory phase and do better if I sleep when I feel the need. It feels like there is inflammation in my brain affecting my cognition and in my experience it is best not to fight it. Best to sleep, somewhere warm and let one's body heal.
  • Heat treatment for the neck and back can promote vasodilation which helps reduce head pain. Likewise hot showers or short hot baths.
  • I have to avoid getting exhausted by activity and my ability is even less than usual. Otherwise I get post exertion malaise (PEM) which makes the migraine worse.
  • It helps to drink plenty of fluid.
  • Sometimes the inflammatory phase is accompanied by a symptom which causes my mind to race, involuntarily and to an excessive degree, which feels like a vicious spiral, as though my brain is on fire. This is exacerbated by too much onion (quercetin). At these times, when hop tea does not work but Mg usually helps a little, I have also found a wee medicinal dram of alcohol and I mean wee, about a quarter measure, damps this down, which I ascribe to the way alcohol acts as a depressant of brain activity, hence its effect when taken in larger quantities. In this situation the benefits significantly outweigh the mild proinflammatory drawbacks. 

Outside a migraine phase...

I cannot tolerate any maize corn as this always causes a migraine.

It looks like I cannot tolerate eating any meat from an animal which has been fed maize either. I have tested this and now order regeneratively farmed meat, like 100% pasture fed beef and lamb which I can eat outside a migraine phase without ill effect. If I buy meat from a supermarket from animals which have been fed standard animal feeds containing maize then it sets off a food intolerance headache lasting 12-18 hours which occurs even when not in a migraine phase and can significantly exacerbate a migraine phase.

I am not eating any nuts now. Anything with hazelnuts in causes headache and other nuts like walnuts or pecans seem to cause itching skin around my fingers.

When eating high protein food like meat, at any time, it is helpful to take digestive enzymes including proteases and also DAO (diamine-oxidase) which reduces histamine absorbtion by oxidising it in the digestive system. These reduce the likelihood and severity of any headaches arising from eating protein.

It helps to take B vits complex, B12, also minerals excluding manganese. Also I have beetroot juice in my omega 3 heavy salad dressing every morning (helps vasodilation).

I still have to avoid even very light exertion causing PEM.


My other preexisting dietary constraints.

I am avoiding wheat gluten all the time based on doctors advice. It does seem to exacerbate headachey patches.

I do not eat any dairy, palm oil or coconut oil as they contain high levels of MCTs (medium chain triglycerides) which are proinflammatory as I addressed in a previous blog.

I do not eat any nightshade vegetables as they cause me mouth ulcers along with inflammation of the skin inside my mouth causing me to bite my cheeks (I get the ulcers even if I don't bite myself accidentally) and it also causes a body wide malaise of ache and weakness. This means no potato, tomato, aubergine (egg plant), chili peppers (paprika), sweet peppers, blueberries. I dont know if that is just me but its what I need to do to avoid getting iller.

Good news is... 

By avoiding these common but problematic foods and taking anti-inflammatory supplements, I can turn three days of excruciating headache into three days of being an airhead, which believe me is much better. 



Discussion.

To recap: I get headaches if I eat the wrong foods (anything with maize in or which has been fed maize, any supplement with manganese in). I also get headaches in a regular cycle and these are exacerbated by high protein foods and anything with high levels of vitamin K or manganese in.

Outside the migraine phase of the inflammatory cycle I can eat limited portions of protein without getting headaches and low levels of vitamin K and manganese containing foods, (not supplements though) without getting headaches. 

My method for reaching this conclusion was based on applying scientific logic to personal experience. 

Observations of my condition were recorded in my diary, alongside foods I eat. I tried to make sense of these to see if there was anything I could do to reduce my pain, by painstakingly tabulating them in spreadsheets.

I ran experiments to test foods which seemed to cause problems at one time to see if they caused a problem at different times.

It was confusing at first because there were too many things going on at the same time. I could not tell the inflammatory cycle headaches from the food triggered headaches and just seemed to be getting headaches all the time whatever I did but with inconsistent triggers.

I learned to avoid a lot of foods and ended up only able to tolerate stewed beef short ribs from among supermarket meats and good quality eggs as long as I only ate one per serving and only one serving of protein per day. One serving of short rib stew for example contained half a short rib worth of beef at around the 100g mark and I could not have more protein like an egg on the same day without getting a headache.

I also realised that whatever I ate or didn't eat, there was also an underlying cycle of inflammatory episodes, three days on and three days off and that during the migraine phase, foods which would not normally cause a headache could cause one or compound a migraine making it more severe. 

That meant any protein at all was out in the inflammatory phase, even from vegetable sources like rice or lentils. Though I could eat these and either short rib stew or an egg (but not both) on the other three days in the less inflammatory phase.

I also noticed that supplements containing manganese caused headaches and so did very green vegetables, both of which I thought would be healthy for me but were making my headaches worse.


Deductions.

The key observation though, was realising that if I took a hot shower it helped relieve my migraine.

It took a while to twig but the implication was that vasodilation was helping to reduce the head pain, as heat causes vasodilation, i.e. the blood vessels relax and get wider.

I tried it out several times and it usually worked unless I had one of those headaches brought on by onions where my mind was racing and which responded  well to medicinal alcohol. 

I then began to experiment with supplements which could assist vasodilation including magnesium, which also helped. I also noticed that taking calcium supplements sometimes triggered a migraine. 

Calcium (Ca) is an antagonist for magnesium (Mg), to be clear we need them both but they need to be balanced. My deduction was that too much calcium was lowering magnesium and impairing vasodilation and possibly encouraging vasoconstriction during headaches. 

My conclusion was I needed more magnesium in headachey patches, which did help a little. The problem then was that sometimes I would get muscle cramps from taking too much Mg all the time and it occurred to me the inflammatory cycle seemed to cause Ca/Mg balance to change quite dramatically at one point  in the cycle (which coincided with the onset of the headache) and then change back. So I had to dose the Mg to coincide with the point where my body was acting as if it had just had a dose of Ca, then ease off the Mg dose, which worked. 

Other vasodilation promoters include Coenzyme Q10 and B12 which is also anti-inflammatory. I also find Kirkman B complex and zinc (Zn) supportive. 
(UPDATE 9/8/23 the above struck through are not always helpful actually, depending on timing and I think it is because CoQ10 has a structure similar to VitK which promotes microthrombosis, while B12 interacts in complex ways with the nitric oxide based control of vasodilation/constriction and may not be particularly influential on its own, while Zn is implicated in clotting and may not always be helpful. B vits complex I still consider moderately supportive though containing B12 as these include niacin aka vitamin B3 which is known to cause vasodilation.) 

Manganese and VitK cause headaches or make them worse and since they are known to be implicated in blood clotting it seems possible that my headaches result from vasoconstriction exacerbated with a tendency to blood thickening or even microthrombotic tendency, as these have been recorded in conjunction with longCOVID. 

Its possible my 6 day cycle is caused by recurring COVID just like the other recurring viruses I have. I had an aching right kidney after initial infection which lasted over two years and may have been acting as a refugium for the virus and may still be though the ache is less obvious now, as it is a site for the expression of ACE2 receptor, as is the endothelium of blood vessels and many other locations in the body.

The fact that reducing protein intake reduces the severity of headaches is consistent with this scenario as protein is the type of molecule involved in blood clotting mechanisms (fibrin) and when being digested can contribute to the levels of proteins and amino acids in the blood plasma adding to viscosity and perhaps reacting to increase the size and or frequency of microclots and protein agglomerations.

ME patients have long been known for having slower ESR (erythrocyte sedimentation rates) than normal and lower blood volumes.

It stands to reason that thicker blood in thinner, possibly vasoconstricted and possibly inflamed, blood vessels will not flow as well.

So IMHO that is the long and the short of it and the key facts I managed to untangle to save myself from the worst effects of an ongoing migraine cycle.

This is a WIP (work in progress) which I am publishing while working on it to get the facts out for others to read. Will try to polish it up and add links etc later. 

Hope it helps.

UPDATE 9/8/23 I have seen a pattern in the 3 day migraine which can be described as M shaped, appropriately enough, the migraine pain is worst (peaks) on the first and third day and is almost not detectable on the second day as long as I dont eat any protein. 

UPDATE DISCUSSION 9/8/23 Regarding protein, it strikes me as a possible hypothesis that the symptoms of headache due to vasoconstriction might be explained by the periodic blocking of ACE2 receptors by SARS-2-COV spike protein, leading to vasoconstriction due to the inhibition of angiotensin conversion to the vasodilatory form. 

The M shaped curve of migraine intensity might be a result of my immune system interacting with the spike protein itself and whatever is producing spike protein. There are more than one candidates for this but first among them must be the virus variants themselves and given my experience with other recurring viruses this is likely. 

Given my predisposition for one day migraines before COVID and after a recurring infection resembling enterovirus since 2015-7, it may be that the post COVID M shaped curve is composed of two types of migraine with different but interrelated causes. These one day migraines used to occur predictably after any recurring infection bout as my immune system was clearing up the aftermath, the timing of which was most evident with bouts of HSV2 as the symptoms are so marked. 

So it seems possible that the second phase or hump of the M shaped 3 day migraine is immunological mop up inflammation migraine, following on from a viral infection recurrence which causes the first hump of migraine directly by releasing spike protein which blocks ACE2 and vasodilation causing vasoconstriction headaches. 

That is my current working hypothesis for management, it follows that each phase of the migraine needs appropriate treatments. The first phase needs vasodilation therapy like heat treatment and possibly B3 (niacin) though this is not good for your liver in large amounts. The second phase needs anti-inflammatory treatments like Vitamin D, Turmeric and Linseed oil for Omega 3 lipids. This approach seems to help.

Will update again if there are further changes to my condition or perspective.

























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Saturday, July 10, 2021

Three Years later. Loratidine, MCTs and summer cold conundrum summary.

Three years and one bout of COVID-19 and two vaccinations later and I am still trying to understand what happened to me a few years ago and still finding myself perplexed about current symptoms but everyone is perplexed about SARS-Cov-2 now and longcovid is increasingly regarded as a condition potentially related to ME CFS. 

So I continue to think and blog about my own experiences of ME CFIDS in the hope that they will make sense to others and be helpful somehow.

One thing I am sure of now is I am not reacting to salicylates anymore, if I ever did. I can now eat a bowl of cherries, which are chocablock with salicylates, in the middle of the grass pollen season, without any adverse reactions, which is a pleasing state of affairs to be sure, since I do like cherries.

In retrospect I was probably wrong about salicylates and they may have been a red herring. It was hard to see the wood for the trees at the time, I now think what happened every summer for five years was... 

  • a grass pollen allergy, properly diagnosed by skin prick test,
  • was treated with loratidine which I took as an antihistamine and this may have made upper respiratory tract (URT) infection more likely, as this is a known side effect of loratidine.
  • The allergic response to grass pollen may have been made worse by coconut MCTs (medium chain triglycerides, see previous blog article below) which may have made me hypersensitive to allergens and also TH2 shifted.
  • The loratidine related URT infection manifested as a summer cold and may have been exacerbated by MCT related TH2 shift, which would tip the immune system towards allergy and away from antiviral responses.
  • Oedema probably resulted from the proven hypersensitivity to grass pollen and may have been exacerbated by TH2 shift, also possibly URT infection related inflammation.
  • Eating honey may have introduced grass pollen exacerbating inflammation.
  • Eating fresh coconut oil may have exacerbated ongoing hypersensitivity and TH2 shift due to a putative mechanism involving membrane lability due to bilayer membrane molecular kinetics.

This is the most rational explanation I can come up with which explains my experiences and makes the least number of assumptions in accord with Occam's razor.

I have taken steps to treat myself by avoiding MCTs in coconut, dairy and palm oil. Also monitored lipid intake and biased it towards heavier (than MCT) lipids such as one might find in lamb fat and other animal fats as well as plenty of vegetable oils such as sunflower rapeseed oil (sunflower has too much omega 6 and not enough omega 3) for cooking and on salads, walnut oil. 

Also I have of course stopped taking loratidine.

Since stopping MCTs and loratidine and deliberately eating heavier lipids, I have been free of these previously recurring summer colds with oedemas and my allergic response to grass pollen, while still evident, it much less extreme than it used to be. 

Food for thought!


Meanwhile, as part of my struggle with ME CFIDS, I have developed recurring (at least weekly) migraines which are not seasonal but do seem to be cyclical of their own accord as it were, as well as resulting from PEM (post exertion malaise) and influenced by food choices all tied together, it would seem, by histamine. 

Another complex problem I am still trying to make sense of, so will leave discussion to another blog article, considering how confused I got over the summer colds with oedemas. 

I comfort myself that science is mostly about finding out what is true the hard way, by observing phenomena accurately and testing competing hypotheses, at least half of which will be wrong. So I guess being wrong and more importantly being willing to admit you are wrong are a part of what science is all about.


Saturday, October 06, 2018

Coconut - the downside for ME CFIDS patients - possible TH2 shifting.

Further to my previous on problems with food. I have recently chanced upon a research paper which describes a phenomenon which may explain the symptoms I have been getting.

The experiment involved mice being fed coconut oil, which made a significant percentage of them vulnerable to TH2 shift and inflammatory reactions including anaphylaxis.

Dietary medium-chain triglycerides promote oral allergic sensitization and orally induced anaphylaxis to peanut protein in mice.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3563838/?report=classic
J. Li et al.

CONCLUSION

Dietary MCT promote allergic sensitization and anaphylaxis by affecting antigen absorption and availability and by stimulating Th2 responses.
MCT stands for medium chain triglycerides. In this case derived from coconut oil, which is considered a health food and often recommended for ketogenic dieting. The evidence applies only to mice but...

Over the last 5 years I have been suffering from summer headcolds which included severe oedemas in the upper respiratory tract. These may be an exacerbation of a previous tendency to TH2 shift in the summer since ME onset in 1986. The difference between these limited inflammations and the whole body response of anaphylaxis is that these oedemas were localised to tissues where an immune response was ongoing. If a virus is involved it remains unidentified but this condition was accompanied by intercostal cramps and tendency to hives, possibly headaches too and these lesser symptoms are apparently recurrent for me, fit the diagnosis of enterovirus, possibly echovirus which may be recurring like another repeatedly diagnosed virus does for me (HSV2 diagnosed by PCR still recurs 6 to 12 times a year, 32 years after infection, which triggered ME in the context of previous diagnosed EBV). This may be a result of the D in CFIDS (chronic fatigue immune dysfunction syndrome) which causes atypical things to happen with my immune system.

The colds with oedema typically produced pronounced nasal polyps and completely blocked my right ear once as well. The oedemas involved in these headcolds were greatly exacerbated by eating honey and lime and also coconut oil which I construed indicated salicylates, as I mentioned in my previous blog.

Honey and lime drink, which I unthinkingly took for a cold remedy, contains a lot of salicylates from honey but also lime has caused me problems with photsensitivity since and I cant rule that out as a factor and lime and all citrus have been added to my foods-to-avoid list. Honey is also reputed to contain pollen including grass pollen to which I am allergic as proven by a skin test.

Coconut oil, which I was eating regularly over the years this happened, contains salicylates but also MCTs, so this makes it difficult to be sure what has happened, as the MCTs may have exacerbated the oedema by another route as per the paper above, which I may have confused with the effect of salicylates.

I felt the salicylate sensitivity was further corroborated by the fact that I did end up having to avoid green vegetables during oedemas and also afterwards a string of headaches appeared to be triggered by green veg. All low salicylate foods seemed to be more tolerable for me. But green veg may contain potential allergens in the form of lectins which is something I am trying to understand and the headaches were often accompanied by mild asthma which suggests an inflammatory basis but by what route the inflammation occurs I cannot be sure.

So to be honest I would not call this a conclusive level of proof for the salicylate theory. An alternative hypothesis is that I was allergic to the honey and the green veg due to increased absorption of allergens induced by MCTs. However this is why testing food intolerance needs to be based on results and not solely on theory and I continue to test the bounds of my diet to check I am not being neurotic without good reason or making my life harder than it needs to be through lack of awareness.

If a thing makes me ill I need to avoid it, I just need to understand what it is so I can apply the knowledge effectively. There are some things I wont test any more like nightshades and coconut, because the evidence is sufficient for me, the years I ate coconut I got oedema and since I stopped eating coconut the oedemas stopped. Salicylates/lectins sensitivity I will continue to test, albeit very carefully, because it is variable and not as severe if I am not eating coconut.

A reaction to allergens does not rule out exacerbation by salicylates either, which are known to promote oedemas in some people. This is probably not an allergic reaction in itself IMHO, possibly a result of the way salicylates can interfere with prostaglandin pathways etc. This is odd because salicylate is normally regarded as an anti-inflammatory, but salicylates do have a wide range of effects and there are close connections to the inflammatory pathways, not all of which are beneficial. It remains a mystery but if coconut MCTs played a part and altered my reaction to allergens and salicylates combined, then if I do not eat coconut MCTs any more I may be able to tolerate salicylates better.

For me a breakthrough came after noting the long term coincidence in timing of these oedema attacks and my use of coconut oil in cooking, in a concerted attempt 5 years ago to improve my dietary intake of healthy lipids. I decided to stop eating coconut oil last year and this year the headcold with oedema attacks have not recurred, unlike the previous 4 years.

I am still having problems with vegetables and headaches but I found reducing gluten and including apple cider vinegar in my diet seemed to help.

It is my belief that somehow MCT coconut oil was setting me up for inflammatory reactions by some effect comparable to the observed TH2 shifting in mice (TH2 stands for T-helper cell type 2, which is the pro-allergic pathway,) and increased allergen absorption at Peyer's patches and this was behind my apparently new food intolerances.

TH2 shifting is known to be a vulnerability for ME CFIDS patients. Dr Paul Cheney identifed this clinically a long time ago and a recent paper from Maddy Hornig et al corroborates this diagnosis.

Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome.
https://www.ncbi.nlm.nih.gov/pubmed/25824300
M. Hornig et al.
Our results indicate a markedly disturbed immune signature in the cerebrospinal fluid of cases that is consistent with immune activation in the central nervous system, and a shift toward an allergic or T helper type-2 pattern associated with autoimmunity.

It occurs to me at the time of writing that its not impossible that the TH2 shift which may apply in my case due to ME CFIDS exacerbated by coconut MCT  might create a situation in which I developed an allergy to a latent virus, hence the strange mix of symptoms I experienced.

Hopefully avoiding coconut will mean I can avoid oedema reactions in future. Though if it is MCTs then its not just coconut as palm oil also has a high fraction of MCTs, though palm oil's capacity for allergic sensitisation has not been specifically tested and probably ought to be. Dairy also has them but I dont eat dairy anyway due to previous problems with it exacerbating summer allergies which I put down to casein at the time but on reflection may have been the same phenomenon.

I count myself lucky the oedemas caused, apparently by infection, when eating coconut were only in my upper respiratory tracts and not in vital organs. But this is a potentially dangerous phenomenon and something I feel its my duty to bring to other peoples' attention, despite the fact my understanding of it is incomplete.

I have now recovered from those episodes but coconut is definitely off the menu.

FYI

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Saturday, January 06, 2018

Salicylate intolerance, oedema and headaches in ME CFIDS.

Another chapter in the story of food intolerance linked with the progression of my ME CFIDS has been unfolding in the last few years. I think it is important to blog this in memory of Annabel Senior and her struggle with ME related food intolerance which eventually became so severe it contributed to an early death.

She reached a point where she could not eat anything at all without adverse reactions. Her coroner's report was among the first in the UK to attribute CFS as a cause of death. The following quote is from the National CFIDS Foundation patient memorial.
Annabel Senior, aged 60, died on January 8th after 45 years of CFIDS/ME. Toward the end, she was unable to eat anything due to multiple abreactions. She lasted for nearly 53 days without food, and only gave up water toward the end, because she was too weak to swallow. Annabel was 15 when she became sick and died at age 60. The coroner’s report said, “”Death due to Chronic Fatigue Syndrome…1a. Left ventricular failure, 1b. Occlusive coronary artery atheroma.” She leaves her constant caregiver and husband, Richard. Annabel lived in Conway Valley, North Wales in the United Kingdom.

+URL to a short article entitled Did food intolerance kill Annabel Senior? FYI

Not all PWME become so severely ill in this way but food intolerance is a difficulty for some. I am hoping this is a situation which can be helped by knowledge about foods. So far I have found it best to avoid nightshade vegetables, high amine foods, MAOi foods, dairy and soya and have recently added another to the list, high salicylate foods.

It first began to manifest about five years ago when I began to get a summer cold every year, with very blocked and swollen nose qualifying as nasal polyps.

To put this in context I have had problems with my immune system in summer ever since 1986 immediately after ME CFIDS onset when I started to get chronic recurring virus  accompanied by severe allergic asthma and hayfever every June - July period and an NHS type allergy challenge test later confirmed a grass pollen allergy a decade after ME diagnosis. I had previously been tested in my youth due to chronic asthma which was found to be related to house dust mite allergy, not pollen allergy. I had grown out of the house mite allergy with the help of a lot of rowing, which was a sport which did not bring on attacks, so I was able to get fit and strong and rowed for my school and college. Somehow the allergy returned and shifted to pollen at the onset of ME in 1986 when I was aged 21-22.

As part of this ME CFIDS problem in summer I also experienced a tendency towards developing pus filled cysts and strep type bacterial infections during that summer period of raised allergy. Clearly something strange was happening to my immune system in the summer months. I say this for posterity because even today I have no idea what it is other than it fits the bill for Dr Paul Cheney's observations of ME CFIDS related TH2 shift symptoms.

To add to the summer difficulties over the last five years or so I began to experience a late summer cold every July - August. I discovered by accident that hot honey and lime was a very bad idea as a cold remedy in my case as it made my nose swell up like a balloon (the lime also made my skin feel like it was sunburned when it wasn't, but that is another story). After reading around the internet I realised that honey has a very high salicylate content and that salicylates can cause this kind of oedema reaction and after a few exploratory tests satisfied myself this was a real issue.

I also discovered that loratidine antihistamine can cause upper respiratory tract infection as a side effect. I had been taking it to help with my hayfever but suspect it may have contributed to the yearly summer cold.

Three years ago I started to get a series of headaches. I consulted my food diary and could not believe what I was seeing. I was eating lots of healthy green vegetables like broccoli and peas and lettuce and kale. To my dismay it was these very green and healthy vegetables which were causing the headaches. I soon discovered that these vegetables have high salicylate content and when I switched to low salicylate vegetables, of which there are many, the headaches reduced markedly.

So I am writing this as a simple heads up to say, salicylates can also be a problem with this condition. FYI there is a useful online website detailing salicylate levels in different foods at salicylatesensitivity.com.

[EDIT 27/5/23 I have since come to consider that this problem with green vegetables may have been due to high levels of vitamin K in green veg as VitK is involved in blood clotting. Please see subsequent blogs for updates.]

I have written this in the hope that PWME who have food intolerance might read this and benefit from my experiences learning to identify the types of food which can cause a problem.

Wednesday, May 10, 2017

No more potatos. Nightshade alkaloid intolerance and exclusion in ME CFIDS in relation to calcium, apoptosis and the mitochondrial pore.

I have heard of more than a few people with ME who suffer food intolerance and for some it can become dangerous. This is a facet of my condition too and I have to avoid dairy and soy for example as well as high amine foods, MAOi foods and other foods which I know from experience repeatedly cause symptoms.

I also now avoid nightshade vegetables; i.e. potatos, tomatoes, chili and sweet peppers, aubergines etc and get iller if I don't. Though stopping eating them was not straightforward and had unexpected consequences, so I thought I should let people know what happened and what I learned from it so that anyone else who is obliged to go down this route can be a step ahead.

I have had ME CFIDS since 1986 but my intolerance to nightshades has been getting worse since about 2010 and I excluded them from 2012 onwards.

Nightshades.

It took a while for me to realise it was nightshades. I kept biting the inside of my own mouth and getting mouth ulcers. At first I thought I was being clumsy but then realised the lining on the inside of my mouth was swelling which is why I was biting it by accident. When I took care not to bite my mouth, I still got ulcers anyway and I realised there was some kind of immune reaction involved.

I eventually decided to use the food diary I always keep now after consulting an expert in food intolerance, Prof Jonathan Brostoff who raised my awareness of food intolerance in general, after which I learned how to test for food intolerance with an elimination diet.

So I began to log ulcer incidents and correlate them with foods and after a couple of years found they were happening regularly after eating curry, potato and tomato plus other random looking incidences. I was puzzled but googled these three foods plus mouth ulcers and it spat out nightshades. Once I had familiarised myself with the other foods in this family, a lot of the seemingly random incidences suddenly made sense. So I decided to try excluding all nightshades from my diet and as a result the ulcers reduced in frequency.

It was a bit more complicated as I still got ulcers after eating olives and other foods with alkaloids in them which are not nightshades. I am still unsure about why this is. As a working hypothesis I assumed I had a general alkaloid intolerance and it was causing a hypersensitivity reaction of some kind. It may be more complicated than that, but the point is excluding the high alkaloid foods prevented ulcers and inflammation. However things then got even more complicated.

It took a couple of years for the ulcer frequency to reduce to near normal levels, partly because I was still learning which foods were a problem, but much to my relief the ulcers eventually stopped. However during that time I began to experience changes as follows.

Changes after stopping nightshades.

  • excruciating muscle pain
  • mitochondrial (ATP translocase) blood tests for white blood cells normalised
  • cell free DNA blood test improved
  • viral recurrence frequency increased
I lived with a cricked back on both sides under the shoulder blades and terrible muscle cramp pain restricting my movement for the best part of a year before I finally realised it wasn't going to fix itself and that I needed to try something new. Considering the problem was muscular I decided to try a basic sports science approach and boost mineral supplements to see if I could fix it. Thankfully super-doses of extra calcium over a few weeks did the trick and made the cramps manageable again, though I had to balance calcium with magnesium to keep my heart rhythm stable. (I later found extra sodium salt helped with muscle pain as well FYI.) At the time I had no idea why calcium fixed it or why it had become so severe in the first place though it did occur to me that being on a dairy free diet probably didn't help.

Blood tests on the mitochondrial function of my white blood cells (neutrophils) showed that it was returning to normal from a previous pathologically low state, yet I still had ME. Also my cell free DNA, which measures rate of cell death, was reducing from extremely high to just high.

Both these improvements bode well on the face of it, the only problem was I still felt lousy and still had post exertion malaise and still had regular recurring viruses which are a hallmark of my CFIDS. I recently reevaluated the rate of virus recurrence and found it had increased from 8/yr in 2006 to 13/yr ten years later in 2016. It was a perplexing pattern of observations and painful experiences that made little sense. 

It was several years after giving up nightshades that I chanced upon a research paper which seemed to offer a potential explanation. I hasten to add this paper is proper science but the connection to my own symptoms is not proven scientifically but is highly circumstantial and food for thought, to coin a phrase.
Effect of solanine on the membrane potential of mitochondria in HepG2 cells and [Ca2+]i in the cells.By Shi-Yong Gao, Qiu-Juan Wang, Yu-Bin Ji.

Solanine is the name given to one of the toxic alkaloids present in nightshades (another is chaconine which is thought to be similar in action but I only have research on solanine to draw on). The paper above showed that solanine has important toxic affects on human cells.
  • It opens the inner mitochondrial membrane permeability transition pore,
  • this depolarises the inner mitochondrial membrane,
  • releases calcium,
  • this also increases likelihood of cell death (apoptosis).

All of these affects match the changes after I stopped eating nightshades.

  • My suddenly increased muscle pain was remedied by calcium, perhaps because the calcium previously released by solanines was no longer being released, which meant I needed more calcium.
  • ATP translocase and other mitochondrial activity scores in white blood cells improved, perhaps because solanines were no longer depolarising the inner mitochondrial membrane enabling the membrane potential to drive the ATP translocator enzyme normally.
  • Cell free DNA tests improved, perhaps because cells were not being killed by apoptosis induced by solanines opening the inner mitochondrial membrane pore and so were no longer releasing so much of their DNA into my blood.
  • Viral recurrence due to my ME CFIDS condition got worse and increased in frequency, perhaps because infected cells were not dying as easily due to the lower rate of apoptosis as above.
In addition I have read that nightshades contain an active form of vitamin D called calcitriol which may have been raising my internal calcium levels by taking it from my bones, which isn't so good and makes you wonder about cases of severe ME where people get osteoporosis.

Questions?

It raises questions, such as why solanines would be toxic to me but not other people. The truth is they are toxic to everyone but most people can deal with them. I don't have a clear answer about my own difficulty but my guess is my body is not eliminating them effectively for some reason. I am now exquisitely sensitive to even tiny quantities of nightshade and they make me far iller than when I was eating them regularly and habituated to them having eaten them all my life.

Another question is why my ME didn't get better when the mitochondrial activity of white blood cells improved. I don't know but recent research suggests there are other metabolic bottlenecks in ME and it may be that just because one metabolic bottleneck due to nightshade toxin improved, did not mean the other bottlenecks or adverse reactions due to ME CFIDS were improved, so these would still cause a fatigue syndrome. Plus my immune dysfunction definitely got worse as the nightshades were no longer helping my white cells out by inducing apoptosis of infected cells. So swings and roundabouts.

My conclusion is that my intolerance of nightshades is a secondary illness brought about by primary ME CFIDS reducing my digestive and other defences. I talked it over with a friendly sceptic who suggested I should check whether the dosage from eating these foods is comparable with the doses in the research paper, before jumping to any conclusions.

Quantitative Analysis.

So I looked for quantitative data for a back of envelope type calculation and found the following report online of an investigation for the Bureau of Chemical Safety of Health and Welfare Canada, presumably sometime before 1993 and sometime after the latest 1990 reference used in the report.
SOLANINE AND CHACONINE Dr T. Kuiper-Goodman and Dr P.S. Nawrot, Bureau of Chemical Safety, Health and Welfare Canada, Ottawa, Ontario, Canada.

I was interested to note that potato flesh does contain significant amounts of solanine. So I made a back of an envelope calculation, as below, using empirical experimental data for quantity, absorption and excretion half-life from human and animal experiments summarised in Kuiper-Goodman, to get a rough idea.

Unless I messed up the maths or missed something important (not impossible considering how befuddled I get sometimes) the figures suggest normal portions of nightshades could provide enough solanines to create concentrations in some human tissues comparable to the Shi-Yong Gao paper, sufficient to have an effect on mitochondrial membrane potential, calcium release and apoptosis rates.


Calculation of approximate magnitude of solanine concentrations in the body from consuming potato.
Using an upper bound figure of 5mg / 100g for potato flesh TGA (total glycoalkaloid) from the Kuiper-Goodman article (table 1), then each 100g serving of potato flesh adds a putative maximum of 5mg which works out at 5,000 µg per 70,000* mL i.e. potentially up to 0.0714 µg/mL, if it is all absorbed, which it isn’t but this is addressed below. This compares to the Shi-Yong Gao paper value of 0.016 µg/mL to produce depolarisation of the inner mitochondrial membrane. *(Assuming about 70L human body volume.) 
The experiments summarised in Kuiper-Goodman (para 2.1.1.2) show figures for rats absorbing 10-22% of total dose with 90-78% excreted within 24 hours in faeces and urine.
Human experiments (para 2.1.1.4) indicate tritiated I.V. solanine is rapidly removed from blood plasma and sequestered in blood cells then transferred to major organs, suggesting measured low levels in blood serum during dietary experiments are misleading.
Excretion had a measured half life of 34-68 days, on which basis 1mg per day regular absorption was calculated to give a 50mg load i.e. 50x the daily dose but this experiment does not take into account biotransformation of the tritiated molecules and the real value for glykoalkaloid load ratio is certainly less than 50x.
So if we guess using the lowest value of 10% absorption for solanine 5mg/100g dose food i.e. absorbtion of 0.5mg/100g; it should result in a single dose of 0.0071 µg/mL for a 70 L adult (a tenth of the dose content) and a putative maximum loading up to 50x i.e. very approx 0.3571 µg/mL. The real load is certainly lower due to biotransformation but since the tritium evidence suggests solanines are rapidly concentrated in erythrocytes and then major organs (leukocytes not mentioned), local concentrations may nevertheless rise considerably higher than the estimate for a whole human body volume, due to sequestration.
The Shi-Yong Gao et all study used treatments with 2, 0.4, 0.08, 0.016 and 0.0032 µg/mL and reported significant lowering of mitochondrial membrane potential (P<0.01) at levels of 0.016 µg/mL and above (p 3363). So the putative average concentration from a single dose of 100g potato is 0.0071 µg/mL, just under half the Shi-Yong Gao lower bound for a single dose. It seems feasible that sequestration could take the local concentration significantly higher in some tissues (eg definitely erythrocytes, liver, kidneys and spleen but I saw no info on neutrophils,) for a single dose and that loading could increase this to values potentially exceeding an order of magnitude higher than the Shi-Yong Gao lower bound. Suggesting a range of TGA concentrations which could account for low function mitochondria and also a raised rates of apoptosis in some tissues.
In the real world the case is strengthened by the reality that portion sizes were often considerably larger than 100g eg a 150g bag of kettle chips or a bag of chips from a fish and chip shop or large baked potato. Also Kettle chips and baked potato can include potato skin which has a much higher value for TGA. A greater sensitivity to processed foods containing potato than to potato flesh could likewise be explained by the likelihood that processed potato probably has higher levels of TGA per dose than the potato flesh value of 5mg/100g because in the food industry solanine levels are apparently considered safe at 20mg/100g ie four times higher, so processed mass produced food is able to reach these levels when skin and green potato (TGA up to 11x more at 220mg/100g) can be accidentally incorporated in bleached potato flour for example or a delay between peeling and processing can raise TGA due to time sensitive injury response in the tuber, especially if TGA is regulated per product mass rather than the incorporated potato mass which could explain my sensitivity to apparently small quantities of potato. So a “safe” 20mg dose of TGA would give 0.0286 µg/mL, exceeding the lower bound of the Gao study even without considering sequestration and half life / load.
PS Allegedly similar values for aubergines and sweet peppers btw. http://www.safespectrum.com/articles/potato-toxicity-solanine.php
Soil degradation of glycoalkaloids takes 21- 42 days. https://www.ncbi.nlm.nih.gov/pubmed/19290452


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Monday, May 05, 2014

Why viruses, immunoevasins and mixed Infections may make ME CFS too complex and variable to be easily understood.

I have always believed viruses are important contributors to ME CFS because of my own experiences but to be honest research has not been going smoothly, there have been a couple of high profile disappointments lately but also some good news on the horizon.

In the UK affymetrix studies seeking patterns of gene activation in ME CFS ran into a problem. While discovering real differences between ME CFS patients and normals they also showed that no consistent pattern could be found. The variability between patients seems to have been too great for the small sample size of about 50 patients. But in science a negative result is still a result and people have learned from this. Professor Stephen Holgate since suggested there may be as many as 15 different subtypes of ME CFS. Personally, for reasons set out below, I think that may be a conservative estimate.

The attempt to find a single causal virus was on the face of it set back with the discovery that XMRV was not reliably detected in association with ME CFS, carefully disproved by Professor Ian Lipkin using a double blind experimental protocol. Fortunately Professor Lipkin and colleague Mady Hornig have taken over the reins and are undertaking some very ambitious studies in the USA which have learned from the difficulties with small sample sizes and look very promising with expanded studies in planning. FYI They need and deserve our financial support.


Immunoevasins.

Other fields of virology have also been progressing. Over the last two decades an intriguing picture of how viruses evade human immunity has begun to emerge. As a humble zoology grad I have tried to keep up with aspects of this research which may be relevant to my own condition and I relate discoveries here which are of particular interest to me in the attempt to understand my own illness in the hope that they may be of interest to others.

One of the commonest of the viruses studied is Epstein Barr Virus, EBV for short, which can cause glandular fever aka mononucleosis when contracted in adolescence or later in life and is present in 95% of the population. EBV is a herpes virus which effects different people differently and has frequently been implicated in cases of ME CFS and is known for its ability to persist in and disrupt the immune system causing severe illness in a small number of people (see Dr Lerner on herpes virus induced CFS). It used to be thought that ME CFS was often caused by chronic EBV, but the discovery of ME CFS cases where EBV was apparently not present cast doubt on that interpretation.

There may be more to EBV than meets the eye however since recent evidence (discussed a bit here and in more detail at Simmaron Research) suggests that some ME CFS patients have a compromised immune response to EBV. Somehow their immune cells forget how to mount an immune response to EBV leading to higher rates of latent EBV replication and lowered ability to deal with EBV reactivation. So by some measures (i.e. assessing the immune response to EBV as a way to decide if EBV is present,) it can appear that EBV is not present, when really it is!

In any case, logic suggests that even if some cases of ME CFS are not caused by EBV this does not mean that no cases are caused by it, as one cannot rule out the possibility that EBV causes a proportion of ME CFS and other viruses cause a proportion of other cases. Since XMRV has been disproved, it is easier to say that assuming one singular pathogen is responsible for ME may be a mistake. This may seem a bit vague so one reason for discussing immunoevasins here is to look at why this is a very real possibility.

In the intervening period since ME CFS research turned away from chronic EBV, research of EBV which is also implicated in cancer and autoimmune disease has uncovered how EBV can evade the human immune system by making products which jam our defences. These products are called immunoevasins and we are still learning how they work. We have also learned that other viruses can likewise make comparable immunoevasins which attack the same weaknesses in the human immune system. Below are discussions of two examples, EBV's viral version of interleukin-10 and EBV's BNLF2a gene, an antigen processing blocker.

To be clear, the suggestion I am making is that ME CFS cases could look similar because they have one thing in common, us, human beings. ME CFS patients are all human and we have the same weak points in our immune system. Viruses would naturally evolve to exploit these weak points and where they succeed, different species of virus could cause similar types of problems in the immune system of their host. This is a different way of looking at ME CFS from the search for one causal virus such as XMRV and after the results of XMRV tests and the CFS Research Foundation's analysis of Dr J Kerr's results, it needs to be considered.

I must stress at this point, proof conclusively linking or debunking the action of immunoevasins in relation to ME CFS symptoms has not been acquired, this blog is speculation. However the known effects of some of these immunoevasins bear comparison with ME CFS symptoms. Thus far, the more we learn the more credible the scenario is becoming not only that a virus like EBV could cause the primary immunological symptoms of ME CFS but that other viruses and possibly biotic bugs can too, by attacking the same weaknesses in human immunity.


Viral Interleukin-10.

One of EBV's immunoevasins, a secret weapon which has been known about for over two decades now, is a molecule which mimics a human immune messenger molecule called interleukin-10 or IL-10 for short. Viral versions are known as viral interleukin-10 or vIL-10.

After much careful research we now know EBV's version of vIL-10 can effect the human immune system and release cytokines which encourage allergic and autoimmune reactions as well as reduce antiviral activity (as linked above). This matches the TH2 shift observed by Dr Paul Cheney in his ME CFS / CFIDS patients, which people commonly report as part of their ME and which has experimental corroboration. Dr Cheney has specifically discussed the way in which pathogens mimic IL-10 as a possible cause of TH2 shift in ME CFS patients.

The main effect of EBV's vIL-10 is to change the activity of defensive white blood cells making it easier for EBV to survive. EBV predominantly survives as a persistant infection inside white B cells which by means of other immunoevasins it activates and transforms prematurely into long lived memory B cells inside which it can persist, though it does infect other cell types. This is interesting because these are the very same B cells which are wiped out by rituximab treatment which we know helped some ME patients in Norway.

On the other hand vIL-10 makes NK (natural killer) cells less active. NK cells are an important immune defence against many pathogens and they have been shown to be less active than normal in some CFS studies (eg Brenu). vIL-10 also decreases the activity of CD4+ T helper cells which normally produce cytokines which activate NK cells.

If EBV reactivates and infects new cells it produces more immunoevasins including vIL-10, which must pass into the intercellular medium to have its effect and in so doing can spread around the whole body causing system wide changes. EBV is using vIL-10 to prevent NK cells from destroying the cells it has infected. By doing this it also makes its human host more vulnerable to other bugs which NK cells would otherwise kill.

This is a wide range of bugs including yeasts and biotic infections because NK cells are thought to be essentially innate killers, not specifically attacking a particular type of antigen like B cells or T cells, they simply eat anything which is not showing "self" antigens. So NK activity is stopped by a self antigen not started by a bug antigen. Not surprisingly the immune system has a failsafe to regulate NK cell activity to stop it accidentally eating its owner's body and that failsafe is IL-10. vIL-10 can do many of the same things as IL-10 and as a result NK cell suppression occurs with every reactivation episode of EBV. Each cycle the host immune system would be laid low for a while as is often reported in cases of ME and yet different aspects of the immune system like B cell transformation can be stimulated by the very same virus. I can only speculate at this stage that where EBV reactivation was continual, NK deactivation probably would be too. Alternatively both could vary in intensity over time through periodic bouts, which matches the experiences of some patients.

Speculatively speaking this fits some aspects of the altered immune response in ME CFS I have experienced which has been corroborrated anecdotally by many other people; i.e. a poor response to some biotic infections at certain times, vulnerability to virus infections and an altered inflammatory response to them, also raised allergies and tendency to rheumatic joint pain, which could all be explained by the effects of vIL-10.


TAP inhibitors: how EBV's gene "BNLF2a" silences infected cells.

Another more recently understood secret weapon of EBV is made by a gene called BNLF2a. Once inside the cell, one of the first things EBV does, as well as making vIL-10, is making the product of the BNLF2a gene which stops the cell being disposed of by white cells. These particular white cells for the record are CD8+ killer T cells which, unlike NK cells, can target specific bug antigens presented on the outside of cells and select infected cells for demolition.

To do this EBV exploits an Achilles heel of the immune system which is that an infected cell must alert white T cells waiting outside to consume infected cells. It may seem a bit burocratic, but unless the infected cell reports properly the white T cells cannot sense what is going on inside the infected cell because the cell membrane gets in the way. The infected cell makes its report by moving virus antigens inside the cell through the membrane to the outside, to act as flags, using a special "transporter associated with antigen processing" or "TAP" for short. EBV's secret weapon, the BNLF2a gene, "turns off" TAP and prevents flags from being raised, so the CD8+ killer T cells outside cannot tell anything is wrong.

Its like a baddie in a movie kidnapping someone and tying a gag over their mouth so they cannot cry out, in this way the EBV can hold a cell hostage and live inside it for a long time, occasionally reactivating to provoke another "bad patch" and infect more cells and other people. This allows these viruses to maintain an infection in a host for longer and thereby spread themselves to others. This is probably why NK cells continue to be useful in the immune sytem's evolutionary arms race with pathogens, as a failsafe, since a cell which does not have functioning TAP will also not present the self flags which appease NK cells, so NK cells should eat them once their existing self flags are recycled. But this failsafe relies on active NK cells and as already mentioned EBV does its best to deactivate NK cells with vIL-10.


Viral Evolution.

So EBV inflicts a double whammy on the immune system, disabling key defences both inside and outside cells, which is probably why it is such a common virus. Luckily for us a virus as successful as that evolves over time by natural selection to become less fatal, simply because if it kills its host it dies too and cannot spread. That doesn't stop it making the host very unwell, but it might explain why a host with ME CFS could be so unwell for so long and yet not die. Viruses would evolve to do exactly that.

Again EBV is not the only virus which can turn off TAP. For example the common herpes simplex viruses HSV I & II make ICP47 (1 & 2) both block TAP inside the cell. Cowpox virus CPXV12 blocks TAP, so does US6 from human cytomegalovirus, so does UL49.5 from varicellovirus. All of these viruses can disable TAP, yet the less closely related species of virus evolved convergently to do it in different ways suggesting that disabling TAP is highly advantageous to viruses and implying that TAP is both a central mechanism in anti-viral defence and because of this also an Achilles heel, a key weakness in our immune defence like IL-10, only inside cells instead of outside them.

It takes little imagination to conceive that the combination of vIL-10 and TAP inhibitors could be very disruptive to the effective clearance of infections by the human immune system resulting in the kind of ongoing low level infection which could cause chronic immune activation which is typical in ME CFS cases.

Personally I think this really is relevant because of my own experience with ME CFS, which began some time after a severe adolescent EBV infection and yet involved other recurrent viruses which were not EBV itself.


Are Immunoevasins the answer?

Its too early to say. If we learned anything from XMRV surely it was to be cautious about this kind of complex biochemistry and raising hopes without quadruple checking the evidence. Experiments are needed to prove or disprove any hypothesis. Yet the discovery of these immunoevasins has the potential to explain many perplexing yet common ME CFS (CFIDS type) symptoms in one go, so they need to be looked at and understood better.

However its worth pointing out that if we hypothesise immunoevasins may play a part and accept the apparent absence of EBV in some cases of ME CFS might be misleading, looking for one single virus to blame for all ME CFS would still be a mistake. The reality emerging from immunoevasin research is that EBV is not alone in using viral Interleukin-10 or TAP inhibitors to trick the immune system.

Cytomegalovirus for example also produces a viral version of Interleukin-10 (as does Orf Poxvirus which humans can catch from sheep and so does equine herpes virus type 2 "EHV-2" for short, see paragraph 3 of the introduction). They are probably not alone because IL-10 represents a weak point in human immune defences as it deactivates key immune responses. CMV also produces a TAP inhibitor and is not alone, (as linked above see fig5 p578).

It makes sense that any viruses which acquired a copy of the IL-10 gene or of a viral forgery would tend to survive and remain with us. In evolutionary terms the selection pressure favouring the use of vIL-10 is very great. This might also apply to some biotic infections which could also benefit from making counterfeit IL-10 because of the way it reduces NK cell activity. Likewise any virus which can disable TAP has an advantage and will persist better than one which cannot. This implies there may be more viruses using these tricks and that a range of different infections could impact our immune systems in similar ways ie deactivating NK cells, activating allergies, promoting autoimmune disease with persistent relapsing remitting intracellular infection causing periodic or chronic immune activation. In a nutshell, ME CFS.

Experts like Dr Jonathan Kerr and Prof Stephen Holgate have stated that there are probably many subtypes of ME based in part on empirical evidence from affymetrix studies as well as clinical experience. Certainly there is a lot of variation between different cases which I discuss in more detail in a section below but this makes it all the more plausible that vIL-10 producing pathogens may account for some ME CFS subtypes.


Speculation on Mixed Infections.

Immunoevasins are significant for mixed infections because they explain how two or more viruses might interact with each other inside their host, raising the possibility that more than one kind of virus is involved in individual cases of ME CFS through unfortunate combinations. (Something I have tried hard to understand because of my own case history involving mixed infection with recurrent viruses.)

One study on both EBV and CMV provides an example of how viruses can interact with each other, showing that where elderly people have both EBV and CMV they are more likely to experience inflammatory disease  from their EBV infection if CMV is present. This suggests EBV and CMV interact within the patients' bodies making the combination more harmful than either one on its own. The same may be true of interactions between other viruses.

At this point, what we know raises more questions than it answers. A finger of suspicion points at EBV because of the way that it can make itself at home in B cells and turn their activity to suit itself using immunoevasins.

But 95% of the population has EBV and they dont all get ME CFS. We know that if you get it young it barely causes a snuffle, but in your teens it can put you in bed for months because you are better able to fight EBV the younger you are. It also varies for individuals, some people are not badly affected by it, others are. Broadly speaking the fact that EBV does affect people so differently makes it more plausible that it could be behind some cases of ME CFS.

We also know CMV's immunoevasins grant it some abilities similar to EBV's, enabling it to disable the immune system and become a persistant infection. Again it is a common virus and not everyone with it has ME CFS but these are two viruses we know more about than many others so are good examples to discuss, even though we are left wondering what else is going on and how many more can do likewise.

The possibility worth exploring is that where one virus like EBV or CMV can disable the NK response, other viruses which can't do this themselves can take advantage of that to infect cells elsewhere in the body in different tissues, to which they are specifically adapted.

This alone could make mixed infection more severe than you would expect judging by the sum of the affects of individual viruses. One reason for this is that viruses adapt to their host and a successful virus does not kill its host as this reduces the time they have to spread themselves. Viruses tend to evolve to balance their "aggression" to be sufficient to survive and spread and no more. It is only when viruses switch hosts that they tend to become lethal plagues until the virus evolves and its lethal affects attenuate.

However where a virus is disabling an aspect of a host's immune system not targeted by a second virus which is sufficiently aggressive to survive in a healthy person, the second virus may prove overly aggressive for an immune system already compromised by the activity of another virus. So a combination of viruses may cause greater debility than one virus on its own.

Evolutionarily speaking this could happen and keep on happening where mixed infections of a particular combination which is unfortunate for the host are relatively rare events compared to the total number of infections by those viruses in the whole population. This is because a virus will primarily evolve to suit the most common infection scenario, since that is the way it will normally spread.

What we may be seeing with the rising incidence of ME CFS like illness is a reflection of the increased chance of getting an unfortunate mixed infection in the modern world. This could be due to increase in travel, especially air travel as well as the total size of the human population of the world.

A further discussion, which is speculation at this point, is that where secondary viruses can disable TAP, the compromised cells may become a refuge for any viruses which can infect them including vIL-10 producing viruses. This might allow this kind of illness to become not only persistant but progressive, acting like a ratchet of infection, claiming more and more host cells for the viruses to live in as the infection continues. This deserves consideration with respect to more severe ME CFS cases.

I believe this line of thought could be significant for understanding ME CFS because of my own experience with at least two viral infections which I believe interacted with each other resulting in ME CFS with recurrent viruses.

There are other alternative hypotheses. For now they are all just hypotheses. There could still be one virus like the one we hoped XMRV would be, but then you have to explain the wide variation in gene activity seen in the London affymetrix studies. The cause of ME CFS might even be a new kind of disease, like prion disease, which we simply haven't encountered before. We still can't rule these out but for now the interaction of viruses using immunoevasins is a sufficient hypothesis, employing facts we do know and the best I can currently find, to explain what happened to me, though it remains to be seen if this is the real cause for the millions of people who are afflicted around the world.


Speculation on Variability in ME CFS.

The variation among ME CFS patients presents a puzzle which mixed infections and their immunoevasins might explain, but for now we don't know for sure what proportion of variation this would account for.

vIL-10 suppresses NK cells, stimulates B cells and has the potential to encourage autoimmune illness which could cause even more clinical variation in symptoms between different patients, even when caused by the same infection, because antigen specific immune reactions are by their very nature a dice throw and so if they happen to cause autoimmune disease can affect any part of the living body due to the way the immune system creates random antibodies in its search for a way to destroy invaders.

There is a theory that EBV in particular contributes to autoimmune disease by making autoimmune cell lines of B cells, which should die off, into long lived memory B cells. These normally act as parent cells to clones of cells intended to fight specific pathogens. Where the B cell is accidentally attacking the body it is normally disposed of, but if infected by EBV they can be incorrectly confirmed as a bonafide defender leading to the production of a clone army of B cells causing autoimmune disease in whatever tissue they happen to be specific to, which is completely random. This might contribute to autoimmune reactions in some ME CFS patients, as the Norwegian rituximab trials suggest it does.

This implies there may be at least two sources of variability involved in ME. Firstly a large number of different virus combinations, secondly the random chance of autoimmune reactions. This is without considering the genetic variability of individuals, which constitutes a third kind of variability which could alter the course of the disease.

Timing is also known to make a difference to the course of viral infections. As previously mentioned, EBV for example is often much more severe when contracted by a teenager than by a baby. When an individual contracts viruses, relative to life history and events like contracting other viruses, may make all the difference in how mixed infections play out for different individuals.

Besides this the disease itself is known to change over time both in the long term and for some people in the short term creating cycles of fluctuating illness. So the assessment of patients and their biochemistry can show variability for that reason as well, making it all the more difficult for clinicians and experimenters to spot patterns and join the dots.


Solving the Riddle.

The implication of viruses evolving strategies which converge on weak points in the human immune system and the possibility of mixed infection in ME CFS is that epidemiologists studying outbreaks may be looking at intricate complexity, not necessarily a simple disease caused by a single infection. For example when looking at an ME outbreak they may be looking at the intersection between epidemics of two or more different viruses, each seeming relatively innocuous on its own, in the context of individual differences in susceptibility caused by genetics and timing.

It is possible to conceive that we are in a situation where variability means that two patients with exactly the same condition might provide different biochemical results at any given moment in time despite having comparable clinical histories. This would imply that in order to understand ME CFS, which we don't, we need to discern relevant patterns of biomarkers for the disease over time as well as between different subtypes. It may be one of those situations where small efficient studies really won't get the relevant information and bigger really is going to be better.

Noone does bigger better than the USA and Prof Lipkin and colleague Mady Hornig are already embarked on this process (as linked above).

This will hopefully lay the groundwork for identifying and characterising immunoevasins and the way they affect our human immune systems and in my opinion this will eventually lead to an understanding of ME CFS.

If there is anyone who can make headway in this field of study it is Ian Lipkin (wiki) the professor who proved that XMRV was not the answer to ME CFS. He and his expert team have a good reputation for using effective biochemical analytical tools, using careful experimental protocols, to identify viruses involved in epidemics.

He is already working on identifying viruses in white blood cells in ME CFS, which is good news to say the least and has suggested a worthwhile next step on the journey to understanding ME CFS, along with many other human diseases, would be to map the molecular fingerprints of the human microbiome, all the microscopic symbionts and pathogens which live within us, which we know very little about.

He has made a heartfelt plea for ME CFS patients to support this ambitious project to sequence the entire microbiome in order to lay the foundation for future research.

Its a big project and needs at least a million dollars to get it started. By crowdfunding standards this is very achievable, if 100,000 people gave $10 each that would do it! Once completed it would put him and the rest of the scientific community in a better position to detect immunoevasins and other patterns of activity in pathogens linked to disease of all kinds.

Considering the realpolitik of ME research, supporting this project would also make a visible statement, that the ME CFS community are self-empowered, are serious about finding out the truth and want to help those who want to help us. By funding this work we can not only advertise our cause but we can ensure that this knowledge is applied as quickly as possible to understanding ME CFS. Besides enlightened self interest this work will benefit all humanity and noble as that is, it also lays down a marker in an important conversation about enlightened mutual interest and why the disabled and impoverished ME CFS patient community has been left to fend for itself when a percentage of all healthy people in the developed world will be joining our number every year until the cures are found.

It is an historic opportunity for the ME CFS community to contribute to their own future and the future of humanity. Like the sequencing of the human genome, it is a great undertaking which will help spur advances in technical know how and understanding benefiting medical research across the board and far into the future.

If we are remembered for nothing else, completing this project would be something to be proud of.

To quote Eleanor Roosevelt, "it is better to light a candle than to curse the dark." Lets beat this thing together, it has got to be worth $10.

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