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Immune Study Adds to Evidence Of Body-Wide Problems With Energy Production in Chronic Fatigue Syndrome (ME/CFS)

Increased expression of CD24 …could thus reflect abnormalities in maintaining appropriate ATP generation (in ME/CFS). The authors

Numerous studies suggest problems with energy production exist in chronic fatigue syndrome (ME/CFS). The huge energy needs exertion places on the muscles and brain suggest they’re an obvious place for energy production problems to show up. Ramping up to fight off pathogens also places extreme demands on energy production in immune cells. Now comes a study which suggests that energy production problems in a subset of B-cells could be setting people with ME/CFS up for problems with inflammation and autoimmunity.

B-cells and ME/CFS

The first couple of successful Rituximab trials brought renewed interest in the immune cells most effected by the drug – the B-cells. The last, large Rituximab trial unfortunately failed – the drug does not work in ME/CFS – but the Rituximab effort succeeded in other ways.

First off, it brought two creative and dedicated researchers, Oystein Fluge and Olav Mella to the field and energized ME/CFS research in Norway.

B-cell

A B-cell producing antibodies to fight pathogens

Secondly, the B-cells – which play a huge role in immunity (and autoimmunity) – finally got some study in ME/CFS.  Keeping with ME/CFS’s time-honored tradition of falling between the cracks in medicine, several studies found no indication of altered levels of “classical B-cell markers”.

Something unusual did, however, pop up, in an extended analysis, which went well beyond the classical markers usually explored. In 2015 a study found that a molecule called CD24 was highly expressed in a group of B-cells.

CD24 is an adhesion molecule which turns on various signaling networks – it basically tells cells what to do. It is most highly expressed on early stage or transitional B-cells as they emerge from the bone marrow.

During the normal transition from immature to mature metabolically active B-cells, early B-cells are tested again and again for evidence that they may be turning into autoantibody producing cells and many are removed.  Over time, as these cells transform themselves into mature B-cells, the CD24 molecule gradually disappears from their surfaces. High levels of these molecules in people with ME/CFS suggested that a problem with B-cell maturation might be present.

Since antibody producing B-cells play a major role in fighting off infections, having a bunch of immature B-cells hanging around the immune systems of ME/CFS patients could constitute a problem.

Plus there’s evidence that the CD24 molecule plays a role in several diseases.  CD24 polymorphisms (genetic variants of CD24) have been associated with increased risk for and accelerated progression of autoimmune diseases including multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematous. CD24 can also be over‐expressed in many cancers, including B cell lymphomas.

In short, it’s not a molecule you want to ignore.

Energy Production Problems in the Immune System

Front Immunol. 2018 Oct 22;9:2421. doi: 10.3389/fimmu.2018.02421. eCollection 2018. CD24 Expression and B Cell Maturation Shows a Novel Link With Energy Metabolism: Potential Implications for Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Mensah FFK1, Armstrong CW2, Reddy V1, Bansal AS3, Berkovitz S4, Leandro MJ1, Cambridge G1.

In a 2018 study, a UK and Australian group took B-cells from ME/CFS patients and healthy controls, stimulated them and then monitored what happened.  As before, they found an increased frequency of CD24+ B-cells in ME/CFS patients.

What made the increased frequency of these naïve CD24 packed B cells in ME/CFS so interesting, though, was their mode of energy production.

Examining the metabolism of the ME/CFS patients’ cells, the researchers found a “strong(ly) positive” association between the amount of glycolysis and lactate produced and the expression of CD24 molecules on ME/CFS patients’ B-cells. Put another way, the more glycolysis was used to produce energy and the greater the lactate production (a by-product of glycolysis) – the more the CD24 molecule showed up on ME/CFS patient’s B-cells.

energy production me-CFS

Findings suggesting that a body-wide problem with energy production are present in ME/CFS are piling up.

Lower levels of mitochondria in these cells suggested one reason ME/CFS patients’ B-cells may be stuck in this mode.  Not surprisingly, the authors found this more prominent B-cell subset in ME/CFS was also largely unresponsive to stimulation.

That suggested that not only do the energy problems in ME/CFS extend to the immune cells but that they could be impacting immune functioning – in this case by keeping ME/CFS B-cells in a naïve state – that may be associated with disease.

Plus increased levels of the CD24 molecule have also been associated with a damaging state called “senescence”.  Instead of undergoing a process called autophagy during which a cell’s contents are safely recycled, during senescence – which is often associated with aging –  damaged mitochondria cause cells to slowly deteriorate while producing scads of pro-inflammatory factors.

An exercise physiologist, Graham Salmun, recently reported that his exercise study results suggest senescence is indeed occurring in ME/CFS.  He believes problems with aerobic energy production are a) impairing ME/CFS patients ability to produce energy and b) creating a senescent state that is causing chronic inflammation.

Anaerobic Thresholds, Fatty Acid Problems and Autophagy: Dr. Klimas’s Exercise Study

Conclusion

This study provided an intriguing metabolic snapshot of the immune system. The fact that increased expression of the CD24 molecule has been associated with autoimmune disorders and cancer makes the CD24 finding in ME/CFS interesting, but the metabolic connection the researchers found may be more important.

Their findings suggest that the same problems producing energy found elsewhere in ME/CFS may also be occurring in their immune cells.  Plus the findings suggest that a state of senescence, chronic inflammation and cellular unresponsiveness may be present as well. The possible penalties of having an immune system with a broken aerobic energy production system could go beyond fatigue and pain and extend to problems with autoimmunity, and perhaps in rare cases, cancer.

Studies finding an increased reliance on anaerobically produced energy in the muscles, the brain, in neutrophils and now in some of the B-cells all suggest that a body-wide disruption in energy production may be present in ME/CFS.

 

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30 Comments

  • Learner1

    November 29, 2018 at 5:40 pm - Reply

    Interesting. Is there a way of testing for this now?

    And any ideas what a treatment might be? I get IVIG and am in the queue to do Rituximab, but this sounds like a different direction. I’d sure like to know sooner, rather than later…

    • Katherine Autry

      November 29, 2018 at 6:17 pm - Reply

      I would LOVE to know how you got IVIG. Based on what diagnosis? Did your insurance cover it?

      Thanks.

  • Hopbine

    November 29, 2018 at 6:24 pm - Reply

    Cort, how does this mesh with ‘Tracing Chronic Fatigue Syndrome to mtDNA: Hypometabolism due to Mitochondrial Dysfunction is Key to ME/CFS’ by B Day on Amazon?

    • Cort Johnson

      December 1, 2018 at 7:47 pm - Reply

      How interesting! I had never seen that before.

      • Hopbine

        December 2, 2018 at 11:33 pm - Reply

        I think you can find the author on s4me and PR.

  • Francis Martin

    November 29, 2018 at 7:35 pm - Reply

    I’d be a bit wary of IVIG since we don’t know what causes ME/CFS. E.g.here’s an extract from Ron Davis paper on red blood cell deformability (published this week) in ME/CFS:
    “(ME/CFS) is arguably the last major disease we know almost nothing about. It is a multi-systemic illness of unknown etiology” [https://www.omf.ngo/2018/11/28/omf-funded-rbc-deformability-study/].

    On the other hand if you do it then OMF, plus those on this forum, may wish to know whether it works etc.

    All the best.

  • Maschelle

    November 29, 2018 at 9:19 pm - Reply

    I am one of those with body-wide muscle pain. Connective tissue and my skin are included. I understand that not all ME/CFS patients have chronic, severe (downright debilitating) pain? I’m curious about the lactic acid connection mentioned in your article. Could production of lactic acid in these cells have something to do with it?
    I also have a life-long dislike of sweets. The only exception being sugar in my coffee. But the entire time I’ve had ME/CFS I’ve had a ravenous appetite for sweets. It’s insane. And, of course, it is causing weight gain. Could the findings of the study explain that as well?
    Very well written and concise article! Thank you for keeping us in the loop, and doing it in a way that I, at least, can understand.

    • Cort Johnson

      December 1, 2018 at 7:46 pm - Reply

      Interesting how that can flip! When I over do it I have a craving for sweets as well. I would not be surprised at all if lactic acid was producing a lot of pain in some people – me among them…

  • Wayne

    November 29, 2018 at 9:30 pm - Reply

    This is exactly what is going on with me at the moment. 20% of my B cells are abnormal and it looks as though I am developing Lymphoma. From my own experimentation, I have found that supplementing with Citrulline Malate can make the metabolism operate more aerobically with less lactic acid & less ammonia production. I note with interest that Fluge & Olav have already patented a blend of Citrulline Malate & Arginine, however my own research leads me to believe that just plain C.M. is better. I have an appointment booked to see an Immunologist in 2019, so will try and get my CD24 levels checked then. Comments?

    • debsw

      November 30, 2018 at 4:46 am - Reply

      This is very interesting Wayne. I also recall Fluge & Mella patenting this treatment after a patient suffering from transient ischemic heart pain experienced relief of her ME/CFS symptoms after taking isoborbide mononitrate (a blood vessel dilator). I hope that nitric oxide is researched more in the future given the fundamental role it plays in autonomic control as a vasodilator.

      I’m not sure if I would want to experiment with Citrulline supplements if I had low blood pressure because it might make it worse, but maybe it is helpful for anyone who has normal or high blood pressure? As well as ME/CFS, I have asthma, which is characterized by narrowing of the airways. I have never experienced any controversy or sceptism about this diagnosis (unlike ME/CFS) but I’m not sure that medicine understands the intricacies of this incredibly common illness a whole lot better than ME/CFS.

      In some respects, I find the two illnesses have similar triggers and both can manifest in acute or chronic attacks, although ME/CFS is so, so much more debilitating for me, especially given I can take steroids to help control the asthma.

      Interestingly, on the occasions that I have needed to take prednisone (a glucocorticoid) it has also helped my ME/CFS. I couldn’t possibly guess at the cause(s) of this illness but it isn’t beyond the realms of possibility that for some of us our blood vessels constrict in response to exertion, pathogens and allergens, no different to asthma, thereby impairing oxygen delivery to the cells and creating significant oxidative stress. Just a possibility. I wish you all the best with your health.

    • dejurgen

      December 1, 2018 at 6:41 pm - Reply

      After debsw’s reply I took another look into Citrulline Malate. I combined it with a few search terms.
      It appears it’s the Arginine is the thing boosting NOx levels, good for more dilated blood vessels. Citruline has better food uptake and is converted into Arginine making it more effective then taking Arginine as a supplement I read. I recently learned that Glutathione helps the functioning of NO by binding, preserving and or activating it. So I looked up “Citrunline Malate Glutathione” and got this: https://jissn.biomedcentral.com/articles/10.1186/s12970-015-0086-7
      Adding a bit of glutathione to L-Citruline supplements did improve the increase of NO significantly “However, nitrite and NOx for L-citrulline + GSH were significantly greater at 30 min post-exercise”
      => As NO is easy killed by oxidative stress that also seems to indicate it might somehow reduce oxidative stress after exercise. Unfortunately we run low on Glutathione.

      According to en.wikipedia.org/wiki/Cyclic_guanosine_monophosphate
      “soluble GC (sGC) is typically activated by nitric oxide to stimulate cGMP synthesis”
      “cGMP is a common regulator of ion channel conductance, glycogenolysis, and… …lead to vasodilation”
      => So increased NO not only imporves vacsolidation but also improves glycogenolysis (breaking down glycogen to glucosis) and regulates ion channel conductance; Issie believes Ca ion channels are dysfunctional in FM (and ME?)

      Now I searched for “Citruline Malate NADPH” and found that en.wikipedia.org/wiki/Malate_dehydrogenase_(NADP%2B):
      Malate is not just a participant to the Krebbs cycle but with the correct enzyme it produces NADPH.
      => So supplementing with Citruline Malate rather then Citruline may produce both NO and NADPH; that increased NADPH can recycle Glutathione to its reduced form. If this happens, One gets simultaneously more NO and Glutathione which is good for exercise recovery according to the first linked study.

      Nice find Wayne and debsw!

      • Wayne

        December 1, 2018 at 8:40 pm - Reply

        I am so glad you found this useful. Thanks for your research and reply. My functional liver tests show that my Glutathionation is low. I thought it must of been because there was so much ammonia/lactic acid in my bloodstream. Supplementing with Citrulline Malate improved my health noticeably in a short space of time. It stimulates the urea cycle, which helps clear the blood of ammonia / lactic acid. My brain fog has gone, my muscle pain has reduced considerably and my capacity to exercise has increased. I have told 2 Australian ME/CFS experts about C.M. They had no idea it could help. They were both very interested though. I would like to see more research in this field, but in my opinion, it is E.B.V. In the bone marrow that is the root cause of at least one sub set of ME/CFS patients. Professor Pender from QLD in Australia is making leaps and bounds in that field, but at this stage the research is more M.S. focassed. Have a great day!

        • dejurgen

          December 1, 2018 at 9:39 pm - Reply

          Glutathionation is low.
          -> Most likely cause here is oxidative stress. If I get the things in the earlier lengthy comment beneath correct then much of the lactic acid does also result from increased oxidative stress.
          -> Ammonia can increase oxidative stress by interfering with heme in the mitochondria, potentially letting them produce more ROS.

          Supplementing with Citrulline Malate improved my health noticeably in a short space of time.
          -> How much would you take, what form and for how long already? Is the effect stable? Did you try the non Malate form? I ask because Malate IMO can be good if it is removed from the Krebbs cycle fast enough while producing NADPH. If it can’t get removed fast enough then it may have the opposite effect by blocking the Krebbs cycle, producing less ATP and more ROS.

          “It stimulates the urea cycle, which helps clear the blood of ammonia / lactic acid.”
          -> I doubt this a lot. When I look at https://en.wikipedia.org/wiki/Urea_cycle I see Citruline is an intermediate. Increasing it should slow down step 2 and with it step 1 in the first table, effectively slowing down ammonia removal. As this puzzled me I looked into it.
          -> Potentially having more Citruline reduces urea production and leaves more ammonia for uric acid, a welcome anti-oxidant that is low in people with ME. But I doubt this is what makes the difference in ME.
          -> https://en.wikipedia.org/wiki/Urea: “Urea has also been studied as a diuretic.”, so helps reducing blood volume. Having less would be a good thing in ME IMO. Would you have urea blood values tested? If so, are they low or high?

        • dejurgen

          December 1, 2018 at 9:52 pm - Reply

          Previous (part 1) comment blocked, now part 2 with fewer links ;-).

          The most likely 2 options for help I see is:
          1) Citruline boosts Arginine; Arginine boosts NO; NO improves vasodilation as you already mentioned.
          2) From wikipedia(Creatine):
          “Creatine is not an essential nutrient[19] as it is naturally produced in the human body from the amino acids glycine and ARGININE, with an additional requirement for methionine to catalyze the transformation of guanidinoacetate to creatine.”
          “Creatine is found in vertebrates where it facilitates recycling of adenosine triphosphate (ATP), the energy currency of the cell, primarily in muscle and brain tissue.”
          => The latter sounds helpful a lot in ME!
          “Recycling is achieved by converting adenosine diphosphate (ADP) back to ATP via donation of phosphate groups. Creatine also acts as a buffer.”
          -> Did you ever try Creatine as a supplement (ask doctor when trying, possible side effects)?
          Note that Glycine is made of Serine and is used in both the construction of Creatine and Glutathione; Rich van K’s protocol includes a phosphor form of Serine.

          • Wayne

            December 1, 2018 at 10:02 pm -

            Hi. Thanks again. I tried Creatine many years ago without any noticeable benefit. I could always try some again. The improvement from the Citrulline Malate was noticeable within 48 hours. In 23 years of ME/CFS it has given me the most noticeable improvement of any supplements thus far.

          • dejurgen

            December 1, 2018 at 10:35 pm -

            Hi Wayne,

            Much may be related to absorption and bio-availability. After all increasing Arginine is believed by many to be the desired effect. Supplementing Citruline is believed to increase it better then to supplement Arginine directly. Maybe it better increases Creatine then supplementing Creatine itself too?
            Maybe you can find it in blood test results: testing for Creatine is pretty standard IMO. If there were a clear difference before and after it would be easy enough to spot.

            I’ll have to check with my doctor. I may already have taken Citruline supplements in order to decrease side effects of a flue vaccination. I tried the same product later once more when I was hit bad. If so, It didn’t help me. It was a liquid in big glass ampules. It wouldn’t be the first thing that works great for one and fails another person with ME.

          • Wayne

            December 1, 2018 at 11:29 pm -

            Hi. Citrulline malate is a fine white powder that mixes with water better than creatine. It is inexpensive.
            I use 2.5grams (1/2 tsp) 3 times a day. It is best taken at least an hour before physical activity. PS. I’ve just now taken 3grams of creatine and I’m off to the beach. Take care.

          • dejurgen

            December 1, 2018 at 11:54 pm -

            Forgot to mention in the blocked part 1:
            The potential reduction in urea production by taking Citruline Malate supplements could lead to less urea being available to Helicobacter pylori, a bacteria often told to make ME worse. Less urea would decrease the bacteria’s ability to survive the strongly acidic environment of the stomach as decomposing urea allows the bacteria to build a more alkali environment around itself.
            https://en.wikipedia.org/wiki/Urea_breath_test:
            “urea breath test… …is based upon the ability of H. pylori to convert urea to ammonia and carbon dioxide.”

            If you often had stomach pain before Citruline supplements and it did reduce after it, it might be worth checking for the bacteria.

            As to the blood tests, Creatinine rather then Creatine is a common test. Loosely said it’s the waste product of Creatine.

            Good luck with the Creatine supplements. Feel free to report any experiences with it ;-).

        • debsw

          December 3, 2018 at 9:37 pm - Reply

          Thank you so much Wayne and Dejurgen for this wonderful information and research. I am going to try Citrulline Malate + GSH (+ B vitamins) as I think it might help. Unfortunately there doesn’t seem to be a branded supplement that combines these two supplements but the research on these two supplements combined them at a ratio of 1(Citrulline Malate) : 10 (GSH). Nitric oxide is produced through a specialized sub-loop of the urea cycle and so boosting the urea cycle probably has more than one benefit, as you noted Wayne, and can also help clear lactic acid and ammonia build up.
          I have never been able to find any specific research on nitric oxide and ME/CFS in the literature but Cort did comment once in a blog that anecdotally it is high in some and low in others. Also, Fluge and Mella found low production in the blood vessels of some patients and have obviously patented a treatment. Dr Pall was the largest proponent of the nitric oxide theory for ME/CFS. Interestingly, nitric oxide is a very important regulatory chemical in many biochemical reactions, and plays an important role in immune control. Low nitric oxide is likely to result in poor immunity, while high nitric oxide can trigger the release of a cascade of inflammatory cytokines. Low nitric oxide is likely to result in high blood pressure while high nitric oxide is likely to result in low blood pressure. High nitric oxide is toxic to the brain and peroxynitrite (a by-product of nitric oxide) can disrupt mitochondria function. What this means in theory is that Citrulline Malate maybe helpful for some and harmful for others.
          In 2016 Loebel found antibodies to beta adrenergic and muscarinic receptors in approximately a third of patients. The meaning of this finding is unclear and issues with these receptors have also been implicated in POTS. If my understanding is correct, the neurotransmitter acetylcholine acts on these receptors to trigger the release of nitric oxide as part of the autonomic control of blood pressure. Note the link between acetylcholine and the brain (the choline connection) and neurotransmitter balance (synergistic links to serotonin, dopamine, etc) and Dejurgen you made the interesting connection to ion channel function. Thanks once again Wayne and Dejurgen for sharing the information.

          • dejurgen

            December 3, 2018 at 11:18 pm -

            Hi debsw,

            “these two supplements combined them at a ratio of 1(Citrulline Malate) : 10 (GSH)”
            -> Wow, that’s very high on GSH! The research I did found https://jissn.biomedcentral.com/articles/10.1186/s12970-015-0086-7 found the following as best of what they tested:
            “L-citrulline (2 g/day) + GSH (200 mg/day)”, about the reverse!
            -> Maybe you mistakenly wrote 1:10 in place of 10:1. If not, please be careful. I believe a strong single shot dose of GSH can have strong undesired effects. Good luck with what you try.

          • debsw

            December 4, 2018 at 6:03 am -

            Oh no, I’m so sorry, that was a typo. The ratio is 10:1. Thanks for the correction and word of warning regarding GSH. Will scrap the GSH and just start out very cautiously with small amounts of Citrulline malate. Many thanks!

          • dejurgen

            December 4, 2018 at 9:28 am -

            I think it’s mainly “normal” to large single shot doses of GSH that are problematic. With the 1:10 ratio the GSH dose would have been huge.
            The problem I see is that in a highly oxidative stress situation much of the newly added GSH probably quickly converts to oxidized GSSG. Glutathione’s anti-oxidant potential depends on a very high ratio of GSH-GSSG and quickly increasing the pool of GSSG would sink that one. In a highly oxidative stress situation it would already be low to begin with.
            If one takes a low dose of slow release GSH the situation differs. Then the increase of GSH per time is more modest, decreasing utilization speed / conversion ratio to GSSG and the body has more time to remove / deconstruct GSSG to keep the ratio OK. I say remove / deconstruct as I assume in ME the Glutathione recycling ratio is already close to maxed out. Recycling speed will not be limited by availability of reduced Glutathione IMO.
            As the study showed better anaerobe tolerance, not aerobe tolerance with a 10:1 ratio in healthy people it might be helpful in ME to start with low doses of Citruline on its own and slowly adding GSH in maybe a 20:1 ratio and see its effect. As it doesn’t seem to increase aerobe capacity and anaerobe always is costly in ME I’d not use the margin to do more but rather to heal better. Success. I won’t try it myself yet. I first need to get my gut problems under control. Doing two things at a time makes observing changes near impossible.

    • Cort Johnson

      December 1, 2018 at 7:44 pm - Reply

      Ha! I had no idea that Fluge and Mella have patented a blend of Citrulline Malate and arginine. Thanks for pointing that out. Good luck with the immunologist and the potential lymphoma.

  • dejurgen

    November 30, 2018 at 12:32 am - Reply

    I can’t get the first full so I’ll detail the exact way I searched for this for repeatability:

    I used https://duckduckgo.com/ with setting region to “United States” and searched for “CD24 oxidative stress”

    https://www.ncbi.nlm.nih.gov/gene/100133941
    “Reduced CD24 expression decreases oxidative stress and genomic instability. CD24 A1626 G is more frequent in OLP patients, contributes to disease risk”

    https://www.researchgate.net/publication/270906876_Forced_extinction_of_CD24_stem-like_breast_cancer_marker_alone_promotes_radiation_resistance_through_the_control_of_oxidative_stress
    “We show that forced extinction of CD24 expression is associated with decreased proliferation rate, lower levels of reactive oxygen species (ROS) and decreased genomic instability.”

    => So if reduced expression and forced extinction of CD24 expression equal lower levels of ROS and decreased genomic instability then increased CD24 may well mean plenty of ROS production by these guys. Not good :-(, but good it’s been detected :-).

    I just stumbled upon another “nice” one: https://www.sciencedirect.com/science/article/pii/S089158490100630X
    “ADP stimulates the respiratory burst”

    => The study is in rat’s but it seems to be a basic mechanism so it may be valid in humans too. When few ATP is generated but ATP demand is high then the amount of ADP will increase. If indeed ADP stimulates the respiratory burst (a massive release of H202) in a wide range of cells then we are in deep trouble. As ADP should be high post exercise it may well be important in initiating PEM; according to something Cort wrote recently H202 only peaks delayed after exertion. That delay sounded weird at the time but combining it with this may make sense.

    If we then compare our immune cells to a farming machine with a tank of pesticide, it seems that increased CD24 makes it leak all the way from the farm to the site of application. If the ADP thing would hold through then it would be like poking extra holes in the tank during exertion. Net result: most of the road is sprayed well and the last 5% of the tank can be used to kill bugs.

    Comparing it to us: our blood vessels are sprayed with plenty of ROS but the immune cells are near depleted when they arrive at the site of infection making them ineffective to fight pathogens. That resembles the natural killer cell thing in ME: overactive but underwhelming in their ability to kill pathogens.

  • dejurgen

    November 30, 2018 at 12:35 am - Reply

    *** redo with “https://www” replaced by “***” to get through the spam filter

    ***.ncbi.nlm.nih.gov/gene/100133941
    “Reduced CD24 expression decreases oxidative stress and genomic instability. CD24 A1626 G is more frequent in OLP patients, contributes to disease risk”

    ***.researchgate.net/publication/270906876_Forced_extinction_of_CD24_stem-like_breast_cancer_marker_alone_promotes_radiation_resistance_through_the_control_of_oxidative_stress
    “We show that forced extinction of CD24 expression is associated with decreased proliferation rate, lower levels of reactive oxygen species (ROS) and decreased genomic instability.”

    => So if reduced expression and forced extinction of CD24 expression equal lower levels of ROS and decreased genomic instability then increased CD24 may well mean plenty of ROS production by these guys. Not good :-(, but good it’s been detected :-).

    I just stumbled upon another “nice” one: ***.sciencedirect.com/science/article/pii/S089158490100630X
    “ADP stimulates the respiratory burst”

    => The study is in rat’s but it seems to be a basic mechanism so it may be valid in humans too. When few ATP is generated but ATP demand is high then the amount of ADP will increase. If indeed ADP stimulates the respiratory burst (a massive release of H202) in a wide range of cells then we are in deep trouble. As ADP should be high post exercise it may well be important in initiating PEM; according to something Cort wrote recently H202 only peaks delayed after exertion. That delay sounded weird at the time but combining it with this may make sense.

    If we then compare our immune cells to a farming machine with a tank of pesticide, it seems that increased CD24 makes it leak all the way from the farm to the site of application. If the ADP thing would hold through then it would be like poking extra holes in the tank during exertion. Net result: most of the road is sprayed well and the last 5% of the tank can be used to kill bugs.

    Comparing it to us: our blood vessels are sprayed with plenty of ROS but the immune cells are near depleted when they arrive at the site of infection making them ineffective to fight pathogens. That resembles the natural killer cell thing in ME: overactive but underwhelming in their ability to kill pathogens.

    • dejurgen

      November 30, 2018 at 1:08 am - Reply

      “Examining… …“strong(ly) positive” association between the amount of glycolysis and lactate produced and the expression of CD24 molecules on ME/CFS patients’ B-cells.”

      => Looking into the paper they seem to only have found a strong association between glucose, lactate and CD24 expression.
      => As in many papers before it has been IMO assumed it was due to glycolysis.
      => BUT the Penthose Phosphate Pathway shares part of the key pathways with Glycolysis AND may (when strongly activated) consume as much or more glucose (and oxygen!) and produce as much or more pyruvate/lactate.
      => According to my calculations Glycolysis generates 6 ATP + 6 pyruvate from 3 molecules of glucose; The PPP generates 4 ATP + 5 pyruvate + 6NADPH from 3 molecules of glucose plus 3 atomes of oxygen; when pyruvate gets toxic high the liver needs to regenerate it at the cost of 4 ATP per two pyruvate to yield back one molecule of glucose
      => This regenerating very high levels of pyruvate costs plenty of energy and oxygen in the liver; degrading some of this pyruvate to lactate temporarily reduces this cost at the increase of lactate buildup in the blood and tissues.

      => Without a more detailed analysis it is IMO impossible to see the difference between massive anaerobe energy production (due to local lack of oxygen) and massive PPP usage (due to very high local ROS levels);
      => This would make more sense in the brain: there are not supposed to be found high lactate levels there but they are there in ME. Brain inflammation and brain oxidative stress are seen in ME. Massive usage of the PPP to regenerate glutathione local in the brain does make more sense IMO and just as well generates lactate in the brain.
      => This would also align with the Dutch doctor having ME who found a strong upshoot in lactate starting later then 20 minutes after going from his bed to the bathroom and back; that makes little sense; the delayed ADP/ROS + PPP idea would fit in quite nicely IMO.
      => This would also fit in well with the humongous air hunger we get after deep overexertion: glutathione/anti-oxidant capacity is deeply depleted; H202/ROS binds to hemoglobin (happens when anti-oxidant capacity tanks) and strongly decrease RBC oxygen capability; the body (desperate to produce bare minimum levels of anti-oxidant) activates the PPP in a massive and long lasting way; an hour long extreme breathing is needed to both clear some of the ROS from the RBC (like bigger brother carbon monoxide clearing gets done by applying plentiful oxygen) and providing the liver with copious amounts of oxygen
      => the need for breathing would resemble the anaerobic response seen by running for your life during 5 minutes, but then lasting that severe and worse for an hour
      => pain in this hypothesis would not be due to lactate but due to the very high amounts of ROS and depleted defenses against ROS; lactate would mainly be a marker of activating this mechanism
      => The idea that we overbreath and that the blood has plenty of oxygen but we just don’t use it may result from measuring oxygen content in the returning vein in the arms or muscles; Did one ever measure the oxygen content of the vein coming from the liver? If not, I’d think that would be totally different!

  • Jason

    November 30, 2018 at 7:49 am - Reply

    Is there any way of down regulating TH2/B cells?

    • Cort Johnson

      December 1, 2018 at 7:41 pm - Reply

      if I have it right it may be that upregulating the system would be helpful – get those immune cells out of the energy funk they may be in. Alan Light has also proposed that poor energy production is leading to immune and possibly even autoimmune problems. I guess time will tell.

  • Grete Linerud

    November 30, 2018 at 9:15 am - Reply

    Thank You! Are there any suggestions considering medicalinterventions regarding this hypothesis?

    • Cort Johnson

      December 1, 2018 at 7:39 pm - Reply

      My guess is that if the energy problems are validated that whatever can fix those; that is whatever can boost energy in ME/CFS will be helpful.

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