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MAIT Immune Cell Findings Unite U.S. and U.K. ME/CFS Researchers

The US and the UK are said to have a “special relationship”. That special relationship hasn’t generally extended to ME/CFS research, given a decidedly different focus on ME/CFS in the two countries – a strong focus on biological research in the US and more of a focus on CBT/GET in the UK.  That might be changing, though.

Derya Unutmaz at Jackson Labs and Jacqueline Cliff of the London School of Hygiene and Tropical Medicine | LSHTM appear to have both independently landed on the same immune cell in chronic fatigue syndrome (ME/CFS). Given the multitude of immune cells found in the body, that has the potential to be rather special.

UK ME/CFS Biobank

A large NIH funded UK Biobank enabled these researchers to produce one of the largest ME/CFS immune studies done.

The specialness doesn’t stop there. The samples tested by these two teams – all 300 of them – come from the UK ME/CFS Biobank – which since 2014 has received major funding from the National Institutes of Health (NIH) in the US. (The Biobank has also received funding from The ME Association, Action for ME, and ME Research UK.) Plus, the NIH provided most of the funding for the Cliff project.

The UK ME/CFS Biobank is big. It contains serum, plasma, peripheral blood mononuclear cells (PBMC), red blood cells/granulocyte pellet, whole blood, and RNA samples from over 500 ME/CFS and multiple sclerosis patients and healthy controls. Plus, it includes an extensive dataset of 700 clinical and socio-demographic variables.

The Cliff study focused on the immune system – a natural system to target given the infectious onset many experience and the symptoms common to all patients. An immune “hole” could give a pathogen time to do more damage, set off an autoimmune response, or alter immune functioning in some other way.

Immune studies in ME/CFS are not uncommon, but the Cliff team researchers (sounding very English at least to my ears) described their results as “discrepant” and inconclusive. Interesting research findings have not been reproduced in ME in part, they asserted, because of small study sizes, varied research methods, and sometimes a less than stellar quality of the studies.

This Biobank study is different, they believe. A large study with a well characterized patient group, they clearly believe its results will stand the test of time.

The Study

Front Immunol. 2019 Apr 16;10:796. doi: 10.3389/fimmu.2019.00796. eCollection 2019. Cellular Immune Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Cliff JM1, King EC1, Lee JS1, Sepúlveda N1,2, Wolf AS1, Kingdon C3, Bowman E3, Dockrell HM1, Nacul L3, Lacerda E3, Riley EM1.

The Patients

The Cliff study examined the samples from over 400 patients and controls (251 ME/CFS (54 severely affected and 197 mild/moderate), 46 multiple sclerosis, 107 healthy controls.)

The patients met either the Canadian Consensus Criteria or the 1992 Fukuda Criteria (or both) and were mostly recruited via the UK National Health Service. The patients were determined to meet either criteria after their responses to a Symptoms Assessment form were fed into a computerized algorithm that maps their symptoms onto the different ME/CFS study case definitions.

Since the Fukuda definition does not require post-exertional malaise – the core symptom of ME/CFS –  it was surprising to see the group potentially accept patients who only met that definition. It wasn’t clear from the study what proportion of patients, if any, met only the Fukuda criteria, though. Severely ill patients were mostly home or bed bound. Their blood samples were taken during home visits.

People who had taken antiviral medications or drugs known to alter immune functioning, had a recent history of vaccination, had a history of other chronic diseases such as tuberculosis, cancer, uncontrolled diabetes, etc., had a severe mood disorder, or who had been pregnant or breastfeeding in the past 12 months were excluded.

One part of the study focused on natural killer (NK) cells – key players in the early, innate immune response. Given the NK findings in ME/CFS, the group’s decision to analyze NK cells was not a surprise, but they gave their analysis a twist. Because cytomegalovirus (CMV) infections have such profound effects on our NK cells (and the rest of our immune system), the relationship between CMV infections and NK cells was assessed to determine whether a past CMV infection could be responsible for the NK cell abnormalities seen in ME/CFS.

Results

The Next Big Thing in Immune Research? MAIT cells Pop Out Again

The big news from the Cliff study is the increased frequency of the CD8+ mucosal associated invariant T cells or MAIT cells.  The UK authors noted that an increased frequency of MAIT T-cells has not been published before, which is true, but Derya Unutmaz, leader of the NIH ME/CFS Research Center at the Jackson Labs, has been talking about them in ME/CFS for several years.

MAIT cells

MAIT cells form a bridge between the gut and the immune system. (From Dr. Oh’s NIH Conference presentation)

Unutmaz reported finding high levels of MAIT cells in ME/CFS patients.  Unutmaz’s findings suggest that the MAIT T-cells have been repeatedly activated in ME/CFS and that they evidence the same activated/burned out pattern he’s found in other T-cells.  He and Dr. Oh at Jackson Labs are trying to determine which stomach bacteria has turned them on and then find a way to eliminate or reduce it.

MAIT cells are known for the role they play protecting the lining of the gut against toxic bacteria. Their name – mucosal invariant T-cells – derives from the high levels of these cells gathered around the mucosal surfaces of the gut (e.g. the lining). In effect they are the gut’s innate immune cells – sentinels guarding the gut wall which can, in contrast to other T-cells, react immediately to invaders.

They’re different from other T-cells which get activated after being triggered by an antigen from a pathogen. Instead, they’re activated by fats and vitamin B2 metabolites produced by plants, bacteria (E. coliPseudomonas aeruginosaKlebsiella pneumoniaL. acidophilusS. aureus, and S. epidermidisC. albicansC. glabrata, and S. cerevisiae ) and fungi. Because cytokines produced by viral infections can activate them as well, the high degree of MAIT cell activation is not necessarily due to bacteria in the gut – but it’s the most likely scenario.

MAIT research only started popping up after 2010, when studies revealed these unusual cells were able to detect bacteria and fungi and respond with pro-inflammatory cytokines. Since then many studies have suggested that MAIT cells play an important role in infectious diseases, autoimmune diseases and cancer. MAIT cells are not always pro-inflammatory, but increased levels, particularly of cytotoxic MAIT cells, are believed to be associated with pathogenic states.

In contrast to Unutmaz’s apparent (but unpublished) findings of high levels of MAIT cells in ME/CFS overall, this study found a high proportion of MAIT cells only in the severely ill ME/CFS patients. They noted that a small number of the severely ill patients were reported to have “exceedingly high” frequencies of these cells.

Most of the MAIT cells in the severely affected ME/CFS patients (as well as in the MS patients) were in their cytotoxic (killing) form.  They’d probably been activated by a bacterium in the gut and were apparently on the prowl, ready to pounce. While the increased proportion of MAIT cells only weakly discriminated the severe ME/CFS patients from the healthy controls, the high percentage of killer T-cells (cytotoxic T-cells) found was moderately discriminative.

Interestingly, the Cliff study authors pointed out that peripheral MAIT cell levels in healthy volunteers can increase 2-fold following exercise. Finding similarly high levels of MAIT cells in the severely ill patients suggested they were in a similar post-exercise state without having engaged in any exercise.

Slight Increase in ESR Surprises

Interestingly, symptoms associated with inflammation/infection were more common and more severe in the ME/CFS cohort than in the MS cohort (go figure!). Perhaps that’s not a surprise, since ME/CFS has been shown to impact functioning to a greater degree than MS.

The slight raise in erythrocyte sedimentation rate (ESR) – an inflammatory marker – in mild/moderate cases of ME/CFS compared to the other groups (Including the severe ME/CFS group) was surprising, though, given that very low ESR’s are thought to be typical in this disease.

Laboratory studies. These tests can be used to exclude other diseases associated with fatigue. The most consistent laboratory abnormality in patients with CFS is an extremely low erythrocyte sedimentation rate (ESR), which approaches zero. Typically, patients with CFS have an ESR of 0 to 3 mm/h. A normal ESR or one that is in the upper reference range suggests another diagnosis. https://www.consultant360.com/content/chronic-fatigue-syndrome-update-diagnosis-primary-care

Natural Killer Cells

As the Cliff study introduced a new factor into ME/CFS research (MAIT cells), it took a hatchet to the last big immune finding in ME/CFS – natural killer cells. The study found no significant differences in NK cell proportions, types, KIR receptors or activation markers before or after they stimulated them.

Some NK markers did stand out, but only in patients who had been exposed to CMV. The authors suggested a past CMV infection in some of the ME/CFS patients had likely caused the NK cell abnormalities in ME/CFS – not ME/CFS.

The Cliff study, however, used a different test of NK cell functioning than some groups have used in the past. The British group assessed both T and NK cell functioning by determining how the cells responded to stimulation; i.e., did they produce distinctive markers and/or start producing cytokines. The ME/CFS patients’ cells apparently whizzed through that test – they perked up and started producing cytokines, leaving the authors to report that no functional issues with these cells are present.

NK cell functioning

The Cliff study suggested that the NK cell findings in ME/CFS may be due to patients with past CMV infections. They did, not, however, use a NK cell functional test used by others in the past.

Dr. Klimas, however, uses a more direct functional NK cell assay which measures the number of target cells killed. Plus, instead of the PBMC’s used in the Cliff study, she uses whole blood – possibly a critical factor, given Ron Davis’ and Fluge’s findings that something in the plasma is affecting the cells. In fact the first hint of a blood-borne factor in ME/CFS showed up in NK cell studies.  That idea that something in the blood was impacting functioning first showed up when Dr. Klimas realized that a study which found no evidence of problems with NK cell functioning had not used whole blood in its tests.

The UK study authors noted that small study sizes have hampered immune results in this disease, but size was not an issue for the 2011 Klimas/Fletcher study (176 ME/CFS patients, 230 healthy controls) which found significant declines in NK cell functioning, and those declines were associated with increased fatigue levels. In an Australian study, Brenu also used a target cell killing test to show reductions in T-cell functioning. The UK study authors did not allude to other possible functional tests or the whole blood issue in their manuscript.

Exhausted T-cells?

The UK study authors did find a number of T-cell abnormalities: increased proportions of effector memory CD8+ T cells, decreased proportions of terminally differentiated effector TEMRA cells, and some minor changes elsewhere – whose effects are unclear. The UK authors suggested, though, they could be due to “ongoing antigenic stimulation” due to an unresolved infection or autoimmunity.

Either could presumably produce a state of “immune exhaustion” which some have hypothesized is present in ME/CFS.

Derya Unutmaz focused on key players in autoimmunity and inflammation called TH17 cells in his U.S. study. He wasn’t surprised to find high levels of TH17 cells – which are regulated by the gut –  but he was shocked to find low levels of the IL-17 cytokine they produce. That finding also suggested that the immune cells in ME/CFS might be in a state of exhaustion.

The Cliff study’s IgG antibody tests found no evidence of increased herpes virus reactivation in ME/CFS, and some evidence of it in MS. The group didn’t close the book on the possibility of herpesvirus reactivation in ME/CFS, though, stating that other antibody tests for EBV might produce different results.

Conclusion

The Cliff study was a large UK Biobank study using both Fukuda and/or Canadian Consensus Criteria to identify its patients. The study’s finding of moderately increased ESR levels in the mild/moderate patients was surprising, given past reports of low ESR levels in ME/CFS.

Except in patients who have been exposed to cytomegalovirus (CMV) in the past, the study found no evidence of natural killer cell issues in ME/CFS. The researchers did not, however, use a functional assay used successfully in the past which more directly measures NK or T-cell killing capacity.

The study’s major finding was a significant increase of specialized T-cells called MAIT cells in the severely ill patients. MAIT cells are found across the body but are most known for the role they play protecting the gut lining from toxic bacteria. High levels of MAIT cells have been associated with infectious diseases, autoimmunity and cancer.

This is the second recent and, it should be noted, independent report of high levels of MAIT cells in ME/CFS. In fact, these two reports are the first time MAIT cells have been implicated in this disease.

Dervy Unutmaz and Dr. Oh of the Jackson Labs are currently trying to isolate the bacteria triggering the high levels of MAIT cells they’ve found in ME/CFS.

The Cliff study did find moderate T-cell anomalies which could possibly reflect a state of chronic T-cell activation caused by an infection or autoimmune response. Derya Unutmaz also recently reported he’d found evidence of immune cell exhaustion in his T-cell studies.

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30 Comments

  • Sarah R.

    May 26, 2019 at 6:55 pm - Reply

    With the exception of the XMRV studies, I don’t remember any ME/CFS researcher trying to replicate the findings of any other study. This is very trying. It seems that researchers are all going off in different (sometimes similar) directions, but then they don’t use the same definitions of the disease. And in this one study, am I to understand that they used 2 different definitions of the disease? Why would they do that? Is there any chance that anyone could choose the 3 to 5 most promising smaller study results, and try to replicate them? At some point, might we not expect researchers to try to replicate results from studies using the same definition and the same methods?

  • Cort Johnson

    May 26, 2019 at 7:27 pm - Reply

    My guess – and its only a guess – is that Fukuda was used more for the early samples because it was used so commonly when the Biobank began in 2011. It was impossible to tell how many of the samples did not also meet the CCC criteria. It’s possible that most of them did! It should be noted that many studies used the Fukuda critieria effectively.

    It’s possible that NK cell functioning test that Dr. Klimas uses is not available there. I believe the test was developed by her lab.

    Unfortunately, the table with the ESR results would not open for me – so I couldn’t access the range of results. Coming from an interview with an ME/CFS expert who consistently finds low ESR levels in her ME/CFS patients it was very surprising to see that – particularly since my own ESR has been tested 6 times and has always been at the lowest end of the scale. I’ve wondered about that result for years.

  • Eimear

    May 26, 2019 at 7:53 pm - Reply

    Could an anti inflammatory diet calm down those MAIT cells or am I talking through my hat?!

  • dejurgen

    May 26, 2019 at 8:49 pm - Reply

    “particularly since my own ESR has been tested 6 times and has always been at the lowest end of the scale. I’ve wondered about that result for years.”

    That’s one of the things that “kills” our credibility for having a highly inflammatory disease: not showing one of these prime markers. Mine isn’t consistent very low but I’m during winter season often struck by the common cold and any additional infection seems to raise this value, but never into the trouble zone.

    So I was not aware that it even was often very low in ME. So let me give it a creative try:

    From https://en.wikipedia.org/wiki/Erythrocyte_sedimentation_rate we see that
    “The ESR is governed by the balance between pro-sedimentation factors, mainly fibrinogen, and those factors resisting sedimentation, namely the negative charge of the erythrocytes”
    “When an inflammatory process is present, the high proportion of fibrinogen in the blood causes red blood cells to stick to each other.”

    So I looked into fibrinogen, a large factor increasing ESR.

    From https://en.wikipedia.org/wiki/Fibrinogen I get:
    “During tissue and vascular injury it is converted enzymatically by thrombin to fibrin and subsequently to a fibrin-based blood clot. Fibrinogen functions primarily to occlude blood vessels and thereby stop excessive bleeding.”

    => Now that may tell it all.
    A) Fibrinogen is a pro-inflammatory chemical that helps seal off wounds, forms a cloth, new tissue and later this scab has to be cleared up (by a immune process “eating” it away). But we are in a hibernation state. A pro-inflammatory response creating new tissue and cleaning up old tissue is not a typical Dauer/inhibition state. IIRC I’ve seen plenty of indications that ME patients have really low cell division rates. It is in line with my wound healing being very slow when I am at worst. So our bodies may try and avoid this high cost by producing fewer fibrinogen.
    B) The above raises the question “but me must seal off our wounds, so don’t we have any wounds at all (by for example due to massive oxidative stress)?” I’d say we seem to make active use of some excellent techniques to reduces blood loss by blood vessel wounds:
    B1: reduce blood volume a lot. As I’ve written before it’s hard to bleed a lot from a wound with so few blood. When at worst I just don’t need bandages to stop bleeding even if I cut myself half deep. I just lack the blood. My vulnerability to nose-bleeding also disappears when at worst.
    B2: from https://www.engineersedge.com/calculators/pipe_bust_calc.htm I get that maximum safe pipe pressure is 2*material strength * pipe wall thickness / (pipe outer diameter * safety factor)
    With many ME patients having likely really constricted blood vessels this does two things. It decreases the pipe outer diameter and in this formula a smaller outer diameter means greater pipe strength. Also, when constricting a blood vessel the blood vessel cell not only get a bit compressed but the cells become less wide but higher (when seen along the cross section circle of the blood vessels). So constricting the blood vessel makes the inner opening more narrow but increases the thickness of the pipe. A thicker pipe makes again for a stronger pipe in above equation. Together this means that blood vessel constriction increases blood vessel strength mechanically nearly proportional to 1/(constriction ratio)^2 with constriction ratio the open diameter of our blood vessels compared to “normal” blood vessels. So a moderate constriction increases mechanical strength a lot.
    B3: When one has little holes in the blood vessels, dilating them tears open the wound making the whole bigger increasing blood loss a lot and creating chance to further tear the whole open making things even worse. However, compressing the site of the wholes tends to close small wholes near completely and stopping the whole from increasing. It’s a common used technique to stop leaks. That is often enough to stop blood loss altogether.

    => We may have with our low blood volumes and constricted vessels much less need for fibrinogen to stop blood loss from damaged blood vessels. I see clear advantages of having less need to produce blood clothing chemicals and generally having low levels of them in our blood and so may our body.

    I however believe our finest capillaries do see plenty of blood flow blocking immune activity. Plenty (most?) of us have really poor blood flow near skin and in the extremities. So what may be at work? I believe one possible candidate to be NETosis. NETosis is a specialized immune process that forms DNA nets out of neutrophils that are really good at capturing pathogens like bacteria, yeast, viral DNA and things like uric acid crystals blocking blood flow. And they do so with surprising little permanent damage (compared to other immune mechanisms). But they themselves reduce blood flow a lot in capillaries as they act like nets and lines drawn into the blood vessels trying to catch/filter out pathogens. Hence they are a collector of other debris, much like the grid of the sewer often gets stuck with wood, leaves, wires…

    So I looked up ESR and did find this https://www.sciencedirect.com/science/article/pii/S002217591630117X
    When reading the short description text in the search engine NETosis appeared to increase fibrinogen production, contrary to what I expected. But when reading into it I did found:
    “Upon stimulation with PMA, NETs formation resulted in an increase in the area of DNA per cell. The coagulation factor fibrinogen bound to both the neutrophil cell body as well as NETs, while prothrombin, FX and FVIIa binding was restricted to the neutrophil cell body.”

    So it didn’t state more fibrinogen was produced. It rather states that fibrinogen is (potentially/likely) *consumed* in order to “weave” bigger nets with NETosis.

    => Combining the above ideas from low blood volumes and constricted blood vessels with potentially / likely NETosis consuming fibrinogen we get the following:
    Likely (far) lower production of fibrinogen then average healthy people combined with high utilization rates of NETosis using and hence removing much of the produced fibrinogen out of the blood stream. That should yield low fibrinogen values, a key factor in determining ESR in the lab.

    One can argue that this NETosis should increase sedimentation rates a lot as it seems to create a lot of “debris”. I agree it clogs our capillaries. I strongly believe that most of the nets will be present in the smallest capillaries (and block blood flow a lot there). Far fewer will be present in the larger blood vessels as they have less opportunity to span the blood vessel or stick to it. So they “drift” into the smallest capillaries. So the blood, drawn from a large vein, should have moderate amounts of nets in it. It also should have (very?) few fibrinogen in it. When doing that ESR test that should give below average ESR results.

    So the ESR test may be a good indicator of the need to repair larger leaks in blood vessels. We may have alternative mechanisms to stop blood loss so we may have few need for it. If so, ESR is only a marker for one particular but common form of inflammation.

    Our massive immune reaction may be a different one (which has unfortunately no generally used test yet). That may tell us a lot of what inflammatory/immune response may be at work and where it is at work. For now, I suspect massive NETosis in small capillaries to be a major candidate.

  • Forebearance

    May 26, 2019 at 9:07 pm - Reply

    I wish that Dr. Unutmaz and Dr. Oh would try to isolate which fungi could be triggering the MAIT cells.

    Are they aware that many ME/CFS patients have mold poisoning symptoms?

  • Cort Johnson

    May 26, 2019 at 9:26 pm - Reply

    Because MAIT cells are found in the mucosa or lining of the gut (as well as other mucosal tissues it is certainly possible that dietary factors which impact the gut could play a role in their prevalence in ME/CFS. ie. anti-inflammatory diet might make sense. The problem is that we don’t now which bacteria are triggering their proliferation. Dr. Unutmaz and Dr. Oh are attempting to figure that out now.

  • Cort Johnson

    May 26, 2019 at 9:27 pm - Reply

    I don’t know. I imagine that they may. They are trying to figure out what is triggering their expansion in ME/CFS though. It’s no small task given the complexity of the gut!

  • Cort Johnson

    May 26, 2019 at 9:37 pm - Reply

    Ha! Never heard of Netosis before. Interesting particularly about the wall strength of a narrowed pipe.
    Low ESR is also found in diseases with poor red blood cell deformity and low ESR’s were mentioned in the Ron Davis study of RBC deformability. I think you might understand this much better than me! http://www.bloodjournal.org/content/132/Suppl_1/4874?sso-checked=true. They stated

    “Taken together, this data shows that RBCs from ME/CFS patients have reduced deformability. To corroborate our findings, we also measured the erythrocyte sedimentation rate (ESR) for these donors which show that the RBCs from ME/CFS patients had lower (~40%, p<0.01) sedimentation rates."

  • dejurgen

    May 26, 2019 at 10:48 pm - Reply

    Hi Cort, thanks for the link. From the link you provided:

    “Erythrocytes are potent scavengers of oxidative stress, and their shape changes appreciably in response to oxidative stress and certain inflammatory conditions including obesity and diabetes.”
    Note of mine: RBC are erythrocytes.

    and
    “we also measured the erythrocyte sedimentation rate (ESR) for these donors which show that the RBCs from ME/CFS patients had lower (~40%, p<0.01) sedimentation rates."
    This states that in the ESR test ME RBC do stick significantly less together then those from healthy cells as this test actually measures how badly RBC do cloth together over time. Part of this could be lower amount of fibrinogin ("RBC glue") in the blood of ME patients. That should be easy enough to test for IMO.

    "Using scanning electron microscopy (SEM), we also observed changes in RBC morphology between ME/CFS patients and healthy controls"
    Now any DIY person knows it's far easier to glue two flat-ish surfaces together compared to glue to sphere-like surfaces together. Even when using a lot more glue, the contact area of two spheres next to each other is always small. Making it worse, all glue is located at a certain nearby point. A little bit of movement in one of the spheres will tear the glued surfaces apart from each other.

    So even when using the same amount of glue, spreading it among the surface of the flat-ish objects will have a far stronger bond then using one big dot for two equally heavy sphere-like objects. (RBC) Shape does matter and extensive computer simulations may help revealing how much!

    The link with NETosis (also called https://en.wikipedia.org/wiki/Neutrophil_extracellular_traps) is the following. When NETosis happens the neutrophils expel their DNA and that forms nets. These DNA strings and nets are "hanging" in the blood vessels and produce copious amounts of oxidative stress. It's hard to mix this source of oxidative stress more intimate with blood then this. So the source of oxidative stress is also very close to the passing RBC who sometimes get delayed in their movement by being stuck in these nets. That'll bring the source of oxidative stress wright next to the surface of the RBC, increasing the exposure of RBC to oxidative stress a lot.

    There is also a difference in electrostatic surface potential between healthy and ME cells that makes a difference in ESR. Shape of the cells should make a change in it but I cannot determine if it follows the observed changes. Changes of electric properties of RBC and blood liquid (for example more iron from damaged RBC/heme) may play a role.

    I'll stick to amount of fibrinogen and surface shape of RBC as being clear potential drivers for lower ESR in ME patients.

    Note that NETosis generates a "broad spectrum" imune response to "everything and nothing" making it pop out on nearly no single test as there is no need for a specific antigen. That and its "mechanical" properties is why I suspect NETosis to play a role. Also, it's an ideal process to capture plenty of fragmented garbage and pathogens that may be leaking through the sick gut wall.

  • Andie xx

    May 26, 2019 at 10:50 pm - Reply

    Since contracting campylobacter in 2008, I’ve never really been well. I had it for 4 wks, admitted to hospital on a ward for an IV as my BP was so low. I was discharged with no IV and feeling like sh*t.
    Would thus affect my life as i really am not me. I was as sick as a dying dog and no-one gave me anything.
    Any ideas plz as lots has gone on with my body and ACE levels currently are 57.
    I can’t pick myself up. It’s horrible. I was extremely fitearful and always active. Now I’m crap. Cheers x

  • Andie xx

    May 26, 2019 at 10:52 pm - Reply

    I always feel unwell. Can you help? Cheers x

  • Matthias

    May 27, 2019 at 1:30 am - Reply

    Their key finding only relates to the severely ill patients, so I’m not sure what to take away from this, other than severely ill CFS patients might have a different illness, or a different more serious subset?
    As someone with ‘mild’ CFS, it’s always seemed to me like two different diseases. The symptoms I experience, while challenging at times, are nowhere like the bedbound status of serious sufferers.
    I note that the raise in the ESR in the mild/moderate group was only a ‘slight’ raise, so not sure of clinical significance.

  • Francis Martin

    May 27, 2019 at 9:12 am - Reply

    Hi Cort.

    If you look at Bupresh Prusty’s presentation, at last months NIH Conference, you’ll see that (reversible) increased mitochondrial fragmentation is present in ME (5 people with ME – small study). If you filter out the exosomes then the mitochondrial fragmentation returns to normal. HHV-6A virus (and probably other virus’s/bacteria) use microRNA to increased mitochondrial fragmentation and thereby evade the immune response. However, at this point it appears that the increased mitochondrial fragmentation is not caused by viral microRNA.

    Logically your own cells should not fragment mitochondria in response to a viral infection i.e. since this reduces the immune response. However, we are looking at a bacterial infection here; is there an advantage in increasing mitochondrial fragmentation in response to a bacterial infection? I wonder if it is the exosomes released by MAIT cells which cause increased mitochondrial fragmentation?

    I’m struggling to see any evidence of autoimmunity in ME i.e. after the failure of the rituximab trial.

    Regarding the selection of participants, as Ron Davis highlighted following the publication of the nano-needle paper, a biomedical diagnostic test will allow researchers to select participants who have the same disease. Currently, relying on symptoms means that there could be a number of diseases in this or other studies.

  • Francis Martin

    May 27, 2019 at 9:26 am - Reply

    Regarding fungi/mold. From memory, and not much internet research time/knowledge, MAIT cells respond to bacterial which produce riboflavin metabolites (yes the vitamin – riboflavin) i.e. they do not respond to fungi/mold. I suppose the fungi/mold could be responsible for the increase in bacterial which produce riboflavin metabolites i.e. by changing the conditions in the gut.
    Cort did a good article on a paper by Dr. Unutmaz on how MAIT cells recognise bacterial which produce riboflavin metabolites.

  • Donna

    May 27, 2019 at 10:04 am - Reply

    Could it be HEAVY METALS in the body, effecting the MAIT cells

  • chris bickford

    May 27, 2019 at 4:08 pm - Reply

    Fascinating piece of research. It’s interesting how the gut has become such a player in pathology research over the last decade or so. I agree with Francis that this is probably another case where we are dealing with a number of diseases, and it may or may not apply across the board.

    It’s great that this kind of research is happening, but ultimately we need to get more definitive diagnoses for research subjects and patients in general. We all know that there’s something we all share, which is why we’re here, but we also know that there is a dizzyingly broad spectrum of symptoms and etiologies that we are each dealing with.

    I think it’s time we made a push for more complete and targeted diagnostics. If Ron Davis’s nano-needle can isolate particular markers, it should be made more widely available as soon as it is approved. But we already have the excellent work of independent clinicians like Hyde, Myhill, Klimas, etc, which have advanced the diagnostic possibilities and provided more specific clues about our respective independent pathologies Were their methods of testing — ie, Hyde’s Nightingale/body-mapping criteria, Myhill’s ATP profile test — made more widely available, we could begin to parse out more specific subsets of ME/CFS and treat them in a more targeted manner.

    Symptomatic diagnoses are a good starting point (though it’s time to move beyond Fukuda and, as Cort mentioned, make PEM/SEID a central element of a symptomatic diagnosis), but once a patient obtains a symptomatic diagnosis of ME/CFS, there ought to be a next-level diagnostic protocol, with brain imaging, deeper bloodwork, cancer screening, etc.

    Imagine how much better we could target treatment if we all had a more specific picture of our individual conditions. I know this is essentially a fantasy at this point given the low priority ME/CFS has in the medical establishment and the lack of consensus around its etiology, etc, but a fella can dream, can’t he?

  • Francis Martin

    May 27, 2019 at 8:45 pm - Reply

    Chris Armstrong (now OMF Stanford) published the first paper highlighting a change from untilising glucose, for cellular energy, to proteins and fats [2015]. Chris highlighted that the change in cellular energy production would reduce the amount of stomach acid produced and cause a shift in the microbiome i.e. to a more pathogenic state (more riboflavin producing bacteria). MAIT cells specifically respond to riboflavin producing bacteria. So the increase in MAIT cells may tie in with Chris’s theory. Check out Chris’s (2016?) Webinar on this.
    Another possibility is leaky gut— but why would it become leaky?

  • Cort Johnson

    May 28, 2019 at 1:48 am - Reply

    Good point regarding the findings only in the severely ill patients – whom it is possible are different or atypical in some way. Unutmaz appears to be finding MAIT cells in ME/CFS patients at large. It’ll be interesting to see what Unutmaz is finding in his own large set of US patients when he publishes.

  • Cort Johnson

    May 28, 2019 at 1:52 am - Reply

    Thanks Francis. The exosome findings are really interesting – as was Prusty’s presentation. (A blog on that and Dr. Oh’s search for the MAIT trigger here – https://www.healthrising.org/blog/2019/04/15/nih-chronic-fatigue-lipkin-davis-prusty-oh/).

    From what I’ve heard B-cell mediated autoimmunity is less likely but some autoimmunity is T-cell mediated. I imagine that’s still a possibility.

  • Cort Johnson

    May 28, 2019 at 1:55 am - Reply

    Interesting. I didn’t know that about the stomach acid. Perhaps the shift to more pathogenic, pro-inflammatory bacteria is damaging the stomach lining?

  • dejurgen

    May 28, 2019 at 12:11 pm - Reply

    When reading Francis Martin’s comments on riboflavin (vitamin B2) I was puzzled how it could be bad by triggering MAIT cells and the immune system to go in overdrive. Vitamin B2 is after all supposed to be much needed and good for health. Would this mean I have to stop supplementing vitamin B2?

    When rereading the link Cort provided I found (as Francis also stated less explicitly) that MAIT cells react to a vitamin BE PRECURSOR. So it seems supplementing vitamin B2 itself should not trigger MAIT cells.

    From http://www.uniprot.org/uniprot/Q95460 I did find
    “MAIT lymphocytes are preferentially located in the gut lamina propria and therefore may be involved in monitoring commensal flora or serve as a distress signal.”

    When learning more about en.wikipedia.org/wiki/Lamina_propria I learned that this lamina propria thing is connective tissue that lies BENEATH the epithelium and is full of immune cells and has blood vessels and lymph vessels. So it seems any stuff that is detected by MAIT cells residing mainly in the lamina propria must have past (breached?) the epithelium (first gut layer when traveling from inside the gut towards the rest of the body).

    From http://www.omim.org/entry/600764 and http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492155/ I got “MR1 is ideally suited to bind ligands originating from vitamin metabolites.”
    “metabolites of vitamin B represent a class of antigen that are presented by MR1 for MAIT cell immunosurveillance.”
    “concluded that since many vitamin biosynthetic pathways are unique to bacteria and yeast, MAIT cells use these metabolites to detect microbial infection.”

    Of importance here: you need not only a vitamin B precursor but also a specific protein called MR1. Together they bind to a new molecule and it is that new combined molecule that is recognized by the MAIT cells and triggers the immune system.

    From en.wikipedia.org/wiki/Major_histocompatibility_complex,_class_I-related I get
    “The MR1 protein is able to bind to molecules derived from bacterial riboflavin biosynthesis, and then present it to mucosal associated invariant T cells for activation.”
    “Within cells, MR1 is mostly stored inside the endoplasmic reticulum, where the binding of bacterial riboflavin-related molecules to MR1 occurs, causing it to be sent to the cell surface for presentation.”

    So again this says that MAIT cells won’t recognize the riboflavin precursor directly but only the bonded combination of MR1 and the riboflavin precursor.
    Also important IMO is that this MR1 is produced in (most) human cells and that this MR1 is mostly stored inside the endoplasmic reticulum, meaning that the riboflavin precursor has to travel into the core of our human cells.

    Now comes the last piece of important information. From http://www.ncbi.nlm.nih.gov/pubmed/27393664 I get
    “We briefly describe how the antigens recognized by MAIT cells are generated from an unstable precursor of the riboflavin (Vitamin B2) biosynthesis pathway”
    The word UNSTABLE seems to be vital here. This unstable vitamin B2 precursor is shed by bacteria in the gut. In order to form a MR1-riboflavin_precursor complex that is needed to activate the MAIT cells, this unstable precursor has to travel to the gut content, some mucus on top of the gut lining, the entire epithelial layer of the gut itself and then has to travel through the wall of our cells in order to reach the ER in the core of our cells in order to form this MR1-riboflavin_precursor complex.

    For me it takes few imagination to see that, as this riboflavin precursor is specifically called unstable, that in a healthy gut the time to travel from the bacteria producing it to the core of cell inside the lamina propria is high enough for a high percentage of it to have degraded before reaching this ER core of these cells inside the lamina propria.

    In a heavily damaged gut however, the layer of slimy mucus may be depleted as the gut is to sick to produce much of it. The epithelial layer may be thinned reducing traveling time. The cells in it may be damaged by oxidative stress so that their walls are letting through more chemicals faster. Between adjacent cells their may be some space for chemicals to travel faster from the gut to the inside of the body. Their may be even entire breaches in the gut wall. When I ate two tiny apples (which I apparently am intolerant to) and I have the water in the toilet colored deep blood red as a result I imagine it’s because the gut wall is damaged more then a bit by it. Entire wholes in the gut wall should be highways for both the unstable riboflavin precursor and for the bacteria producing it itself in the first place. That should hugely cut down traveling time from the bacteria producing the unstable chemical until it reaches the ER core of the cells in the lamina propria. If these cell walls are further weakend by heavy oxidative stress or by digestive enzymes leaking through the gut wall or being secreted by nearby bad bacteria then an even better highway from the bad bacteria to the ER of these cells is constructed.

    Depending on how unstable this riboflavin precursor is, having the same type and amount of riboflavin precursor producing bacteria in a healthy gut versus a heavily damaged gut could mean an order of magnitude difference in how much MR1-riboflavin_precursor complex there is swimming in the lamina propria and hence mean a vast difference in how much these MAIT cells are activated.

    => Would this be the first diagnostic marker for “leaky gut syndrome”?
    => Would this finally move leaky gut syndrome from unproven alternative hypothesis to proven, solid and most importantly fairly easy diagnose-able science?

    Final note: many good bacteria may have learned to produce and release less of this riboflavin precursor in a co-living evolutionary way. They have spend more time together with our gut so can be better adapted to avoid triggering our immune system. That can be an additional factor in this immune response but the breached gut seems the dominant here IMO.

  • Francis Martin

    May 28, 2019 at 1:41 pm - Reply

    Regarding stomach acid; I recall Chris Armstrong’s webinar (December 2016?) included this. I think Chris was interested in pursuing it but resources —. As you know Chris in now part of OMF; I’m sure he would discuss this with you.

  • Geraldine c Owens

    May 28, 2019 at 1:44 pm - Reply

    I have been suffering from ME/CFS since the accute onset of a severe bronchial infection on January 3rd 2015. I’ve given up getting any help from my doctors. Are there any specialists that deal with this disorder? I live in Franklin MA 02038
    My daughter is moving me to assisted living. I am familiar with their self assigned mission to get all elders on their feet, socially involved and attending every function under the sun. Currently I am in an independent Retirement Community. Due to my extensive fatique and intolerance to exertion of any kind, the management has agreed to serving my meals in my room. I’m socially isolated, but can sleep whenever I need to. I am, after three+ years, getting lonely and a bit daft. Where can I find medical help? Thank you for any and all help you can give me. And, indeed, answer the question begged by my (and I guess) many others: has your research been put into practice, and if so, is it accessible to ordinary people? Do you have a research project that would benefit me by my participation?

    Thank you.

    Geri Owens

  • dejurgen

    May 28, 2019 at 4:39 pm - Reply

    “Chris Armstrong (now OMF Stanford) published the first paper highlighting a change from untilising glucose, for cellular energy, to proteins and fats.”

    At Healthrising I discussed several times before that the unability to use glucose fast enough during periods of rapid energy consumption should create periods/bursts of strong peaks in protein consumption. In this view in ME during “base” low activity the body should be able to provide a fairly large amount of energy by glucose metabolism. However when we start any short exertion or far worse stronger or longer lasting exertion then glucose metabolism (or better said glucose plus fat metabolism together) can’t follow increased demand and the body turns to rapid consumption/”pillaging” of protein stocks to provide energy. Much of it would be stripping it’s glucose and use it in the (fast anaeorbic) glycolysis pathway and also in the Pentose Phosphate Pathway IMO. But nevermind how protein is consumed during exertion, it should result in very strong spikes in protein usage for energy purposes. Combine that with a poor blood circulation especially around the capillaries and we have massive ammonia waste from protein metabolism that has to be converted per minute. Chances are high this creates spikes in uric acid production together with other protein/ammonia waste products.

    Now when searching this riboflavin_precursor MR1 thing I stumbled upon http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3118197/. It’s quite hard to interpret as it’s difficult and it is titled “Major histocompatibility complex class I-related chain A/B (MICA/B) expression in tumor tissue and serum of pancreatic cancer: Role of uric acid accumulation in gemcitabine-induced MICA/B expression”. The goal here seems to be to activate the immune system in order to kill cancer cells, not to calm the immune system down. It’s not my usual way of thinking. So I would appreciate if someone more knowledgeable could look into it. I feel unsure about the exact importance of what’s in it but I feel it may contain quite some clues for ME.
    “Antibodies that block the interaction of MICA and NKG2D can inhibit NK and T cell-mediated cytolysis”
    “MICA/B expression was correlated with their sensitivity to cytotoxic activity mediated by NK-92 cells, a natural killer cell line that expresses NKG2D receptor”
    “Allopurinol alone did not have any effect on the sensitivity of PANC-1 to NK-92 cell killing. However, allopuinol blocked DNA damaged-induced sensitization of PANC-1 cells to NK-92 cytotoxicity”

    => MICA/B seems to be something like the MR1 thing I described in previous comment. More of it increases strength of immune reaction IMO. It’s difficult to know sure as its not written for the layman.
    => This MICA/B thing has the potential to mess with both NK and T Cell cytotoxicty.
    => Increased uric acid levels have the potential to increase this MICA/B expression a lot. However in this research observed that increased uric acid concentrations alone did not change MICA/B expression. DNA damaged-induced sensitization plus uric acid was needed to get NK-92 cytotoxicity up. Note that the drug Allopurinol reduces uric acid levels.
    => DECREASED NK cell cytotoxicity is often mentioned together with ME. This makes things appear the opposite of higher uric acid levels increasing immune (NK) activity. But remember I talk about (relatively short lasting but intense) BURSTS of increased uric acid production. On average uric acid levels in ME patients are not that high and often even below the values of healthy people. But that could be because all of its daily production is bundled into a short span of time and piling up in the smaller capillaries. As uric acid (an anti-oxidant) would be present in very high concentrations during moments of very high oxidative stress and at locations of the worst oxidative stress it would react fast away. So long after exertion and in the larger blood vessels where it doesn’t pile up concentrations should be reduced. Base production (at full rest) of uric acid should be low too as metabolics research has shown our blood is low on amino acids.

    That leaves the interesting possibility that the combination of “a change from untilising glucose, for cellular energy, to proteins and fats.” and poor blood flow especially in the capillaries and (anaerobe-like) exercise produce a (very) strong burst in local (in the capillaries of the tissue at work) uric acid levels. They create in turn a strong INCREASE in NK toxicity and activity. This would be in line with our immune system reaction in a very strong inflammatory way to exercise. At other times and places (mainly around the big veins one taps blood from) uric acid levels would be below par and hence point to REDUCED NK cytoxicity. What at first would be a huge contradiction (increased versus decreased NK cytotoxicity) would align with recent scientific observations: the immune systems activity spikes strongly after small exercise in ME patients but drops below average (of healthy people) after these spikes.

    It also point to another recently observed thing: exercise does turn our gut haywire (strongly increased immune response in the gut upsetting it). The paper also states that
    “Allopurinol, an inhibitor of xanthine oxidoreductase that converts xanthine to uric acid, blocked uric acid production, MICA/B expression, and sensitivity to NK-92 cell killing”

    Now that is interesting, as I strongly believe I remember that xanthine oxidase is strongly expressed in the gut (but unfortunately I can’t find the link back). And this xanthine converts to uric acid. See chemical reactions in en.wikipedia.org/wiki/Xanthine_oxidase.

    There are also quite a few links to be found how ischemia/reperfusion creates plenty of xanthine mediated oxidative stress. As we have low blood volumes and poor blood flow and we have high (nor-)adrenaline levels (redirecting the already poor blood flow from the gut to more vital organs such as brain and liver), it is reasonable to argue that we often have very poor blood flow and oxygenation of the gut. This should increase “base” xanthine oxidase levels in the gut.

    During exercise blood flow would further be diverted from the gut to the exercising organs, leaving the gut with very poor blood flow. That may increase protein metabolism for energy in the gut capillaries, increasing uric acid and may as well increase (possibly with some delay, is it the ischemia or reperfusion phase?) xanthine oxidase activity. Both combined could create nasty spikes in local uric acid levels in the gut capillaries with very slow removal so high accumulation. If these would turn up the immune system a lot then it would be in line with exercise upsetting our gut a lot. It would see a combined lack of blood and oxygen with a strong increase in xanthine oxidase activity creating very nasty free radicals and creating uric acid spikes amping up the local immune system. It would not necessarily be at the exact same time, leaving possibilities for these sub-processes to be part of distinct (time delayed) steps in the PEM cascade.

    If it would happen, having very poor blood flow and oxygenation combined with high amounts of uric acid in the smallest capillaries (potentially temporary forming crystals due to the too high local uric acid concentration further blocking blood flow and needing immune activation to break these crystals down) plus strong short lasting local NK cell activation due to the high uric acid levels plus high amounts of oxidative (and worse species generated by xanthine oxidase) stress plus a strong ischemia/reperfusion damage afterwards could do massive damage to the gut. The poor average blood flow (and often low percentage of butyric acid producing bacteria with butyric acid reparing the gut wall) would make gut repair very slow. That would leave time for pathogens to further breach the gut wall continuing the vicious circle.

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1358491/ is an interesting link to the relation between xanthine oxidase and ischemia/reperfusion. The full paper is however long. http://www.ncbi.nlm.nih.gov/pubmed/3754347 is another one. Note one does not need to drink alcohol to have this problem, the alcohol cause only gets better funding. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3022077/ is another one.
    http://www.physiology.org/doi/full/10.1152/ajpcell.00112.2001?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed&amp; may be the best and most complete one.

  • dejurgen

    May 28, 2019 at 4:45 pm - Reply

    @Cort: previous comment blocked again 🙂

    Notes on the previous comment:
    * I do NOT see Allopurinol as a drug potentially helping us. It reduces uric acid levels, but only by blocking conversion of even nastier acetylaldehyde to less nasty stuff. There are other paths to break acetaldehyde down but I wish to warn against trying to get a prescription for Allopurinol.
    * It would help point out why both the seemingly opposite ketogenic and vegan diet often improve ME symptoms:
    – The ketogenic diet leaves very few food for the gut bacteria, decreasing their counts and hence decreasing the “magnitude” of a bacterial gut problem. Butyric acid seems to be a very good anti-oxidant as a bonus.
    – The vegan diet seems to be good at reducing uric acid levels a lot. Even with equal amounts of protein, the vegan diet is often considered to be a low purine diet.

  • dejurgen

    May 28, 2019 at 4:55 pm - Reply

    “Chris highlighted that the change in cellular energy production would reduce the amount of stomach acid produced”

    Producing HCl from NaCl consumes quite a lot of energy IMO. Also, the stomach acid has to be neutralized by flushing it with an aquatic NAHCO3 solution in the bowel as the bowel can’t stand an acidic environment. So producing extra stomach acid consumes energy in several ways: once for the production of HCl itself and another time for the increase in water absorption and flushing it again in the gut. Water absorption from the gut itself cost ATP too so this increased use of it to improve digestion is costly in ATP/energy.

    However, poor stomach functioning due to reduced stomach acid is impacting the entire digestive tract including the gut negatively.

    “and cause a shift in the microbiome i.e. to a more pathogenic state (more riboflavin producing bacteria).”
    Could be, but probably he did observe a correlation, not a causation. Could be cause or consequence (or both).

  • Al

    June 5, 2019 at 4:54 pm - Reply

    This finding may also be involved in the MAIT Cell activation:

    FROM: https://emerge.org.au/the-emerge-media-and-research-digest-022-3rd-may-2019/#.XNJVn_ZFxPZ

    W. Ian Lipkin, MD, who found that faecal samples from patients had low levels of bacteria that produce butyrate. Butyrate is important for controlling immune system function.

  • dejurgen

    June 6, 2019 at 12:35 am - Reply

    Butyrate both dampens immune system strength and is a good fuel for the gut itself helping restoring it. So a lack of sufficient butyrate is likely a bad thing.

    Then there is looking the other way around: how do butyrate producing bacteria fare in a gut with a very active immune system? Could it be that they invested more in learning to co-exist with a mild-settings immune system? If so, then they are at a disadvantage compared to strong pathogens when a long lasting period of strong gut immune setting happens. They could survive a short period as gut bacteria are stored in the spleen, but can they survive a long period in sufficient numbers?

    Not having intestine and other parasites means most Western people already start with an immune system in high setting as parasites learned the trick to dampen the immune system to protect themselves. The immune system probably learned to take that into account and pre-corrects by compensating for that in the assumption there are parasites present who dampen it’s action. I’d love to see that question answered.