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A Never-Ending Immune Battle in ME/CFS? The Regulatory T-cell / Herpesvirus Hypothesis

The failed Rituximab trial might seem like the death knell for autoimmunity in chronic fatigue syndrome (ME/CFS) but it’s not – not by a long shot. While the B-cells that Rituximab targeted are at the heart of much autoimmunity, T-cells can also cause autoimmune diseases. They also play a very important role in stopping infections.

Nuno Sepulveda

Once Sepúlveda, a theoretical immunologist, learned about ME/CFS he knew he had to be involved.

This interesting paper, conceived and led by a Portuguese researcher named Nuno Sepúlveda, PhD suggests that both options are on the table in ME/CFS. He proposes that a battle between a subset of T-cells called regulatory T cells (Tregs) and herpesviruses may be causing ME/CFS.

Nuno Sepúlveda’s PhD is in theoretical immunology, and he’s on the faculty of the London School of Hygiene and Tropical Medical.

The study, the third Sepúlveda has co-authored on ME/CFS, is the tale of both a new hypothesis and a new researcher entering the field.

I asked Sepúlveda how he got involved.

My interest in ME/CFS and the conception of this research came a bit by chance as most things in life. I am a statistician by training but I did a PhD project on theoretical immunology in Gulbenkian Institute for Science in the outskirts of Lisbon. In my PhD theory (supervised by Dr Jorge Carneiro, second author of the paper), I developed mathematical theories on how regulatory T cells regulate autoimmunity throughout life; these cells are thought to be master regulators of the adaptive immune system.

In my post-doctoral research, I was a statistical geneticist and a biostatistician doing research in genetics, immunology and epidemiology of tropical and infectious diseases.

Along the way I met Luis Nacul and Eliana Lacerda (we are all from the same faculty/institution) who asked me to help them with the statistical analysis of UK biobank data.

One day I came across a review paper about autoimmunity and ME/CFS, and I got amazed that no one had done a comprehensive assessment of the role of regulatory T cells on ME/CFS.  So I thought to resuscitate my old work on regulatory T cells and give it a go. Then I got hooked up in the field.

We can see how this field widens. Luis Nacul PhD, the senior author of the study, has spent much of his career deeply embedded in ME/CFS. The former leader of the CureME team at the London School of Hygiene and Tropical Medicine, as well as the UK ME/CFS biobank, Nacul is now the Medical and Research Director of the Complex Chronic Diseases Program at BC Women’s Hospital in Vancouver, Canada. He enrolled Sepulveda in taking on ME/CFS.

The Model

“Given this observation, one can hypothesize that these (ME/CFS) patients might be healthy individuals who, by chance, were infected with a microorganism with a strong molecular mimicry to a human protein.” Sepúlveda et. al.

Nuno Sepúlveda 1 2Jorge Carneiro 3Eliana Lacerda 4Luis Nacul 4 Myalgic Encephalomyelitis/Chronic Fatigue Syndrome as a Hyper-Regulated Immune System Driven by an Interplay Between Regulatory T Cells and Chronic Human Herpesvirus Infections. Frontiers in Immunology.   eCollection 

The story begins with the infectious onset that many people with ME/CFS experience. The ferocious immune response that pathogens evoke puts a strain on the immune system’s regulatory processes. The “policeman” of the immune system  – the regulatory T or Treg cells – are tasked with ensuring that the immune system in its frenzy doesn’t run amok and start attacking the human body.
Regulatory T-cell (Treg) (red) cosying up to an antigen (blue)

Regulatory T-cell (Treg) (red) cosying up to an antigen (blue)

It’s an inexact science. As with any complex system, the immune system walks a fine line between too much and too little regulation. Too much suppression by the Tregs will impair the immune system’s ability to fight off invaders, while too little suppression could result in autoimmunity. Each of us is genetically predisposed one way or the other.

People genetically predisposed to more Treg activity would be better at suppressing autoimmunity, but they might also be more prone to letting infections flourish when their Treg cells mistake the pathogenic antigens as self –  and call off the immune response.

Other individuals predisposed to less Treg activity might be more effective at wiping our pathogens, but more prone to developing autoimmunity. (Since infections, evolutionarily speaking, are more destructive, the authors believe this subset might be more prevalent.)

The big question is where do people with ME/CFS fit in?  On the one hand, many of their symptoms mimic those found in autoimmune diseases – suggesting they may be immunologically predisposed to have an overly strong immune response to pathogens but are poor regulators of that response.

On the other, many people come down with ME/CFS in response to an infection – which suggests they weren’t all that good at fighting off pathogens.

The Third Way – the ME/CFS Way?

There is a third way, though – a kind of a worst of both worlds way –  and that’s what this group’s mathematical modeling, the first of its kind done in ME/CFS, uncovered. If the authors are right it could explain why people with ME/CFS are in such a fix.

The Herpesviruses

The authors demonstrated how such a situation could happen by modeling the effect of herpesviruses on the T regulatory cells in ME/CFS in different immunological contexts.


Using HHV-6, the authors proposed that an ME/CFS state could occur when a smoldering infection is responded to by a T-cell clone with a high potential for producing an autoimmune state.

T-cell clones are populations of T-cells which contain both T regulatory cells and T effector (helper) cells.  Because their composition reflects the immune milieu around them, a T-cell clone with a high autoimmune potential reflects a T-cell clone existing in an environment loaded with self-antigens; i.e. antigens from a pathogen which look like they come from humans. In this example, an HHV-6 infection producing many self-like antigens is present.

Because the infection is smoldering and the viral load is low, though, the full T-helper immune response which would serve to stop the infection is not initiated.  Nor do the T regulatory cells fully step in to ward off an autoimmune response.

Instead, the virus, replicating slowly, triggers both responses. As the Treg cells tamp down the chronic immune response, they also shut down the the cytotoxic NK cells. With the immune system not geared up in either direction, the smoldering infection continues in perpetuity causing high energy costs as well as inflammation and fatigue, and there you have it – a metabolically exhausting state of inflammation and fatigue; i.e. ME/CFS.

Epstein-Barr Virus

A similar situation may occur with EBV when a Treg clone with a high autoimmune potential co-occurs with a low T-cell killing rate.  Instead of a blatant autoimmune response that racks the body, or an effective response to the pathogen, you get partial amounts of both: you get both a sucky immune response to a pathogen AND an autoreactive reaction.  If the authors are right it’s no wonder ME/CFS is such a puzzle and so difficult to treat.

How do the authors believe this shows up biologically? In a high density of and increased percentage of Treg cells in ME/CFS patients compared to healthy controls and people with autoimmune diseases. That’s actually what they see in their ME/CFS patients in their lab.

Different Roads Taken

Interestingly, the authors believe both autoimmune diseases and ME/CFS start off the same path – both are triggered by the cumulative effects of an autoreactive response to a common viral infection – but then both flit off on different paths.

Treg cells immune response

The ways Treg cells tamp down the immune response

Herpesviruses may be setting off autoimmune reactions in both autoimmune diseases and ME/CFS, but in ME/CFS the Treg cells kick in to dampen down the autoimmune response.

Unfortunately, as they’re doing that they’re also bollixing up the immune response to the pathogen – leaving ME/CFS patients in the strange state of both defending against a pathogen and trying to dampen down an autoimmune response at the same time – a metabolically exhausting situation.

The authors believe that a genetic predisposition affecting T-cells would probably be present in ME/CFS, and pointed to genetic polymorphisms that have been found.  Defective T-cell responses to Epstein-Barr Virus have also been found in ME/CFS. Further study of the T-cell repertoires in ME/CFS are needed, though, as well as studies to validate whether Treg density and percentages are increased in ME/CFS.

T-cells – perhaps the single most impactful immune cell in the body – have become the focus of interest of a number of other ME/CFS researchers including Derya Unutmaz at the Jackson Labs, and Mark Davis at Stanford.

Smoldering viral infections have also become a hot topic in ME/CFS. Bob Naviaux and Bhupesh Prusty propose a smoldering HHV-6 infection, and Marshall Williams proposes a smoldering Epstein-Barr infection may be present in ME/CFS, as well.

A Further Widening Field

The “widening” of the ME/CFS field is continuing with Sepúlveda. When I asked him what he’s working on next he reported he was bringing new researchers (and new funders) into the field as well. His research into this possible aspect of ME/CFS is continuing full-bore.

Currently I have a PhD student working full time on a project extending some ideas about the role of regulatory T cells on ME/CFS. This project is funded by the Portuguese Foundation for Science and Technology and my student is doing his research in the Molecular Medicine Institute in Lisbon. I am also trying to find/identify candidate molecular mimicries between viruses and human proteins that could explain ME/CFS.

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  • Issie

    May 5, 2020 at 8:11 pm - Reply

    Histamine can also moderate the autoimmune system with regulation of our T suppressor Cells. But there again comes in the need of regulation and how much of it is in the body. We don’t want too much either. But we do need some. May very well be that some of our issues with MCAS is a compensation. And getting the Histamine receptors to work properly, not only helps to regulate mast cell effects, but also moderates the immune system. The H2R turns on Suppressor T cells and histamine is needed to turn on this receptor. There is a fine line as to how much response we want. Histamine is needed to help with the autoimmune function and T cells. But too much, and we have a problem. Ive been enjoying a fascinating study of the Immune system and Inflammation in regard to regulating of histamine response. It can have more functions than just this and can aid in clean up of toxins in the body too. (Note, despite having had very bad MCAS, I no longer take antihistamines. And in the process of resetting my histamine receptors. This is in hope to moderate my immune system and inflammation. So far, so good.) I have always felt the core of our issues come down to Autoimmune dysfunction and inflammation and you can pick the order.

    Really enjoyed this blog Cort. Good job!

  • Carol Perry

    May 5, 2020 at 8:16 pm - Reply

    Really interesting. When I first got sick my diagnosis was autoimmune vasculitus I had a positive ANA and ANCA so no one looked for virus. After 4 years of methotrexate and prednisone , nothing was helping. I had HHV6-A ,then EBV, CMV and coxackie. Now borrelia. This guy may be on to something. The deregulation is coming from somewhere.

    • Cort Johnson

      May 5, 2020 at 8:41 pm - Reply

      Interesting. Have you been able to try Rituximab? I know someone with a long case of ME/CFS with autoantibodies associated with vasculitis who is now on Rituximab and responding.
      The more pathogens the more possibility of an autoimmune reaction occurring I would think – and not just to the virus. If cells around the virus are damaged they can emit antigens the immune system has to deal with as well.

  • Alison Wiltbank

    May 5, 2020 at 8:31 pm - Reply

    This is interesting research, and corresponds with my history of getting a severe herpes simplex infection in my early 30’s. I also have ME/CFS and recently discovered that I have Mast cell syndrome. I read Cort Johnson’s description of mast cell syndrome and and diagnosed myself by treating with loratadine and Benadryl. My brain fog cleared overnight. I also have a history of melanoma.
    I noted with interest a recent PBS documentary of Dr. Jim Allison, who won the Nobel prize for his work on T cell receptors and figuring out a successful treatment for melanoma. Could this all be connected?

    • Cort Johnson

      May 5, 2020 at 8:37 pm - Reply

      Ha! Loratidine and Benadryl – two easily found OTC drugs. Isn’t that something.

      The T-cells are so centrally involved in the immune system. I’m not surprised that there’s so much interest in them.

  • Learner1

    May 5, 2020 at 8:38 pm - Reply

    Great job Cort! This is important work and will be significant for many patients. It’s exactly the scenario that my ME/CFS specialist discussed that was going on with my infections and autoimmunity. It would be lovely to have a follow-up after this and Prustys findings that would be practical strategies that patients can use today. how does this change how we look at our antibody tests? How does it change how we look at our autoimmunity? How does it change whether or not antivirals can be prescribed and aren’t they now worth a try even if classic antibody responses aren’t convincing in the traditional way? Valganciclovir was a game changer for me. I was on it for 20 months and it took away my brain fog and a good deal of fatigue. But I know so many patients who can’t get their hands on it, with tragic results. We need more ammunition to take to our doctors along with strategies that we can try, even if it is to do n = 1 experiments today, before large scale clinical trials are completed. Thanks again for the insightful articles.

  • Leigh Mann

    May 5, 2020 at 8:42 pm - Reply

    Thank you so much! Please keep up the great research. I’m 51 now, housebound since 2009 after a tick bite. Have EBV, hhv6, fibromyalgia (ME?), CFS. Please find a cure so don’t have to continue to live in a suspended state.
    Matawan, New Jersey, USA

  • Lori England

    May 5, 2020 at 8:47 pm - Reply

    Hi Cort. Dr. Derya Unutmaz is from The Jackson Laboratory in Farmington, CT not “Jackson Hole Laboratories.” My uncle is a lifetime trustee of “the Lab” so I’m very familiar with it. Thought you would want to make that correction. Best regards….

    • Cort Johnson

      May 5, 2020 at 9:57 pm - Reply

      Of course. A slip of the pen so to speak. Thanks for pointing that out.

  • Tracey Anne

    May 5, 2020 at 8:48 pm - Reply

    I was just thinking today, that if someone met me out and about, I could seem like a perfectly normal person… unless you tracked my daily activities a little bit more closely. I’m fine and then I’m not fine. I think I’m doing brilliantly but that’s only comparison to how very unwell I’ve been over the last few years.

    I am in a seemingly ongoing power struggle with General Immune, an autocratic, slightly deranged military dictator. Now he’s fairly on the ball and doesn’t miss much – I don’t become unwell with colds etc., very often and if I start to brew something a bit more comprehensive, it usually submits fairly rapidly.

    The General has his sentries out in various regions – if I’m not very, very careful I can trigger a multitude of immune issues – Eczema, Asthma (relatively new!), Interstitial cystitis, Irritable Bowel Syndrome, Irritable Brain Syndrome (really not good), fungal issues, heart rhythm issues and so on.

    I become annoyed because I get tired. Last Saturday, it was a beautiful day – sunny and breezy. I was working in the morning and wanted to complete some more of an online course, I’ve been putting off doing for years! What I did not want to do was have-a-rest. It was was what I needed to do but not what I wanted to do. I am now allergic to my bedroom, apart from at night. So I didn’t actually get much achieved – I just flitted from one thing to another.

    Living with a hyped-up, super diligent immune system is exhausting and it is an invisible battle. Even I don’t give myself credit for all the effort I put in to trying to live a vaguely normal life…

  • Issie

    May 5, 2020 at 8:50 pm - Reply

    I agree. I’m on an herbal treatment as an antiviral, hopefully to get rid of Post Lyme Syndrome. Lyme and some virus can remain in the body and come back out when lest expected. It can change form and go into cells and become a part of our DNA. Body doesn’t attack properly because it recognizes it as self. Or it over attacks and goes too far. But the herbal I’m on is an 18 month attempt to get virus, pathogens etc in order. I’m using Lomatium. (Word of caution, make sure liver is working properly before attempting. Can cause a dreaded rash, on first taking, if your liver doesn’t detox well enough. Will detox through your skin.)

  • Tracey Anne

    May 5, 2020 at 9:15 pm - Reply

    Hi Issie,

    I haven’t tried the Lomatium yet – I tried to get it but will have to order online. I have noted your caution. What I am taking, is an Astragalus, Elderberry and Garlic Complex, recommended to me by a naturopath. I just think I’m under siege and feel I want to support my body in combating viruses that may have got a bit out of control. This article reminds me of the Amy Proal PhD talk on one of the Solve ME/CFS Initiative Webinars (November 14, 2019) in which she discusses ‘her article outlining evidence that ME/CFS is driven by complex pathogen-host interactions…’

  • Pete

    May 5, 2020 at 10:19 pm - Reply

    Mine started 20 years back with a staff infection during ACL surgery. 11 days I’ve antibiotics and quarantine and my leg was saved from amputation. Ever since me/cfs and autoimmune disorders flared immediately. Despite going to icu for mono as a teen, I show constant EBv infection. Past and present. This theory makes sense with my experience

  • dejurgen

    May 5, 2020 at 10:38 pm - Reply

    Currently Issie and I are working on some ideas on ME/FM/MCAS/… and it includes histamine, dopamine and hypoxia. Issie is better at handling the histamine and dopamine part, I delve deeper into the hypoxia thing.

    Issie already mentioned the effect of histamine on Treg cells.

    TK talked about a likely strong to very strong effect of dopamine on his/her health in and searching up(dopamine, T-cell) gives plenty and plenty of research papers on dopamine affecting both Regulatory and efector T-cells. Its effect is mostly consistent in the different researches, but it seems to depend on “circumstances” too.

    The idea of an immune response failing to root out a smoldering infection but a prolonged smoldering infection risking to trigger auto-immune fits with my idea of there being widespread systemic hypoxia near the smaller capillaries in the body in ME/… The immune system consumes plenty of oxygen when at full power and that is not available if partial hypoxia is too widespread. The many different toxic chemicals released by the immune system in their turn impede oxidative phosphorylation more then a bit. It’s a potential tricky situation to resolve. So I looked up (T-cell, hypoxia) and yes, HIF (a strong regulator of plenty and plenty of processes under hypoxia) regulates T-cells and T-cell activation regulates HIF so there is a strong interconnection that can create another vicious circle. There are plenty of papers on the interaction between hypoxia and T-cells. And both hypoxia and T-cells can create plenty of oxydative stress. Oxydative stress can trigger the immune system. Cycling in and out of hypoxia can trigger the immune system to clean up hypoxic damage. Plenty of things can go wrong it seems.

    See for example with title “Hypoxia-inducible Factors Regulate T cell Metabolism and Function” and with title “Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function”.

  • Sheri

    May 6, 2020 at 2:00 am - Reply

    Hi Cort,
    Thank you for your incredible writing and investigative skills. Could you please watch this video and review the CFS info from it?
    Here is the link:

  • Julie

    May 6, 2020 at 3:51 am - Reply

    Tracey Anne — I love your Irritable Brain Syndrome — lol! I am certain I will be using that in a sentence very soon, Thank you!! 🙂

  • Steve

    May 6, 2020 at 1:09 pm - Reply

    Hi Issie, not sure how to respond to you directly, but I note from your comments here you have battled, with some success with MCAS, and seem to have a journey you’re on. Im relating to some of your comments, and would love to know more about how you have tamed you’re Histamine issues. Any way we could chat about that? I have Crohn’s, and a load of food intolerances, but the histamine element has massively ramped up and become a real issue, alongside the usual CFS stuff.

    Another great blog Cort!!!! Thanks

    Cheers, Steve

  • Carolyn

    May 6, 2020 at 1:15 pm - Reply

    @ Alison Wiltbank–Alison, what dosages of Benadryl did you take and for how long? I am ready to try something that has such minimal side effects with a great potential to help. Thank you for sharing!

  • Betty Mekdeci

    May 6, 2020 at 1:35 pm - Reply

    Be very careful in trying to diagnose yourself with mast cell disorder. I may have reported this before, but it warrants repeating if I did.

    Because of Multiple Chemical Sensitivity and many other allergies increasing since I was diagnosed with CFS, I thought that mast cell disorder might be involved. I tried a child sized dose of an antihistamine and an H2 blocker on my own and it seemed helpful so I went to some allergists who would test for mast cell disorder. I had many, many allergies on skin testing, mostly to chemicals and metals like nickel. They gave me several drugs (in small doses) to try at once as kind of a trial by testing. The next day my vision was blurry. I thought I might be having some kind of reaction so I stopped all the medication, but the blurriness did not go away. I was concerned so I went to an optometrist who diagnosed me with very high eye pressure and rushed me to a glaucoma specialist. This doctor diagnosed narrow angle glaucoma (which can be triggered by these drugs in predisposed individuals). He recommended laser surgery which I had and it seemed to work. Two weeks later, we flew to Maui to visit our daughter. After a day in Maui, my left eye turned red and began to droop. I also had the worst headache of my life. I contacted the glaucoma specialist and sent a picture of my eye. He became very concerned and sent me to his former partner who lived on Maui. He was also concerned and put me on some eye pressure control drops. As soon as we returned to Florida, the glaucoma specialist rushed me to a neuroradiologist who diagnosed me with carotid cavernous fistula. This is a very dangerous condition where the artery behind the eye ruptures and connects to the vein. It can result in a fatal stroke or loss of vision in the affected eye. I immediately underwent a 7 hour surgery where they went up the arteries in the groin on both sides and into my brain. The doctor separated the artery and the vein with platinum coils. It took several months for the double vision following the surgery to go away and now I will have glaucoma for the rest of my life. Fortunately, it is being controlled at this time with eye drops. So, given the extreme sensitivity that many CFS patients have to medications and chemicals, be very, very careful.

  • Joy

    May 6, 2020 at 3:22 pm - Reply

    How to suggest to researchers “candidate molecular mimicries between viruses and human proteins that could explain ME/CFS.” Years ago, the inventor of the Cunningham Panel tested my blood and told me I am making antibodies to my own dopamine. So the virus causing my ME mimics dopamine. HSV1 and an unknown virus I got from a lone star tick bite are the most likely culprits in my case.

  • Cort Johnson

    May 6, 2020 at 4:36 pm - Reply

    A slightly deranged military dictator! I added heart palpitations and dizziness to the equation last year when I was pushing too hard. I stopped all caffeine – even my daily 100% chocolate bar (or two). That’s helped but now even a little chocolate brings it back. I’m walking a much finer line now. It is however helping me to rest more which is good

  • Cort Johnson

    May 6, 2020 at 4:39 pm - Reply

    Fascinating Joy.

    Knocking out dopamine would cause huge problems – problems that might very well mimic ME/CFS.

    I think there is a lot of interest in molecular mimicries. The question is whether we have enough researchers working on this to really make a difference. I don’t know. The interest in autoimmunity certainly seems to be rising, though.

  • Cort Johnson

    May 6, 2020 at 4:43 pm - Reply

    Hi Pete – a blog on EBV is coming up. Stay tuned.

  • Issie

    May 6, 2020 at 5:16 pm - Reply

    You can PM (private message) me on Corts blog of Healthrising. I have lots of info there. I have an official DX of MCAS and had an over night Intensive Care stay at a hospital when it attacked my heart, called Kounis Syndrome. My approach has been changed drastically, in the last year, as I am no longer trying to block my histamine receptors but to get them to working properly. I am not using antihistamines.

    Histamine plays a huge part in the autoimmune system and how it functions. We do need it, just not too much of it.

  • Issie

    May 6, 2020 at 6:50 pm - Reply

    @Steve, Here is a link of how I got on my journey of discovery in regard to histamine and it being a “good” thing. And in my research on the possibility of MCAS being a compensatory response. It is so different than anything I had ever heard before and I went in very skeptical. But I have realized that I had harmed myself with all the antihistamines and had stopped very important processes in my body. Its moderating response, that is the key. I don’t have it completely mastered, but am a lot closer.

  • Tony

    May 10, 2020 at 6:25 am - Reply

    This is me! I have been diagnosed with TPO and DNA auto antibodies and panhypogammaglobulinemia (an over and under active immune system with ME/CFS). Now what do I do to get well?

  • Kim

    May 24, 2020 at 6:11 am - Reply

    This was fascinating. It could explain so much. It’s been a while since I delved in to this stuff – could someone tell me what “cytotoxic NK cells” are? (4th paragraph under the HHV-6 subheading.) So is there a skirmish between the Tregs and the Teffectors?

    • Cort Johnson

      May 25, 2020 at 1:16 pm - Reply

      Basically yes.