Archive for May, 2020

The Blood Vessel Crunch: A Unifying Hypothesis for ME/CFS

This is another hypothesis paper that gives one hope – and makes one wonder if the authors might have a handle on what’s happening with chronic fatigue syndrome (ME/CFS). The paper proposes that a tantalizingly simple problem – an autoimmune attack on just one receptor – out of hundreds of potential receptors –  could be causing virtually all the symptoms of ME/CFS.

B2AdR

Could an autoimmune process attacking the B2 adrenergic receptor be causing the symptoms of ME/CFS?

Receptors dotting the surface of a cell don’t seem impressive, but they’re actually the key to the activity of our cells. Lock onto a receptor and you make the cell change. Most drugs don’t target cells – they target the receptors on cells.

Could just one messed up receptor, though, produce the symptoms of ME/CFS? If it’s an important enough receptor found in enough places – yes, it can, and the receptor in question in this paper –  the beta-2 adrenergic receptor or B2AdR is indeed a heavy duty receptor.

Found in the blood vessels in the brain, the skeletal muscles and the heart, it is a downstream mediator of the sympathetic nervous system (fight or flight system)  which among other things, controls blood flows.

The evidence for B2AdR dysfunction in ME/CFS is building. It’s not overwhelming – it’s not a done deal, but it’s pointing in a very intriguing direction.

One study from a Simmaron collaborator has found elevated levels of B2AdR autoantibodies (antibodies that attack the receptor) in ME/CFS and another is believed on the way. Small mutations in the genes that produce the receptors have been found as well. Plus, similar mutations have been associated with a kind of mild ME/CFS-like state as well. Finally, Scheibenbogen’s work suggests that ß2AdR autoantibodies stimulate the ß2R signaling, but in a subset of ME/CFS patients their functioning has been blunted.

Simmaron Research collaborated with Carmen Scheibenbogen in a pilot study of B2AdR autoantibodies in ME/CFS by contributing patient samples and funding in 2018.

Unifying Hypothesis?

That was enough evidence for Klaus Wirth MD and Carmen Scheibenbogen MD in Germany to believe they had to get the word out and in doing so built a grand, indeed a “Unifying” hypothesis of ME/CFS.

A Unifying Hypothesis of the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Recognitions from the finding of autoantibodies against ß2-adrenergic receptors. Klaus Wirtha, Carmen Scheibenbogen, Autoimmunity Reviews, 2020

Numerous documented problems in ME/CFS including low heart rate variability, chronotropic incompetence (inability of the heart rate to increase appropriately during exercise), something called QTc shortening (shortened ventricular repolarization)

The ß2AdR’s in the blood vessels play an important role in opening or dilating the blood vessels  enough during exercise to accommodate up to 20-fold increases in blood flows muscles will see.  In order to do that the blood vessels release a wide variety of vasodilators such as adenosine, ATP, prostaglandins, (PGEs), prostacylin (PCI), bradykinin (BK) and protons.

scheibenbogen

Carmen Scheibenbogen has been studying autoantibodies in ME/CFS for several years

During exercise the body also needs to send blood to the active areas and shunt it away from non-exercising areas. The arteries clamp down to send the blood forcefully to the small blood vessels in the muscles which in turn must open to receive and use the large quantities of blood they need. This process of clamping down on the blood vessels in one end and opening them up on the other is called “functional sympatholysis”.

The authors believe that the heightened sympathetic nervous system activity clamps down hard on the arteries. Meanwhile the B2AdR dysfunction impairs the ability of the small blood vessels to dilate. This dysbalance between vasoconstrictor and vasodilator forces – with the vasoconstrictors winning – triggers the release of  painful vasodilating substances in an attempt to open the blood vessels. The entire process is, in turn, enhanced by the metabolic/energetic problems in the muscles.

In what appears to be a rough blood vessel equivalent  (i.e. leaky small blood vessel syndrome?) this enormous production of vasodilators leak into the interstitial spaces found between the blood vessels, the lymph and the cells.  This happens because one of them, bradykinin,  also happens to be pretty good at enhancing microvascular (small blood vessel) permeability. So now you have some potent peptides in a place they shouldn’t be – which is always a recipe for problems.

Throw that together with a balky energy production system in the muscles and you have a three way mess. The muscles aren’t, in what appears to be a low oxygen (hypoxic) environment, producing enough energy. The bigger blood vessels, on the other hand, are clamped down tight. The small blood vessels stuck in the middle pump out scads of vasodilators which, when they leak out into the tissues exact a price.

This process occurs in dysmenorrhea (menstrual cramps) when tissues in a hypoxic (low oxygen) and hyper-contracted uterus pour vasodilators into the blood causing fatigue, flu-like symptoms, fever, pain and even the sleep disturbances. (Dysmennorhea or endometriosis has been found increased in ME/CFS.)

The situation is a little different in ME/CFS – the authors believe it’s the blood vessels that are in a hypercontractile state – not the muscles. In fact, with the vasodilators pouring out, the authors don’t believe the muscles in ME/CFS are necessarily in a strongly hypoxic state at all.

If a hypercontractile or hypoxic uterus sounds bad, though, consider what hypoxic, hypercontractile blood vessels in the skeletal muscles across the body might be like – maybe something like ME/CFS.

Weird Cardiovascular Findings

The authors propose that  ß2AdR dysfunction could also be responsible for the weird cardiovascular situation found in ME/CFS. Calling the cardiovascular findings in ME/CFS “unique and not found in any other condition or disease”, the authors listed them: hypovolemia (low blood volume), reduced preload (reduced blood flows to the heart), low cardiac output at rest, small hearts, and the kicker – the low renin-angiotensin-aldosterone system (RAAS) activity.

A big and never answered – and rarely asked – question about ME/CFS is: why is the blood volume low? That brings up another more recently asked but similar question:  why are low venous blood flows to the heart consistently found as well? In other words, where the heck has the missing blood gone?

RAAS - Wikimedia

An underactive RAAS system in ME/CFS is a mystery given the low blood volume present. The authors have an idea why.

It’s a big question. For one thing, low blood volume alone could cause the sympathetic nervous system to go onto hyperdrive and put the vagus nerve (the rest and digest system) to sleep.

The real mystery, though, involves what’s going on with the renin-angiotensin-aldosterone system (RAAS) in ME/CFS. Low blood volumes should automatically activate that system to increase the blood volumes, but paradoxically, instead of being increased, RAAS activity appears to be reduced in this disease.

Because, as noted above, low blood volume sends the sympathetic nervous system into overdrive, the inability of the RAAS to do its job could play a major role in ME/CFS. For some reason the RAAS has hardly ever been looked into in this disease.

Wirth and Scheibenbogen have certainly been looking. They turned, once again, to a vasodilator – bradykinin – for a possible answer. While bradykinin attempts to open the blood vessels, it may also be inhibiting RAAS activity and blood volume enhancement at the same time.

The Spillover Effect

The authors don’t believe that these problems are just happening in the muscles. They believe that just about every symptom in ME/CFS could be caused when vasodilatory substances spill over into the general circulation, around the muscles, the lymph nodes, the gut and the bladder.

Provided that enough of these vasodilatory substances were present, every stress on the cardiovascular system could result in fatigue, pain, flu-like systems etc.

Even mental stress, they believe, could cause pain by triggering the sympathetic nervous system to clamp down further on the blood vessels of the skeletal muscles, causing them to emit vasodilators in an attempt to get more blood, and producing pain, flu-like symptoms, etc. For me, personally, this could explain the muscle pain and flu-like symptoms I often experience simply sitting in a chair while doing mental work.

bradykinin

The authors focused on bradykinin – a vasodilator which can also cause pain and increase vascular permeability

The chief vasodilator  – bradykinin – a seemingly all purpose peptide, could also open the blood-brain barrier, and contribute to the intracranial hypertension, small fiber neuropathy, sleep apnea and sleep problems present. Given the low blood volume and preload failure predicted by the spillover of vasodilatory substances, orthostatic intolerance (trouble standing) would be a natural outcome.

An add-on factor in ME/CFS may be a dysfunction of the endothelial cells lining the blood vessels. Autoantibodies to B2AdR receptors could be keeping the blood vessels in ME/CFS from dilating enough.

The chronicity of it all could play a role as well. Given enough cardiovascular stress the B2AdR receptors will simply disappear.

A local TV report triggered Klaus Wirth's interest in ME/CFS

A local TV report triggered Klaus Wirth’s interest in ME/CFS

Mystery Man

But what about Klaus Wirth? We’ve never heard his name before, yet here he is the co-author of a major hypothesis paper on ME/CFS. Wirth, it turns out, an experimental pharmacologist focused on cardiovascular research in Sanofi-Aventis Deutschland in Frankfurt.

During his investigations into small blood vessel diseases he realized how important activation of the beta adrenergic receptors were for blood flows through both the small and large blood vessels. In 2018 his work suggested that beta adrenergic activation plays a vital role in brain blood flows.

Then in March 2018 he happened to turn on a TV show:

In March 2018 I saw a short report on our local TV on a father whose son was bedridden by ME/CFS. He was interviewed for his activities in politics to enhance funding for ME/CFS research. I had no idea of what ME/CFS was and I made a Google search that evening. Next day I went into pubmed. The second abstract I saw was that of Carmen’s group on autoantibodies against ß2-adrenergic receptors. I immediately felt that there might a problem with cerebral and skeletal muscle perfusion and a fundamental and underlying cardiovascular problem. Although I immediately felt that I might be able to understand the pathophysiology it was very tiring to put the pieces of this puzzle together. It took us 1-1.5 years.

Conclusion

Given the vast reach of the cardiovascular system it’s a natural place to look for a cause of ME/CFS, but nobody has looked at it in ME/CFS patients in quite this way before. Banking on studies showing that autoantibodies to the B2AdR receptors are present in a significant subset of ME/CFS patients, the authors draw a vast model of cardiovascular dysfunction which could produce many, if not all, of the symptoms of ME/CFS.

At its core the hypothesis is simple – there’s an imbalance between vasoconstriction and vasodilation in the blood vessels. It starts with a vasoconstriction crunch produced by an overactivated sympathetic nervous system. Damage to BSAdR receptors leaves the small blood vessels near the muscles struggling to open up enough to get the blood they need. With limited blood flows, and with the energy deprived muscles screaming for more blood, the authors envision pain and fatigue provoking vasodilators pouring out in an attempt to open up those blood vessels.

So many vasodilators pour out that they get into the general circulation and leak into the interstitial spaces – the spaces between the blood vessels, the lymph and the tissues – causing pain, fatigue and other symptoms – as well as low blood volume, preload failure and sympathetic nervous system hyperactivity.

One vasodilator, bradykinin, may be responsible for a host of effects including the inability of the renin-angiotensin-aldosterone system to increase blood volume to the proper levels, intracranial hypertension, small fiber neuropathy, sleep apnea and sleep problems.

It’s a grand, unifying hypothesis, indeed. The authors, in fact, see three mechanisms by which these beta adrenergic receptors could be damaged in ME/CFS:  autoantibodies (autoimmune attack), polymorphisms (e.g. mutations) in the gene that produces the receptor, and desensitization to chronic cardiovascular stress. Plus, problems with the endothelium (smooth muscle cells lining the blood vessels) or another form of vascular dysfunction could also strongly contribute.

Stay tuned. A second hypothesis paper focusing on the energy problems in the muscles is coming.

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.

HHV-6

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.