+100%-

Dr. Light has said that he wants to do for fatigue what researchers have done for pain; that is uncover the molecular pathways that cause fatigue.  Some time ago Light presented one of the most spectacular graphs of ME/CFS ever done. I still remember the gasp that filtered through the IACFS/ME conference when Dr. Light showed the slide below . It showed the levels of molecular receptors associated with fatigue and pain skyrocketing after exercise in white blood cells.

Light- exercise - 20111

The most famous graph in ME/CFS history

The healthy controls are on top and the ME/CFS patients are below. It was even worse than it seemed. In a 2011 Bateman Horne Center video, Dr. Light explained that the differences were so extreme that he had to transform the data into log scale format in order to fit the graph on the page.  The expression of some genes was 10 times greater in the ME/CFS patients as in the healthy controls.

Even 48 hours later – still well within the post-exertional malaise (PEM) period for many with ME/CFS/FM – the gene expression was still incredibly high relative to the controls.

Light has found, by the way, that many people with ME/CFS (70%) fit the criteria for FM.  When Light compared ME/CFS patients with FM vs ME/CFS without FM he found only a few differences. When he looked at FM patients without fatigue, though, they looked exactly like the healthy controls. That indicated that the Lights were really zeroing in on how fatigue is produced.

A key distinction between FM patients without fatigue and ME/CFS and FM patients with fatigue emerged when the Lights looked at the baseline findings. It turned out that ME/CFS patients looked like healthy controls at baseline but the “pure” FM patients without fatigue looked very different.  The expression of three genes were dramatically elevated – so dramatically, in fact, that Light suggested that they might not be able to get any higher during exercise.

The fact that the rest of the genes were unaffected by exercise could explain why studies suggest that exercise seems to work so much better in FM than in ME/CFS. FM patients with ME/CFS characteristics do get knocked out by exercise, but the “pure” FM patients – which make up a considerable portion of the FM population – don’t.

Light did, however, find a startlingly different subgroup hidden within the ME/CFS population. After putting them on the bike this rather large group (40% of the study) looked exactly like the healthy controls with the exception of one gene called the alpha 2A receptor (AD2A).

This ubiquitous receptor causes the blood vessels to constrict in order to keep blood from pooling in our legs when we stand. The expression of that gene plummeted in the ME/CFS subgroup. That suggested that when those ME/CFS patients most needed their blood vessels to constrict in order to pound more blood into their muscles, the gene that did that pooped out. Not surprisingly, 70% of the people with this gene expression signature have orthostatic intolerance.

(Talk about from bench to bedside or vice versa. Dr. Light found this group when Dr. Bateman told him about a young man she could not figure out at all. Looking at the gene expression data, Light found zero increase in his ADR2A gene expression. Light then went back and specifically looked at this gene and found this major group characterized by orthostatic intolerance (OI). Unfortunately most OI drugs do not work on these patients; midodrine works for a short period but has side effects.  What a nice example of a physician and researcher working together to break new ground.)

It’s important to note that the Lights were not looking at the cause of chronic fatigue syndrome (ME/CFS) – they were looking at the effects of the cause. Something, they believed – probably in the immune system – was causing the gene expression of their immune cells to go bonkers during exercise.  It could be a virus, it could be an autoimmune process, it could be toxins, it could be any number of things.

The search for the cause came next….

Gene Variants (polymorphisms, mutations) ME/CFS/FM, Autoimmunity and Energy Production

In his talk at the Bateman Horne Center, Dr. Light somewhat apologetically referred to the incremental progress they were making but if this is what incremental progress looks like, I definitely want more of it.

First Dr. Light thanked an array of donors; Dr. Bateman without whom this work could not have been done, the Dept. of Anesthesiology at the University of Utah (good to see an ME/CFS/FM researcher getting departmental funding), plus The Solve CFS Initiative (SMCI) – a key funder early in the Light’s work  – and the American Fibromyalgia Association, as well as patient donors.

Several recent studies suggesting an autoimmune basis to at least a subset of ME/CFS patients had caught their eye.  Intriguingly, both Fluge and Mella and a German group lead by Loebel found evidence of autoantibodies to some of the same adrenergic receptors that had popped up in the Lights’ studies. Furthermore, declines in the antibody levels Loebel found in patients doing well on Rituximab treatment suggested that those autoantibodies – and Light’s dysregulated adrenergic receptor – could be key in chronic fatigues syndrome (ME/CFS).

Evidence emerging that postural orthostatic intolerance syndrome (POTS)- or at least a significant subset of it – had an autoimmune component further piqued their interest.

Wondering whether an autoimmune process was whacking patients as they exercise, the Lights teamed up with an Oklahoma researcher to explore that question.  A small pilot study with 18 ME/CFS patients with either POTS or another form of orthostatic intolerance ensued.  Almost all (14) also met the criteria for FM.  They looked for evidence that the immune system was attacking those receptors that had been so remarkably elevated during exercise.

The results were remarkable: autoantibodies to at least one of the receptors (beta adrenergic / muscarinic) were found in almost all (15/18) of the ME/CFS/FM patients.

This suggested that autoantibodies were attacking the receptors involved in increasing blood flow and other aspects of exercise.  Immediately they moved on and asked why these autoantibodies were found.

Back to the genes, they went to determine if gene polymorphisms – slight shifts in the makeup of the genes that produced these receptors – could help explain why the autoantibodies were present. Using a technique that allowed them to measure both the mutations present at birth and those acquired afterwards, they looked at the mitochondrial DNA of those white blood cells.

Why mitochondrial DNA? Because somatic mutations – mutations gained later in life – in the mitochondrial DNA of immune cells could lower the energy levels of in those cells. Lower energy levels in white blood cells could translate into a reduced ability to filter out autoimmune antibodies; i.e. immune cells with low energy could be producing more autoantibodies than immune cells with normal energy levels.

DNA - chronic fatigue

This study found acquired mutations in mtDNA which could impact energy production.

It turns out that mitochondrial DNA is more susceptible to mutation than normal cellular DNA because of the environment tit exists in. As cells produce energy they also spew out free radicals which can damage DNA.  Throw in the increased levels of free radicals typically seen in ME/CFS and you might have a recipe for increased mitochondrial DNA mutations produced after birth.

We haven’t seen much evidence of mutations in the mitochondrial DNA yet, but the Light group found at least one mitochondrial mutation not seen in healthy controls in everyone but one of the 40 ME/CFS patients. Plus more than 70% of them had a variant likely to have a high or moderate impact on the production of a key mitochondrial protein; i.e. most had a gene variant likely to cause a serious problem in energy production. The fact that most of the ME/CFS patients had multiple mutations further suggested the mutations were having a real impact.

Significantly, all of the variants were acquired; i.e. none was present at birth – as the result of something in the environment the ME/CFS patients had bumped into.  They were scattered throughout the complexes that make up the mitochondrial energy pathway.

About 80% of the ME/CFS patients also had mutations in autoimmune genes  (beta adrenergic, acetylcholine and PKA genes), but different genes or gene combinations were found in each patient.  All the patients with mitochondrial gene mutations or polymorphisms also had autoimmune gene mutations.

This set up an intriguing scenario; ME/CFS/FM is not caused by a specific gene mutation but by any of a number of broad mutations in mitochondrial genes and in genes associated with the ability to respond to things like exercise (such a blood flow).

It takes the low energy state conferred by the problems with the mitochondrial genes plus a tendency for autoimmune issues to create chronic fatigue syndrome (ME/CFS).

That was exciting, but then Light went further. What he asked, could be causing all these polymorphisms or mutations to crop up?  The big clue was that the ME/CFS patients did not appear to be born with these mutations – at some later point they showed up.  It appeared that something they had bumped into somewhere had tweaked those genes.

The Gist

  • in 2011 the Light’s found that the gene expression of receptors on white blood cells which responded to muscle metabolites skyrocketed during and after exercise
  • Their findings suggested a large and unusual immune response occurred during and after exercise in ME/CFS/FM
  • One subset of ME/CFS/FM patients with orthostatic intolerance had a very different response
  • Six years later in a small study the Light’s found evidence of acquired mitochondrial mutations that could be impacting the energy levels of these immune cells
  • They also found widespread evidence of mutations in some genes associated with autoimmunity
  • They suggest that the low energy state in the immune cells of ME/CFS/FM patients results in the increased production autoantibodies
  • They believe these autoantibodies may be targeting processes vital to producing energy and the ability to exercise
  • A large NIH grant will allow them to greatly expand their study
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Light suggested that a process called molecular mimicry may be occurring. It turns out that the beta adrenergic receptors affected in ME/CFS are similar in structure to proteins found in streptococcus bacteria. Being exposed to streptococcus bacteria could, therefore, have produced an immune response that mistakenly targeted the beta adrenergic receptors instead of streptococcus bacteria.  Being exposed to other pathogens could result in the immune system attacking other aspects of the “fatigue response”.

This process may have been given a boost by the low energy state ME/CFS patients’ immune cells may exist in. If their immune cells are not filtering out autoantibodies they could be at increased risk of autoimmune disorders.

An intriguing scenario seems be emerging:

  • Exposure to a pathogen results in genetic polymorphisms or mutations that whack the mitochondria in their immune cells.
  • Those low energy states that ensue inhibit the immune cells from filtering out autoantibodies.
  • After exposure to a pathogen those autoantibodies attack the beta adrenergic and other receptors involved in blood flow and other processes. The result is extreme fatigue associated with low levels of exercise.

Thankfully the NIH – in this case NINDS – agrees this is exciting stuff.  In 2017 Kathleen Light scored a nice $1,000,000 ROI grant  to greatly expand (n=300!) their search for mutations in the mitochondria of immune cells in people with pure FM, ME/CFS and ME/CFS/FM as well as (thankfully) other diseases (migraine, depression).

The most difficult part of any study is not the technical stuff – it’s finding participants.   This is a big study and the Lights are looking for patients (particularly the more severely ill) and healthy controls.

Calling “the boss” – his wife (smart man!) –  up to the mic to tell the audience when the study was going to happen, Dr. Kathleen Light said the study would begin this month. They’re looking for everybody and would love to get severely ill patients. As far as studies go, it’s an easy gig – one blood draw and an online questionnaire. It involves no exercise. If you can participate please bring along your significant other to serve as a healthy control.

Dr. Light said information on how to participate in the study would be posted on the Bateman-Horne Center website.

If you can convince your doctor to get the blood draw, you don’t have to be in Salt Lake City to be in the study.  Otherwise, the study is only taking place in Salt Lake City, Utah. Regarding outside participants Dr. Kathleen Light stated:

 Thank you so much for helping us get the word out to potential participants about our new study. Because our sample processing is not the usual type performed by most blood drawing labs, we can only test patients from elsewhere if they come here to Salt Lake City (as some have done), or who can find a researcher or lab near them who is willing to practice and then follow our protocol, which we can provide to these other professionals. It also involves shipping them tubes with the buffer solution we use, and they must flash freeze their samples and return the samples to us frozen on dry ice. Because this is pretty complex, we are hoping to get the majority of our 150 patients from Utah and close surrounding areas.

Aside from the blood draw, the only other part of participating is completing questionnaires for any patient who already has a doctor’s confirmed diagnosis of ME/CFS or fibromyalgia, and that is done online at home. We are also testing parents and siblings of these patients to determine whether gene variants that we identify are shared in other first degree relatives. If patients and other family members wish to come together, we can do their blood draws during the same visit.

If you have further questions please contact Dr. Alan Light at Alan.Light@hsc.utah.edu. (Because of problems with customs and having to keep the sample frozen getting samples from outside the U.S. is not feasible. )

The Future

They’re also applying for a new NIH grant to look for more autoantibodies….ME/CFS researchers take note! The Lights have been good at getting NIH grants and the CFS SEP grant review panel is now manned by an ME/CFS expert. Getting a grant is still a very competitive process but the door, so to speak, is more open than in the past.

The Lights and Dr. Akiko at the University of Utah will also soon begin a propanolol/midodrine trial for ME/CFS/FM patients with autoimmune induced receptor problems.  Dr. Akiko has apparently been using this drug combo to good effect in her fibromyalgia patients.

Are the Lights and others building a bridge to a future understanding of ME/CFS? Time will tell.

The Light’s aren’t the only ones on the hunt for energy problems in the immune cells in ME/CFS. It’s fascinating to see the work in this area evolve. As we’ve seen after the Lights found that receptors on the white blood cells of ME/CFS patients were responding in a bizarre way to exercise, they incorporated results from mitochondrial and immune studies and hit paydirt.  Seizing upon recent similar findings, the Solve ME/CFS Initiative (SMCI) is funding several studies aimed at examining energy production in immune cells.

We now have Ron Davis at Stanford, Dr. Naviaux in San Diego, Armstrong and McGregor in Australia, Fluge and Mella in Norway, Maureen Hanson at Cornell and the Simmaron Research Foundation in Nevada looking at energy production via metabolomics and other means.

If the medical gods look kindly on this work it’s possible that future work could establish that a low energy state – perhaps as the result of exposure to a pathogen – exists in the immune cells of ME/CFS patients, which has triggered autoimmune response which then whacks glycolysis, the mitochondria, the blood vessels and other aspects of energy production causing severe fatigue, PEM, etc.

The Lights recent work, of course, has relied on small sample sets so it has to be regarded as preliminary but with the funds to test their findings out we should get a definitive answer at some point.

 

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